Section 19. Skin Signs of Reticuloendothelial Disease

The disorders of xanthohistiocytic proliferation involving histiocytes, foam cells, and mixed inflammatory cells are divided into Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH).

Langerhans Cell Histiocytosis (Histiocytosis X)

LCH is an idiopathic spectrum of disorders characterized by a clonal proliferation of Langerhans cells. Clinically, LCH is characterized by lytic bony lesions and cutaneous findings that range from soft tissue swelling to eczema- and seborrheic dermatitis-like skin changes and ulceration.

Insight

Histiocytosis can be extremely difficult to diagnose. In infants with diaper rash that will not heal, particularly if there are erosions in the folds or petechiae/purpura, histiocytosis should be considered.

Synonyms Class I histiocytosis, nonlipid reticuloendotheliosis, eosinophilic granulomatosis.

Classification

LCH has four overlapping forms:

1. 1. Letterer–Siwe disease: aggressive LCH with diffuse skin and organ infiltration and thrombocytopenia

   2. Hand-Schüller-Christian disease: LCH with lytic skull lesions, exophthalmos, and diabetes insipidus

   3. Eosinophilic granuloma: single osteolytic bony lesion ± skin/soft tissue lesion

   4. Hashimoto–Pritzker disease: congenital self-healing reticulohistiocytosis

Epidemiology

Age Any age, common 1 to 3 years.

Gender M > F, 2:1.

Incidence Rare, 5/million children.

Genetics Familial case reports.

Pathophysiology

The proliferating Langerhans cell appears to be primarily responsible for the clinical manifestation of LCH. The stimulus for the proliferation may be a disturbance of intracellular lipid metabolism, a reactive response to infection (?viral), a primary immunologic disorder of the host, or an inherited neoplastic disorder.

History

LCH has a broad clinical spectrum, but in the most aggressive form (Letterer–Siwe disease), the infant appears systemically ill with a generalized skin eruption (seborrhea, petechiae, and purpura) followed by fever, anemia, thrombocytopenia, adenopathy, hepatosplenomegaly, and/or skeletal lesions.

Physical Examination

Skin Findings

Type Papules, plaques, vesicles, scale, petechiae, purpura, ulceration, necrosis.

Color Pink, flesh-colored.

Size 1 to 2 mm.

Distribution Flexural areas: neck, axillae (Fig. 19-1), and perineum > trunk (Fig. 19-2).

General Findings

Fever Lymphadenopathy (LAD). Ill appearance.

Pulmonary Infiltrate disease of the lung bases and midzones, pneumothorax.

Liver Hepatosplenomegaly.

Bone Osteolytic lesions: calvarium, sphenoid bone, sella turcica, mandible, long bones of upper extremities (UEs), vertebrae.

Other Otitis media, diabetes/exophthalmus/ bony lesions in Hand–Schüller–Christian variant.

Differential Diagnosis

The differential diagnosis of LCH includes seborrhea, candidiasis, Darier disease, leukemia, lymphoma, multiple myeloma, urticaria pigmentosa (UP), mycosis fungoides (MF), and non-LCH.

Laboratory Examinations

Histopathology Proliferation of Langerhans cells with distinct morphologic (pale eosinophilic cytoplasm, a kidney-shaped nucleus), ultrastructural (Birbeck granules), and immune-histochemical markers (CD1a+, ATPase+, S-100+, langerin (CD207)+, α-d-mannosidase+, peanut agglutinin+).

Radiographic Findings Osteolytic lesion in calvarium, femur, rib, sphenoid, sella turcica, mandible, long bones of UEs. Chest: diffuse interstitial fibrosis in lung bases and midzones, pneumothorax.

Course and Prognosis

The prognosis of LCH varies according to the extent of systemic involvement. Patients with eosinophilic granuloma or Hashimoto–Pritzker disease (congenital self-healing reticulohistiocytosis) have a relatively benign course with excellent prognosis. Patients older than 2 years at the time of diagnosis