Wells’ syndrome (eosinophilic cellulitis)^{23.24.25.26. and 27.} is a disorder of unknown pathogenesis characterized by the tissue reaction pattern known as ‘eosinophilic cellulitis with flame figures’ (see p. 15).

Clinically, there are edematous infiltrated plaques resembling cellulitis, often with blister formation. ²⁸ This is followed by the development of slate-gray morphea-like induration which resolves, usually without trace, over 4–8 weeks.^{24.29. and 30.} Recurrent lesions may develop over a period of months to years. A papulonodular form is uncommon.^{31. and 32.} Milder cases have annular or circinate erythematous plaques. The condition known as ‘eosinophilic annular erythema’ may not be a variant of Wells’ syndrome as once thought. ³³ Subcutaneous nodules are extremely rare. ³⁴ Insect bite-like lesions may occur. ³⁵ There is a predilection for the extremities and trunk; rarely, the face is involved as a major clinical feature. ³⁶ The lesions followed the lines of Blaschko in one case. ³⁷

Wells’ syndrome may occur at any age, although onset in childhood is uncommon.^{30.34.38.39.40.41.42. and 43.} Several cases occurring in the same family have been documented.^{44. and 45.} In one family, the skin lesions were associated with a dysmorphic habitus, learning disability, and elevated plasma IL-5. ⁴⁵

Although most cases of Wells’ syndrome are idiopathic, some are associated with arthropod bites, parvovirus B19 infection, ⁴⁶ parasitic infestation (such as giardiasis and toxocariasis), drug allergy, tetanus vaccine,^{47. and 48.} thiomersal-containing vaccines, ⁴⁹ or an atopic history.^{24.26.50.51.52.53. and 54.} It has followed varicella infection in a child⁴¹ and been associated with HIV infection, ⁵⁵ molluscum contagiosum, ⁵⁶ eosinophilic fasciitis, ⁵⁷ the Churg–Strauss syndrome, ⁵⁸ bronchogenic carcinoma, ⁵⁹ ulcerative colitis, ⁶⁰ and the hypereosinophilic syndrome.^{61.62. and 63.} It has also followed the use of 2-chlorodeoxyadenosine in the treatment of hairy cell leukemia. ⁶⁴

It has been suggested that circulating CD4⁺ CD7⁻ T cells play a pivotal role by producing IL-5.^{57. and 65.} Serum and tissue levels of this cytokine appear to correlate with clinical activity. ¹⁶

Many cases resolve spontaneously, but systemic corticosteroids are often used to treat this condition. Minocycline and doxycycline have also been used in isolated cases. ⁶⁶ Interferon (IFN)-α was used in a case with a clonal population of T cells producing IL-5. ⁵⁷

The hypereosinophilic syndrome (OMIM 607685) is a systemic disorder with involvement of one or more organs and persistent hypereosinophilia (>1.5 × 10⁹/L) in the absence of any identifiable cause.^{82. and 83.} Recent work suggests that a PDGFRA/FIP1L1 fusion gene may be responsible in some cases (see below). It encompasses a spectrum of disorders which includes eosinophilic leukemia and Löffler’s syndrome. Eosinophilic leukemia may initially present as a hypereosinophilic syndrome. ⁸⁴ Cardiac involvement, which may be fatal, is quite common; the lungs, skin, liver, and central nervous system may also be involved.

Cutaneous lesions, which take the form of pruritic erythematous papules and nodules or urticaria and angioedema, are present in one-half of cases. ⁸⁵ Rarely they are the only manifestation of the syndrome.^{86. and 87.} Other mucocutaneous presentations include mucosal ulcerations, ⁸⁸ erythema annulare centrifugum, ⁸⁹ purpuric lesions, eosinophilic cellulitis, ⁶³ skin necrosis,^{90. and 91.} superficial venous thrombophlebitis, ⁹² thromboangiitis obliterans, ⁹³ erythroderma, ⁹⁴ and livedo reticularis. ⁹⁵ Elevated levels of IgE, IL-2, IL-5, IL-10, and soluble IL-2 receptor may be present. ⁹⁶ Dermal endothelial cells express eotaxin, a chemokine that is a potent chemoattractant for eosinophils. ⁹⁷

Cases presenting with episodic or transient angioedema and eosinophilia, but without involvement of other organs, are regarded as a separate entity with a benign clinical course.^{10.82. and 98.} Likewise, the syndrome of hyperimmunoglobulinemia-E with recurrent staphylococcal skin infections, defective neutrophil chemotaxis, and peripheral eosinophilia is a distinct entity.^{99.100.101.102. and 103.} There are two distinct hypereosinophilic syndromes: the better known one, Job’s syndrome (OMIM 147060), is autosomal dominant and caused by a mutation in the STAT3 gene located at 4q21; the other one is an autosomal recessive form (OMIM 243700), in which the mutation has not been characterized. Early-onset eczematous lesions, often misdiagnosed as atopic dermatitis, and characteristic facies are other manifestations of Job’s syndrome.^{101. and 104.} Rituximab, an antibody against CD20, has been used to treat a case. ¹⁰⁵ The case that presented with nodular eosinophilic infiltration of the skin and immunoglobulin isotype imbalance is probably a separate condition. ¹⁰⁶

The precise origin of the hypereosinophilic syndrome is unknown, but it appears to involve a dysregulation of interleukins-3 and -5 (IL-3 and -5) and/or granulocyte–macrophage colony-stimulating factor. ²⁰ Recently, the FIP1L1-PDGFRA (F/P) fusion gene has been identified in some patients with hypereosinophilic syndrome.^{107. and 108.} Such cases have overlap features with chronic eosinophilic leukemia. The two genes that fuse are closely associated at gene map locus 4q12.

Mepolizumab, an antibody to IL-5, appears to be a promising targeted therapy for the hypereosinophilic syndrome. ²⁰ Systemic corticosteroids are the current mainstay of treatment. ¹⁰⁹ Infliximab has also been used. ¹¹⁰

Pachydermatous eosinophilic dermatitis is possibly a variant of the hypereosinophilic syndrome. It is associated with a generalized pruritic papular eruption arising on a pachydermatous base, hypertrophic lesions in the genital area, and peripheral blood eosinophilia. ¹¹⁴ The reported cases were in South African black teenage girls. The etiology is unknown.

Dermal hypersensitivity reaction (DHR) is the most controversial concept in dermatopathology, because of its inconsistent usage, its variable clinicopathological correlations, its enigmatic nature, and the emotive climate that accompanies the use of the term.^{115. and 116.} LeBoit has termed it ‘the last refuge of scoundrels’. ¹¹⁷ Against this background the author of this book now believes that after practicing dermatopathology for 35 years, no other concept/diagnosis appropriately encompasses the pathological findings that occur in some patients in a defined etiological setting. The author is also aware of the disdain held for converts by some persons: ‘the impudence of a bawd is as nothing to that of a convert’ – George Saville, Lord Halifax (1633–1695). The term used by Kossard and colleagues, urticarial dermatitis, comes closest to an appropriate substitute designation for DHR, but by their own admission, urticarial dermatitis applies only to a subset of patients having DHR. ¹¹⁸ Some of the cases reported as papular dermatitis (subacute prurigo, ‘itchy red bump’ disease) are probably further examples of DHR.^{119. and 120.}

The clinical presentation is variable, but lesions are usually intensely pruritic. There may be persistent urticarial plaques, urticated erythema, or a papular eruption involving the trunk and limbs. The latter presentation is usually symmetrical. Involvement of the face and neck is much less common. It may occur at any age. Lesions persist for months or years. Resolution of the lesions, with subsequent recurrence, is sometimes seen.

Dermal hypersensitivity reaction may be idiopathic or follow well-documented events such as drug ingestion, vaccination, an arthropod or snake bite, infection, particularly of viral type, and an internal malignancy, including lymphoma.^{116. and 121.} The author has seen many cases with a generalized eruption that followed local skin contact with the sap of the papaya or the macadamia nut tree. The generalized rash was not an autoeczematization.

Treatment with mycophenolate mofetil, ¹²² or low doses of prednisone combined with either dapsone or hydroxyurea has been used. ¹²³

Eosinophilic pustulosis is an appropriate designation for a spectrum of cases originally reported as eosinophilic pustular folliculitis of infancy (see p. 403). ¹²⁵ Although it was originally regarded as a dermatosis of the scalp, cases with lesions in other sites have been reported. Furthermore, this condition was originally regarded as a follicular process similar to Ofuji’s disease but cases with a predominantly interfollicular infiltrate have since been reported. The papulopustular lesions reported in the genital region appear to belong to this spectrum. ¹²⁶

The etiology is unknown. Scabies infection has not been present.

These conditions should probably have been considered in Chapter 41 with the lymphoid infiltrates. To do so would have created certain logistical problems. For this reason they are again considered in this chapter. Cutaneous plasmacytomas are rare monoclonal proliferations of plasma cells which are usually associated with underlying multiple myeloma, extramedullary (soft tissue) plasmacytomas or, rarely, plasma cell leukemia.138. ^{and 139.} These secondary cutaneous plasmacytomas are usually multiple. They may arise by direct spread from an underlying tumor deposit in bone or soft tissue, or by metastatic spread via lymphatics or blood vessels. ¹⁴⁰ Cutaneous plasmacytomas develop in only a small percentage of cases of multiple myeloma, and of extramedullary plasmacytoma.^{138.140.141.142. and 143.} Only 20 cases were noted in a series of 2357 patients with the diagnosis of multiple myeloma. ¹⁴⁴ They are a bad prognostic sign.^{140. and 145.} Sometimes cutaneous lesions are the presenting sign of multiple myeloma and, rarely, they may antedate the development of the full-blown disease. ¹⁴⁶ It has been suggested that IgA- and IgD-producing plasmacytomas are disproportionately represented in the skin. ¹⁴⁷

Primary cutaneous plasmacytomas, which by definition arise without concomitant bone marrow or soft tissue disease, are exceedingly rare.^{148.149.150.151.152. and 153.} They are included in the current WHO/EORTC classification with the B-cell lymphomas (see pp. 972 and 998). They constitute only 2–4% of all cases of primary extramedullary plasmacytomas. ¹⁵⁴ They usually grow slowly and are solitary; multiple lesions are sometimes present.^{155.156.157.158. and 159.} The prognosis is not as good as previously thought: visceral metastases and death occur in over one-third of cases.^{160. and 161.} Transformation of a cutaneous plasmacytoma into a CD30⁺ diffuse large B-cell lymphoma has been reported, as a consequence of Epstein–Barr virus infection. ¹⁶² Rarely a local triggering stimulus may be involved in the development of a primary cutaneous plasmacytoma. One such case involved recurrent herpes simplex virus (HSV-1) infection of the lip with the development of a plasmacytoma at the site after 15 years of recurrent infection. ¹⁵⁴ The authors hypothesized that recurrent infection resulted in the toll-like receptor activation and, in turn, interleukin-6 release producing plasma cell proliferation, transformation, and survival. ¹⁵⁴ Cases associated with transplantation and chronic immunosuppression have been reported.^{159. and 163.}

Plasmacytomas are dusky red or violaceous dome-shaped nodules which measure 1–5 cm in diameter. They have a predilection for the trunk, but they may also develop on the extremities and the face.

Waldenström’s macroglobulinemia is a lymphoproliferative disorder of the elderly in which IgM-producing lymphoplasmacytoid cells proliferate in the bone marrow and/or lymph nodes and spleen.^{193. and 194.} It is now regarded as a lymphoma of small B lymphocytes, plasma cells, and plasmacytoid cells (see p. 997). Clinical features include weight loss, weakness, anemia, and a bleeding diathesis.

Cutaneous manifestations are usually non-specific and result from hyperviscosity of the blood and the bleeding tendency. They include purpura, discoloration of the fingertips and toes, leg ulcers, ¹⁹⁵ urticaria, bullae, and angioedema.^{196. and 197.} Specific skin lesions are quite rare. They take the form of translucent papules composed of deposits of monoclonal IgM (macroglobulinosis cutis),^{198. and 199.} and of violaceous plaques, nodules, or macular lesions on the face, trunk, or proximal parts of the extremities; the plaques, nodules, and macules are composed of lymphoplasmacytoid cells.^{147.194.198.200. and 201.} The cutaneous lesions usually develop later in the course of the disease, although they may be the presenting feature. ²⁰⁰

‘Systemic plasmacytosis’ has been applied in cases with multiple brownish plaques, asymptomatic generalized lymphadenopathy and polyclonal hypergammaglobulinemia.^{205.206. and 207.} There is one report of a patient with systemic plasmacytosis later developing a nodal T-cell lymphoma. ²⁰⁸ The term ‘cutaneous plasmacytosis’ has been used for the skin lesions when lymphadenopathy is absent.^{206.209.210.211.212. and 213.} This distinction is somewhat artificial as some cases of cutaneous plasmacytosis have subsequently developed systemic disease.^{214. and 215.} The term ‘cutaneous and systemic plasmacytosis’ is now being used for this entity, reflecting the variable systemic involvement that may accompany cutaneous disease. ²¹⁶

Cutaneous plasmacytosis is a rare skin disorder, most common in Japan, characterized by multiple dark-brown papules and plaques, located predominantly on the trunk.^{217. and 218.} There is often a polyclonal hypergammaglobulinemia. Some cases are associated with an underlying malignancy. ²¹⁷ HHV-8 was not detected in one study. ²¹⁹ A case has been reported in a child. ²²⁰

Interleukin-6 (IL-6), a major plasma cell growth factor, has been increased in the serum in some cases. ²²¹

An almost endless variety of terms has been used for comparable lesions involving the penis (plasma cell erythroplasia, balanitis circumscripta plasmacellularis, Zoon’s balanitis), vulva (vulvitis circumscripta plasmacellularis, Zoon’s vulvitis), lips (plasma cell cheilitis), ²²² and other mucosal surfaces (plasma cell orificial mucositis,^{223.224. and 225.} atypical gingivostomatitis, ²²⁶ plasmocytosis circumorificialis²²⁷). The term ‘plasmacytosis mucosae’ has the advantages of relative simplicity, of applying to all mucosal sites, and of indicating that plasma cells are an important component of the inflammatory infiltrate. Oral and genital involvement have been reported in the same patient. ²²⁸

Plasmacytosis mucosae is a rare disorder which most frequently involves the glans penis and/or prepuce of older uncircumcised men (Zoon’s balanitis).^{227.229.230.231.232.233. and 234.} It has also been reported in circumcised males. ²³⁵ Vulval lesions (Zoon’s vulvitis), which usually involve adults, are exceedingly rare, with fewer than 50 cases reported.^{229.236.237.238.239.240. and 241.} It may be the cause of intractable vulvar pruritus. ²⁴² Genital lesions usually take the form of a solitary, asymptomatic, sharply defined red-brown glistening patch measuring 1–3 cm in diameter. Occasionally, several lesions may be present. A tumorous variant has also been described (plasmoacanthoma). ²²³ A plasmoacanthoma in the perianal region has been reported in a patient with intertriginous plasmacytosis. ²⁴³

The lesions are usually resistant to treatment, although circumcision has resulted in the disappearance of some lesions of the glans. ²³² The etiology is unknown, ²³⁶ although herpes simplex antigen has been detected in rare cases, ²⁴⁴ and one case has been associated with autoimmune polyglandular endocrine failure, raising the possibility of autoimmunity in the etiology. ²⁴⁵ It is most probably a chronic, reactive, principally irritant mucositis. ²⁴⁶

Circumcision, as mentioned, is the usual treatment for Zoon’s balanitis, but success with topical steroids and laser have been reported. ²⁴⁷ Tacrolimus (topical) has also been used with a successful outcome.^{248.249. and 250.} Two cases of Zoon’s balanitis have been treated successfully with pimecrolimus 1% cream. ²⁵¹

Castleman’s disease (giant lymph node hyperplasia) is a distinctive lymphoid hyperplasia that occurs predominantly in the mediastinum of young to middle-aged persons. ²⁵⁴ There are two histological variants, a common hyaline vascular type and a less common plasma cell type, which often has systemic manifestations. A mixed variant, the intermediate type, also occurs. In addition, two clinical types have been described: localized disease and multicentric Castleman’s disease. ²⁵⁵

Cutaneous manifestations of multicentric Castleman’s disease are usually non-specific. They include plane xanthomas and vasculitis. ²⁵⁶ Erythroderma has been described. ²⁵⁷ Cutaneous involvement is rare, with only a few cases reported.^{254.258. and 259.} Cutaneous plasmacytosis has also been reported in patients with multicentric Castleman’s disease.^{190. and 260.} An association with POEMS syndrome (see above) has been recorded. ²⁶¹ It may represent a variant of Castleman’s disease.

A variant of the hyaline vascular type with lesions confined to the subcutis and skeletal muscle has been reported. ²⁶² The cases were not associated with POEMS syndrome, human herpesvirus type 8, or monoclonal rearrangements of IgH. ²⁶² The lesions ranged in size from 4 to 6 cm in diameter. They had a yellow-brown to red-brown color. ²⁶²

The pathogenesis is unknown, but elevated levels of interleukin-6, a cytokine necessary for the maturation of B lymphocytes into plasma cells, are often present. Interleukin-6 also stimulates endothelial hyperplasia. ²⁶³ Human herpesvirus type 8 (HHV-8) has been implicated in the etiology of multicentric Castleman’s disease.^{264. and 265.} The cells are usually polyclonal in origin, but rare cases with a monoclonal population of cells have been noted. ²⁵⁵ A sarcoma of presumptive follicular dendritic cell origin has been reported in a case of hyaline–vascular Castleman’s disease of the skin and subcutis; ²⁶⁶ in another case a clonal cytogenic aberration involving the long arm of chromosome 12, with rearrangement of the high-mobility group protein I-C (HMGIC) gene, resulted in a clonal proliferation of follicular dendritic cells. ²⁶⁷ A recent report has suggested that HIV-positive multicentric Castleman’s disease may arise from extrafollicular B cells. ²⁶⁸

Localized Castleman’s disease is generally curable by surgical excision, whereas the multicentric variant often requires systemic therapy and has a poorer prognosis. ²⁵⁵

Two cases of the apparently unique condition of angioplasmocellular hyperplasia have been reported. Lesions are composed of a proliferation of small blood vessels, some with vacuolated cytoplasm, and a mixed inflammatory cell infiltrate with a predominance of polyclonal plasma cells. ²⁶⁹ The lesions presented as solitary nodules on the trunk. The author has also seen a case.

Mastocytosis comprises a spectrum of related diseases in which there is an increase in mast cells in one or more organs. ²⁹⁰ It usually occurs as a sporadic disease that is often transient and limited in children and progressive in adults.^{283.306. and 307.} There may be symptoms, such as pruritus, related to the release of various products from these cells.

Two KIT mutations at the 560 and 816 loci have been demonstrated to result in KIT autoactivation, and they are believed to be responsible for increased mast cells arising originally from the bone marrow.^{308. and 309.} Patients with adult-onset mastocytosis and those with associated hematological diseases, usually express activating mutations of KIT. ³¹⁰ Monoclonality has been reported. ³¹¹

The World Health Organization (WHO) variants of mastocytosis are shown in Table 40.3. This classification focuses on the hematological manifestations of the disease and not the cutaneous ones. ³¹² Accordingly, a more traditional classification will be used, as follows:

Brachioradial pruritus is a rare dermatosis that presents with a chronic intermittent intense pruritus localized to the elbow region in the vicinity of the brachioradialis muscle.^{424.425.426. and 427.} Sometimes the lateral surface of the upper part of the arm, just below the midpoint, is involved.^{428. and 429.} The pruritus, which may be unilateral or bilateral, is often accompanied by a burning sensation. ⁴²⁴ The itch feels ‘deep’. It progressively worsens towards evening. ⁴³⁰ The application of ice packs provides relief. This is a diagnostic feature, not a recommended treatment. ⁴³¹ Several members of the one family have been affected. ⁴³² Their disease was characterized by symptom-free periods. Affected individuals are sometimes referred to a psychiatrist because there is little to see clinically except for mild poikilodermatous mottling suggestive of solar damage. ⁴²⁹

This condition is seen in white people living in tropical and subtropical climates, suggesting that exposure to the sun is of some etiological importance.^{424. and 433.} It has therefore been regarded in the past as a solar dermopathy and part of the spectrum of solar pruritus.434.^{435.436. and 437.} However, in some patients clinical improvement has been achieved by cervical spine manipulation, suggesting that in these patients there may be a component of nerve damage from cervical spine disease.^{438.439. and 440.} It has also been associated with a spinal cord tumor. ⁴⁴¹ The current consensus view is that ultraviolet radiation may act as a trigger in some patients, although underlying neurological cervical injury is also an important etiological factor.^{442.443. and 444.} In one series, the disease could be attributed to a neuropathy in all patients. ⁴⁴⁵ Its etiological similarity to notalgia paresthetica (see p. 298) has been noted. ⁴⁴⁶

Neuropathic scrotal pruritus is another similar condition. It is due to a lumbosacral radiculopathy. ⁴⁴⁷

Brachioradial pruritus is often refractory to treatment with topical or oral corticosteroid, and antihistamines. A controlled trial showed no benefit from capsaicin. ⁴⁴⁸ Several cases have been successfully treated with gabapentin, an anticonvulsant used also in the treatment of neuropathic pain. ⁴⁴⁸

Juvenile xanthogranuloma is a normolipemic histiocytosis composed of cells originally thought to be derived from dermal dendrocytes.^{449.456.477.478. and 479.} However, a subsequent study has suggested that the plasmacytoid monocyte is a more likely precursor. ⁴⁷² Solitary or multiple red-brown papulonodules, 1–10 mm in diameter or larger,^{480.481. and 482.} are found on the head and neck, upper part of the trunk, and proximal parts of the limbs.^{483. and 484.} In one series, a solitary cutaneous lesion accounted for 67% of cases; multiple cutaneous lesions were present in 7% of the patients. ⁴⁸⁵ In the series from Kiel, 81% were solitary. ⁴⁸⁶ The sole of the foot, ⁴⁸⁷ vulva, ⁴⁸⁸ anogenital region, ⁴⁸⁹ finger, ⁴⁹⁰ and proximal nail fold⁴⁹¹ are rare sites. Atypical forms with extensive facial, ⁴⁹² or generalized eruptions^{493.494. and 495.} have been documented. A thickly crusted variant on the scalp has been described. ⁴⁹⁶ Plaque-like and clustered lesions also occur.^{497.498. and 499.} A linear distribution is another pattern.^{500. and 501.} In two-thirds of all cases onset is within the first 6–9 months of life;^{502.503.504. and 505.} approximately 5–35% are present at birth.^{486.506. and 507.} Severe congenital systemic juvenile xanthogranuloma has been reported in monozygotic twins. ⁵⁰⁸ Late onset in adolescence or adult life occurs in approximately 10–30% of cases.^{509.510.511.512.513. and 514.} The term ‘xanthogranuloma’ or ‘adult xanthogranuloma’ is used for these cases. There is a male predominance. ⁴⁸⁵ Spontaneous involution usually occurs after many months or even years; lesions persist in some individuals who develop their first lesions after the age of 20 years.^{515. and 516.}

A small percentage of patients have ocular involvement;^{502. and 517.} visceral, including oral, involvement is exceedingly rare.^{477.493.518.519. and 520.} Rare cases involving a peripheral nerve have been reported. ⁵²¹ One case arose in an organoid nevus (nevus sebaceus), ⁵²² and another in the substance of the breast. ⁵²³ Juvenile xanthogranuloma has been reported in association with neurofibromatosis (sometimes with associated juvenile chronic myelogenous leukemia),^{524.525.526.527.528. and 529.} other hematological malignancies,^{530. and 531.} Niemann–Pick disease (see p. 486), ⁵³² contralateral lymphadenopathy with a histiocytic infiltrate, ⁵³³ adult T-cell leukemia/lymphoma, ⁵³⁴ and urticaria pigmentosa. ⁵³⁵ Juvenile xanthogranuloma has developed in three children as a sequel to Langerhans cell histiocytosis. ⁵³⁶ In another case an eruptive variant developed following treatment of Langerhans cell histiocytosis with chemotherapy. ⁵³⁷ A case resembling juvenile xanthogranuloma developed in a boy at puberty who had homozygous familial hypercholesterolemia, under treatment with low-density lipoprotein apheresis and drug therapy. ⁵³⁸

Although the etiology of juvenile xanthogranuloma is unknown, studies have shown that cholesterol is the principal lipid in the lesions. ⁵³⁹ Furthermore, there are no unusual sterols present. ⁵³⁹ A recent study demonstrated clonality in one case. ⁵⁴⁰ This remains to be confirmed.

Simple tumor excision is the treatment of choice except in the very rare systemic form, in which multimodal chemotherapy is indicated. ⁴⁸⁶

Benign cephalic histiocytosis is a clinically distinct non-lipid ‘non-X’ histiocytic proliferation in children.^{562.563.564. and 565.} Fewer than 50 cases have been reported. ⁵⁶⁶ It is characterized by the development of asymptomatic red-brown maculopapules, 2–5 mm or more in diameter, on the face, whence the condition may evolve to affect the neck, upper part of the trunk, arms, and other parts of the body.567.^{568. and 569.} The palmoplantar regions, mucous membranes, and viscera are spared; ⁵⁶² however, a case with diabetes insipidus has been reported. ⁵⁷⁰ In another case, insulin-dependent diabetes mellitus developed. ⁵⁷¹ Spontaneous regression, complete or partial, occurs during childhood, without scarring.^{562. and 572.} Similar lesions have been reported in an adult with T-cell lymphoma. The exact status of this case is uncertain. ⁵⁷³ There is increasing evidence that benign cephalic histiocytosis is a clinicopathological variant of juvenile xanthogranuloma,^{574. and 575.} or part of a spectrum with it. ⁵⁷⁶

Progressive nodular histiocytosis is a normolipemic non-Langerhans cell histiocytosis in which multiple yellowish-brown papules and nodules develop on the skin and mucous membranes.^{578.579.580. and 581.} The nodules are more common on the trunk, while the papules are widely and randomly distributed on the body. Both types of lesion can occur around the genitalia. ⁵⁸² Similar lesions have been noted in a patient with acute myelomonocytic leukemia, ⁵⁸³ and in another with chronic myeloid leukemia. ⁵⁸⁴ It has also been reported in a patient with a hypothalamic tumor. ⁵⁸⁵ It has been suggested that all these cases are variants of, or closely related to, (juvenile) xanthogranuloma. Another confusing feature is the use of the term ‘progressive nodular histiocytosis’ for cases with morphological features of multicentric reticulohistiocytosis but an absence of the usual systemic symptoms of this disorder (see below). ⁴⁷⁸ Leonine facies have been present in the latter condition.^{478.586. and 587.} In the initial reports of the entity under discussion, the word ‘histiocytoma’ was used instead of ‘histiocytosis’ in the title.

Xanthoma disseminatum is a rare normolipemic histiocytic proliferation of dendrocyte origin. It presents with papules, nodules, and plaques that have a predilection for flexural areas, the proximal parts of the extremities, and the trunk. The face is sometimes involved. ⁵⁸⁸ The lesions are initially reddish-brown in color but become yellow with time. ⁴⁷⁸ Mucosal lesions and transitory diabetes insipidus are present in approximately 40% of affected individuals.^{589.590.591. and 592.} Skeletal involvement has also been recorded. ⁵⁹³ Waldenström’s macroglobulinemia was present in one case. ⁵⁹⁴ The condition runs a chronic but usually benign course. Widespread systemic involvement and death have been reported.^{595. and 596.}

Xanthoma disseminatum appears to be a clinically distinctive disorder in which there is a primary proliferation of histiocytes with subsequent accumulation of lipid.^{597. and 598.} It may represent an evolutionary form of generalized eruptive histiocytoma (see below) and as such be part of the spectrum of dendritic disorders related to (juvenile) xanthogranuloma.

Treatment with CO₂ laser therapy has been successful. ⁵⁹⁹ Azathioprine and corticosteroids were used in a child with xanthoma disseminatum who had hepatic involvement. ⁶⁰⁰ In another patient, a combination of three lipid-lowering agents was used. ⁶⁰¹

Erdheim–Chester disease is a rare, disseminated form of non-Langerhans cell histiocytosis. The age of presentation is typically in the fifth decade of life. ⁶⁰⁶ It is primarily a disease of long bones producing patchy medullary sclerosis on radiographs, with sparing of the epiphyses.^{582. and 607.} Extraskeletal manifestations can occur in almost every organ including the lungs, pericardium, hypothalamus/pituitary, the orbit, and retroperitoneum.

The skin is affected in about 30% of cases. ⁶⁰⁶ Cutaneous lesions include diffuse dermal nodules similar to xanthoma disseminatum, ⁶⁰⁸ xanthelasmas, subcutaneous nodules, intertrigo-like lesions, ⁶⁰⁶ pretibial dermopathy, and pigmented patches on the lips and oral mucosa. Verruca plana-like papules, infiltrated by foamy cells, may also be present. ⁶⁰⁷

The sea-blue histiocyte syndrome (OMIM 269600) is a rare, inherited systemic histiocytosis characterized by histiocytes with deep azure blue granules in the cytoplasm on Giemsa, toluidine blue, and May–Gruenwald staining.457. ^{and 582.} Secondary forms, associated with storage diseases such as Niemann–Pick disease (type B), and other diseases have now been reported. ⁴⁵⁷ Commonly involved organs are bone marrow, liver, and spleen. Cutaneous lesions are rare and found in only a few patients. ⁵⁸² They consist of nodular lesions, and brown pigmented macules, both on the face. When disseminated lesions are present, it may lead to death.

A partial deficiency of sphingomyelinase is a possible cause. ⁵⁸² Two reports have linked the disease to the APOE gene at 19q13.2, which is involved in lipid metabolism (see OMIM log).

Generalized eruptive histiocytoma is a rare histiocytosis, characterized clinically by the development of recurrent crops of hundreds of small reddish papules which are distributed symmetrically on the trunk and on the extensor surfaces of the extremities.^{609.610.611.612.613. and 614.} Approximately 30 cases have been reported. It has been documented in children as well as in adults.^{609.610.615. and 616.} Lesions usually subside spontaneously, leaving macular hyperpigmentation or no residual features. It has been suggested that regression involves apoptosis of the infiltrating histiocytes. ⁶¹⁷ In one case resolution followed exanthem subitum (roseola infantum). ⁶¹⁸ Two cases have been associated with acute leukemia. ⁶¹⁹ Evolution into xanthoma disseminatum has been reported, further evidence of the close interrelationship of the various non-Langerhans cell histiocytoses, which appear to form part of a continuous spectrum.^{620. and 621.}

Although often thought to be a self-limiting disease, recurring crops of lesions continued for 12 years in one patient. This necessitated treatment, which was successful using a combination of corticosteroids, hydroxychloroquine and thalidomide. ⁶²²

Progressive mucinous histiocytosis (OMIM 142630), a very rare, non-Langerhans cell histiocytosis of childhood, was first described by Bork and Hoede in 1988.^{627. and 628.} Sporadic cases in adults have since been reported. ⁶²⁹ Fewer than 20 patients have been described. It is characterized by a progressive eruption of skin-colored to red-brown papules with a predilection for the face and extremities. It appears to have an autosomal dominant mode of inheritance. ⁶³⁰ The gene responsible has not been elucidated.

Multicentric reticulohistiocytosis is an uncommon normolipemic histiocytosis that is characterized by the presence of an extensive papulonodular cutaneous eruption and a severe, sometimes destructive, arthropathy, the onset of which may precede, follow, or accompany the eruption of skin lesions.^{634.635.636.637. and 638.} The interphalangeal joints of the hands are usually affected. Uncommonly, articular damage is minimal. ⁶³⁹ Oral, nasal, and pharyngeal mucosae are often involved. There are isolated reports of infiltrates in lymph nodes, lungs,^{640. and 641.} bone marrow, the skull, ⁶⁴² endocardium, stomach, salivary gland, ⁶⁴³ and perirenal fat. Xanthelasmas of the eyelids are also common. ⁶³⁵ Over 200 cases of this condition have now been described. A retrospective study of 96 of these patients was reported in 2001. ⁶⁴⁴

The cutaneous lesions, which preferentially involve the face and distal parts of the upper extremities, are multiple brown-yellow papules and nodules measuring 0.3–2 cm in diameter. Rare presentations have included the presence of lesions resembling neurofibromatosis⁶⁴⁵ or dermatomyositis, ⁶⁴⁶ and the localization of lesions to the sites of healed herpes zoster. ⁶⁴⁷ Onset of the disease is usually in middle life, and there is a predilection for females. Childhood onset is rare.^{648. and 649.} The clinical course is variable, with eventual spontaneous regression of the skin lesions after 5–10 years or more. ⁶⁵⁰ There may be residual joint impairment as a consequence of macrophages in synovial fluid differentiating into osteoclasts and causing bone resorption. ⁶⁵¹ Malignancies of various types may develop in up to 30% of cases.^{636.652.653.654. and 655.} Myelofibrosis has also been associated with this condition. ⁶⁵⁶ Systemic vasculitis is rarely associated with multicentric reticulohistiocytosis.

Because of the rarity of the disease, no consistent approach to treatment has emerged. ⁶⁵⁷ A combination of an oral alkylating agent with prednisone has been used with variable success. ⁶⁵⁷ Because immunohistochemical staining of the infiltrate in this condition has demonstrated the presence of histiocytes of a monocyte–macrophage lineage, and an abundance of cytokines, including tumor necrosis factor-α (TNF-α), a trial of etanercept (an anti-TNF agent) has been used with prednisone. ⁶⁵⁸ Skin lesions and synovitis completely resolved with this regimen. ⁶⁵⁸ There is a single case report of success with alendronate. ⁴⁵⁷

A related entity is diffuse (multiple) cutaneous reticulohistiocytosis, in which multiple cutaneous lesions, identical histologically to those seen in multicentric reticulohistiocytosis, develop in the absence of arthritis or systemic lesions.^{659.660. and 661.} The terms ‘reticulohistiocytoma’ and ‘reticulohistiocytic granuloma’ have been used for solitary cutaneous lesions of similar histology (see below).

Reticulohistiocytomas (reticulohistiocytic granulomas) are nodular lesions 0.5–2 cm in diameter, with similar histology to the lesions of multicentric reticulohistiocytosis but without associated arthritis or systemic lesions.^{637. and 671.} They are usually solitary, but several may be present.^{671.672. and 673.} There is a predilection for the head and neck, but they may occur anywhere on the skin. Paraproteinemia accompanied several cutaneous nodules in one reported case. ⁶⁷² In a report of 44 cases from the Armed Forces Institute of Pathology (AFIP), the term ‘solitary epithelioid histiocytoma’ was suggested as the preferable designation for this tumor. ⁶⁷⁴

Familial histiocytic dermatoarthritis (OMIM 142730) is an exceedingly rare disorder that presents in childhood or adolescence as a papulonodular eruption on the face and limbs associated with a symmetrical destructive arthritis and ocular lesions. A closely related entity is the autosomal recessive dermo-chondro-corneal dystrophy (OMIM 221800) reported in the French literature. ⁶⁷⁸ The gene responsible has not yet been identified.

Necrobiotic xanthogranuloma, a rare chronic disorder, was first delineated by Kossard and Winkelmann in 1980.^{679. and 680.} It is characterized by the presence of multiple sharply demarcated nodules and large indurated plaques. ⁶⁸¹ Sometimes only papulonodules are present. ⁶⁸² A solitary variant has been described.^{683. and 684.} Lesions are violaceous to red, with a partly xanthomatous hue. Central atrophy, ulceration, and telangiectasia may develop. There is a predilection for the periorbital area, but other areas of the face, as well as the trunk and limbs, are often involved.^{685. and 686.} It has also been reported in a burn scar. ⁶⁸⁷

Paraproteinemia has been present in nearly all the reported cases.^{688.689.690.691.692. and 693.} Two monoclonal paraproteins were present in one case. ⁶⁹⁴ Other less frequent findings include leukopenia, bone marrow plasmacytosis, non-Hodgkin’s lymphoma, ⁶⁹⁵ hypocomplementemia, ⁶⁹⁶ and, occasionally, hyperlipidemia. Normolipemic plane xanthoma has been reported in association with necrobiotic xanthogranuloma, suggesting that the two conditions are part of a spectrum.^{692. and 697.} It has also developed within linear morphea. ⁶⁹⁸ Ophthalmic complications are common and include scleritis, episcleritis, and keratitis. Cardiac and laryngeal involvement has been recorded.^{699. and 700.} Skeletal muscle has been involved without overlying dermal disease. ⁷⁰¹ The clinical course is chronic and often progressive. ⁷⁰²

Necrobiotic xanthogranuloma has been regarded as a paraneoplastic phenomenon, but recent findings raise the possibility that it is an infectious disease in immunocompromised patients, in particular, in those with multiple myeloma. ⁷⁰³ This theory results from the finding of Borrelia organisms in six of seven cases using focus-floating microscopy, a technique in which sections are simultaneously scanned both horizontally and vertically. ⁷⁰³ As the authors point out it is possible that new strains of Borrelia or related spirochetes, not yet properly characterized could be involved in the etiology. ⁷⁰³

Treatment of necrobiotic xanthogranuloma is difficult owing to the chronic and progressive nature of the disease. Therapy is usually directed at the underlying hematological disorder. Melphalan, chlorambucil, methotrexate, cyclophosphamide, plasmapheresis, interferon alfa-2b, prednisone, and local corticosteroid injections have all been used. ⁶⁹³ Thalidomide has also been used to treat this disease. ⁷⁰⁴

Orbital xanthogranuloma is a rare cutaneous disease, first reported in 1991, and characterized by bilateral, rather symmetrical infiltrates around the eyes of adult patients.^{710.711. and 712.} As such, it has some clinical resemblance to necrobiotic xanthogranuloma (see above). ⁷¹³ There is no systemic involvement, but associated clinical diseases have included adult-onset asthma and hematological abnormalities. ⁷¹² Lesions enlarge very slowly over many years.

Only a few cases of cutaneous atypical histiocytosis have been reported.^{714. and 715.} It is characterized clinically by the presence of one or more nodular lesions resembling cutaneous lymphoma. There has been a good response to various modes of treatment in the cases reported so far. The status of this entity is doubtful.

Indeterminate cells are a class of dendritic cells found in the dermis. They display similar histological and antigenic features to Langerhans cells: both express S100 protein and CD1a surface antigens. ⁷¹⁶ They differ by lacking Birbeck granules and by possessing some histiocytic markers such as CD68.

Only a few cases of indeterminate cell histiocytosis have been reported. ⁵⁸² They usually present as multiple reddish-brown to yellowish papules.^{717.718. and 719.} A solitary congenital variant, ⁷¹⁶ and a solitary acquired lesion on the mucosa of the glans penis have also been reported. ⁷²⁰ A large series of 18 patients was described in 2005. ⁷²¹ The authors of this series speculated that this disease might represent various macrophage disorders identified at various time points in the inflammatory response. ⁷²¹ A case that progressed to leukemia has been reported. ⁷²² A case of indeterminate cell sarcoma has been reported. ⁷²³ Vinblastine has been used to treat aggressive variants. ⁷²⁴ Partial remission has been obtained using UVB phototherapy. ⁷²⁵ Electron beam therapy is another option. ⁷²⁶

The eponymous designation Rosai–Dorfman disease⁷²⁷ is more appropriate than ‘sinus histiocytosis with massive lymphadenopathy’, because it is now recognized that in some instances extranodal lesions, including lesions in the skin, may be the sole manifestation of this condition.^{728.729.730.731.732.733.734.735.736.737.738.739.740.741. and 742.} Cutaneous Rosai–Dorfman disease appears to be a distinct entity with different age and race distributions from cases with nodal disease. ⁷⁴³ It also has a wider histopathological spectrum. ⁷⁴⁴ The typical presentation is with painless cervical lymphadenopathy, accompanied by fever, anemia, an elevated erythrocyte sedimentation rate and hypergammaglobulinemia, which has been polyclonal in all but one case.745.^{746. and 747.} Any age may be affected, but 80% of cases develop in the first two decades of life. Extranodal lesions occur in almost one-third of cases, and the skin has been involved in more than 10% of the many cases now reported.^{728. and 746.} Purely cutaneous disease is uncommon; over 100 cases have now been reported, most in the last few years.^{744.748. and 749.}

Cutaneous lesions, which are usually multiple, have been varied in their clinical appearance. ⁷²⁸ There may be nodules up to 4 cm or more in diameter,^{750. and 751.} papules which are erythematous or xanthomatous, ⁷²⁸ plaques, pustules, acneiform lesions, ⁷⁵² pigmented macules, ⁷²⁹ and even a transient panniculitis. ⁷⁵³ In one case, the presentation mimicked a vasculitis. ⁷⁵⁴ The eyelids and the malar regions are the sites of predilection.^{729. and 755.} In the study by Brenn and colleagues of purely cutaneous disease, there was no site predilection. ⁷⁴⁸ Furthermore, 13 of the 22 cases had multifocal disease. Only 4 of the 21 patients with pure cutaneous disease reported from Taiwan had multifocal involvement. ⁷⁵⁶

The disease usually runs a benign, albeit protracted, clinical course, sometimes with significant morbidity. ⁷⁴⁶ Death may sometimes result from infiltration of organs or from immunological disturbances.^{729.757.758. and 759.} The lesions resolved, regardless of the treatment given in 6 of 13 patients, for whom follow-up data were available, in the series of 22 cases, referred to above. ⁷⁴⁸ It is a polyclonal disorder of macrophage origin. ⁴⁵⁶ Its association with coexisting Langerhans cell histiocytosis may represent a reactive proliferation of Langerhans cells within a lesion of Rosai–Dorfman disease.^{749. and 760.} Its association with other histiocytoses may have implications for its pathogenesis. ⁷⁴⁴ The occurrence of other malignancies is so rare that it may be incidental. ⁷⁶¹ Human herpesvirus-6 (HHV-6) has been isolated from a skin lesion in one case. ⁷⁶² Both HHV-6 and HHV-8 were not detected in a further three cases. ⁷⁶³ Recently large numbers of cells positive for parvovirus B19 were found by immunohistochemistry in four cases, suggesting that this may be the etiological agent. ⁷⁶⁴

When anatomically feasible, complete excision is the treatment of choice for persistent or recurrent extranodal disease.^{749. and 765.} When surgical margins are involved, local recurrence is likely. Radiotherapy has shown limited efficacy, while chemotherapy is generally ineffective. ⁷⁶⁵ Isotretinoin has been used to treat this condition,^{755. and 766.} while high-dose thalidomide has been used for extensive cutaneous disease. ⁷⁵⁶ Corticosteroids were used in another case. ⁷⁶⁷ Dapsone has been suggested for cases with a neutrophilic predominance. ⁷⁶⁸ Recently the tyrosine kinase inhibitor imatinib was used successfully to treat systemic disease. ⁴⁷⁶

While it is most unusual to create an entity, in a textbook, on the basis of a solitary report, the case described with this designation seems sufficiently unique to justify a separate description. ⁷⁷⁶ The patient, with history of thrombocytosis, presented with a 5-year history of a violaceous, maculopapular rash primarily on her legs. The rash subsequently progressed to form confluent patches and plaques on her torso and arms. The clinical impression was disseminated granuloma annulare. ⁷⁷⁶

This rare, life-threatening histiocytosis is characterized by a benign proliferation of histiocytes and an uncontrolled phagocytic syndrome, induced by T-cell activation, which in turn may be due to infections of various types. ⁴⁵⁷ Epstein–Barr virus is sometimes the triggering infection. ⁷⁷⁷ There may be an underlying connective tissue disease, malignancy, or HIV infection that depresses the immune system. ⁷⁷⁸

Patients present with fever, splenomegaly, liver dysfunction, cytopenia, hypofibrinogenemia, and tissue hemophagocytosis. ⁴⁵⁶ Cutaneous manifestations are present in up to 65% of cases, but they are a minor component of the illness. ⁷⁷⁹ There may be hemorrhage from the hypofibrinogenemia.

A dysfunction of the cytokine perforin seems to be involved in many cases. Its release may be triggered by the precipitating infection. ⁴⁵⁷ Perforin is implicated in the mechanism of at least two of the four familial hemophagocytic lymphohistiocytosis (HPLH) syndromes. These syndromes have predominantly been reported from parts of Europe, including Turkey, and from Japan. They are listed in Table 40.8. Hemophagocytosis can also be seen in cytophagic histiocytic panniculitis. The median survival of untreated cases is 2–3 months. Treatment of the triggering infection is the first requirement. Ultimately, hematopoietic stem cell transplantation may be required; it is curative. ⁴⁵⁷

Histiocytic sarcoma is the preferred term of the International Lymphoma Study Group for a rare malignant tumor of histiocytes that was formerly called histiocytic medullary reticulosis, and later malignant histiocytosis. ⁷⁸⁰ Many of the earlier cases were not histiocytic when archival material has been subject to current immunohistochemical markers. ⁷⁸⁰ A review of seven suspected cases seen at the Mayo Clinic over a 20-year period produced only one case that had a true histiocytic origin. ⁷⁸¹ Fletcher and colleagues reported 14 cases in 2004. ⁷⁸² Clinical features include fever, generalized lymphadenopathy, hepatosplenomegaly, pancytopenia, and sometimes disseminated intravascular coagulation, night sweats, and abdominal pain.^{783.784. and 785.} The skin is involved in 10–15% of cases, and in some this is the presenting feature.^{786.787. and 788.} Lesions take the form of papules, nodules, or plaques anywhere on the body, but with a predilection for the extremities and buttocks. ⁷⁸⁹ Skin involvement mimicked kwashiorkor in one case. ⁷⁹⁰ Sometimes only a solitary nodule is present initially. Spontaneous healing of individual lesions may occur.

Malignant histiocytosis occurs at all ages; some cases have been reported in childhood.^{791.792. and 793.} As some of these cases may have been other diseases, it is difficult to be certain of the percentage of childhood cases. The prognosis at all ages is poor, although patients presenting with skin lesions form a subgroup with a more favorable outlook.^{783. and 786.} Prognosis might be related to tumor size. ⁷⁸² At autopsy there is usually involvement of many organs. In the series of 18 cases reported by the International Lymphoma Study Group, the median age of the patients was 46 years; 72% presented with extranodal disease. The mortality rate was 58%. ⁷⁸⁰

Polytherapy consisting of vincristine, cyclophosphamide, doxorubicin, and prednisolone achieved complete remission in 22 out of 27 patients in one series. ⁴⁵⁷

The term ‘reactive histiocytosis’, also known as secondary histiocytosis, refers to the increased number of histiocytes that may be seen in a variety of cutaneous infections. These include histoplasmosis, toxoplasmosis, brucellosis, tuberculosis, leprosy, rubella, and certain infections with the Epstein–Barr virus. ⁴⁵⁰ Histiocytes are also prominent in actinic reticuloid. Histiocyte-like myeloid cells have been reported in some cases of Sweet’s syndrome (histiocytoid Sweet’s syndrome). ⁷⁹⁹ In susceptible hosts, particularly those with various immunodeficiency syndromes, infections may trigger idiopathic histiocytic proliferations indistinguishable from Langerhans cell histiocytosis. ⁴⁵⁰

A histiocytic infiltrate has also been reported in two patients with acute lymphocytic leukemia receiving cytarabine. ⁸⁰⁰ Lesions resolved after cessation of the drug.

Intravascular/intralymphatic histiocytosis is a rare, reactive histiocytosis characterized by the proliferation of histiocytes in vascular or lymphatic lumina.^{801.802. and 803.} Most of the reported cases have been associated with rheumatoid arthritis,^{804.805.806. and 807.} but tonsillitis was the associated condition in another patient. ⁸⁰³ Intralymphatic histiocytosis has been reported in the region of the metal implants of a knee joint replacement. ⁸⁰⁸ Granulomas were also present. Histiocytes are sometimes seen in dilated lymphatics in the dermis in Rosai–Dorfman disease. ⁷³⁵

Lesions associated with rheumatoid arthritis are usually asymptomatic, irregularly shaped patches of erythema, sometimes livedo-like, in the vicinity of the involved joint. The case associated with tonsillitis presented with painful induration of the scrotum. ⁸⁰³

In the eruptive variant of xanthoma, multiple small red-yellow papules with an erythematous halo develop in crops. ⁸¹⁰ There is a predilection for the buttocks and thighs, and the extensor surfaces of the arms and legs. ⁸¹¹ The lesions become progressively more yellow and eventually resolve spontaneously over several weeks.

Eruptive xanthomas occur in a setting of elevated plasma chylomicrons such as may occur in uncontrolled diabetes mellitus or following the ingestion of alcohol or the use of exogenous estrogens.^{811. and 830.} Rare associations include lipoprotein lipase deficiency, ⁸¹¹ types IV and V hyperlipoproteinemia, ⁸³¹ normolipemia, ⁸³² pregnancy, ⁸³³ the nephrotic syndrome, ⁸³⁴ chylous effusions, ⁸³⁵ hypothyroidism, the use of intravenous miconazole, ⁸³⁶ and the oral ingestion of 13-cis-retinoic acid. ⁸³⁷ Eruptive xanthomas have followed the use of the antipsychotic drug olanzapine⁸³⁸ and the protease inhibitor ritonavir. ⁸³⁹

The unique case of normolipemic eruptive xanthomas associated with generalized edema is best regarded as a variant of dystrophic xanthomatosis (see above). ⁸⁴⁰

Tuberous xanthomas present a spectrum which ranges from small inflammatory lesions at one end (tuberoeruptive xanthomas) to large nodular lesions at the other. Tuberous xanthomas often form by coalescence of smaller lesions. ⁸¹⁰ They are yellowish in color and are found particularly on the elbows, knees, and buttocks. With treatment of the underlying hyperlipidemia there is usually slow resolution over many months.

Tuberous xanthomas are most characteristic of familial hyperlipoproteinemia (type III), but they can be seen rarely in homozygous and heterozygous familial hypercholesterolemia, ⁸⁴⁵ which includes autosomal recessive hypercholesterolemia (OMIM 603813) due to mutations in the ARH gene at 1p36–p35, ⁸⁴⁶ hepatic cholestasis,^{847.848. and 849.} cerebrotendinous xanthoma, and β-sitosterolemia. ⁸¹¹ This latter condition (OMIM 210250) is autosomal recessive, with the gene localized to 2p21. ⁸⁵⁰ It is caused by mutations in the ABC68 gene or in the ABC65 gene, both of which are located at this gene locus. ⁸⁵¹ Tendinous xanthomas are also present in these latter two conditions, as well as in the hyperlipidemia associated with the protease inhibitor ritonavir. ⁸⁵² Tuberous xanthomas have also been reported in a normolipidemic subject. ⁸⁵³

In tendinous xanthoma, lesions of varying size develop in ligaments, fasciae, and tendons, especially the extensor tendons of the hands and feet and the Achilles tendon. ⁸¹¹ They are firm to hard, flesh-colored nodules which develop slowly over decades.

Tendinous xanthomas are most commonly associated with heterozygous familial hypercholesterolemia, but they have also been reported in cerebrotendinous xanthoma (caused by a mutation in the sterol 27-hydroxylase gene), β-sitosterolemia, familial hyperlipoproteinemia (type III) and hepatic cholestasis, and rarely in normolipidemic individuals.^{811.853. and 857.} Cerebrotendinous xanthomatosis (OMIM 213700) is caused by a mutation in the CYP27A1 gene, which encodes sterol 27-hydroxylase, on chromosome 2q33–qter.

Plexiform xanthomatous tumor is a normolipemic xanthomatous tumor with a distinctive plexiform pattern, composed of a variable admixture of uniform epithelioid and xanthomatous cells. ⁸⁵⁸ Lesions are usually solitary, but up to four lesions may be present. All cases reported have been in males. ⁸⁵⁸ Some cases may represent a morphological variant of tuberous or tendinous xanthoma, but lesions are usually smaller than those in these other two variants of xanthoma.

Planar xanthomas are yellow, soft macules or slightly elevated plaques which are further subdivided on the basis of their location into xanthelasmas, intertriginous xanthomas, ⁸¹¹ xanthoma striatum palmaris,^{831. and 859.} and diffuse (generalized) plane xanthomas.^{810. and 811.} A further variant, planar xanthoma of cholestasis, is sometimes recognized.^{811. and 860.}

The verruciform variant of xanthoma is composed of asymptomatic, usually solitary, flat plaques or warty lesions up to 2 cm in diameter. ⁸⁸⁸ A giant lesion measuring 15 × 20 cm has been reported. ⁸⁸⁹ They may vary in color from gray to pink or yellow, depending on the thickness of the overlying epithelium. There is a marked predilection for the oral cavity, ⁸⁹⁰ although lesions have also been reported on the vulva, ⁸⁹¹ perianal skin, ⁸⁹² scrotum,^{893.894. and 895.} penis, ⁸⁹⁶ and occasionally extragenital skin.^{897.898. and 899.} Multiple papules of the hands and feet have been reported in association with verrucous genital lesions. ⁹⁰⁰ Verruciform xanthomas have developed in association with epidermal nevi,^{901. and 902.} a seborrheic keratosis, ⁹⁰³ a fibroepithelial polyp of the vulva, ⁹⁰⁴ a squamous cell carcinoma,^{905. and 906.} an arteriovenous hemangioma, ⁹⁰⁷ recessive dystrophic epidermolysis bullosa,^{898. and 908.} discoid lupus erythematosus, ⁹⁰⁹ and lymphedema of the leg.^{910.911.912. and 913.} They have occurred in immunocompromised patients with HIV-1 infection, ⁹¹⁴ with graft-versus-host disease, ⁹¹⁵ and in association with human papillomavirus (HPV).^{916.917. and 918.} Because similar morphological changes are identified in CHILD syndrome (see p. 256) resulting from mutational inactivation of the 3β-hydroxysteroid dehydrogenase (NSDHL) gene, located at Xq28, a search was made for mutations in this gene in cases of sporadic verruciform xanthoma. A novel missense mutation in exon 6 of the NSDHL gene was demonstrated in two of the nine patients tested. ⁹¹⁹ This mutation is not the usual one encountered in the CHILD syndrome. Lesions may persist for long periods. It is assumed that the formation of the xanthoma cells is secondary to degeneration of or damage to cells in the overlying epithelium.^{897.914.920.921. and 922.} The xanthoma cells are thought to be derived from dermal dendrocytes. ⁹²³ Lipid metabolism is usually normal, although verruciform xanthoma has been reported in association with an undefined systemic lipid storage disorder. ⁹²⁴

Papular xanthoma is a very rare condition consisting of multiple discrete yellow-red papules on the face and trunk and occasionally on mucous membranes.^{449. and 478.} Only eight cases have been reported, according to a paper in 2007. ⁹²⁹ The condition has been classified with the histiocytic infiltrates because affected individuals are usually normolipidemic, ⁴⁴⁹ but as there are no primitive histiocytes or other inflammatory cells in the lesions it seems best to classify it as a xanthoma. ⁹³⁰ Furthermore, qualitative abnormalities in the lipoproteins may be present. ⁹³¹ Papular xanthoma, particularly in children, may be clinically indistinguishable from juvenile xanthogranuloma. ⁹³² Rarely, it is congenital. ⁹³³

Papular xanthomatosis has been reported in a patient with the Sézary syndrome, ⁹³⁴ and in one with erythrodermic atopic dermatitis. ⁹³⁰

The skin lesions in adults tend to be persistent, although childhood cases are often self-healing within 1 to 5 years. ⁹³³ An adult case has been treated successfully with doxycycline. ⁹²⁹

There is one report of three patients with HIV infection who developed a papular facial eruption in association with an IgA gammopathy. ⁸¹⁹ Although there is some clinical similarity with the plane or papular xanthomas associated with lymphoproliferative disorders, the histology of these lesions is unique.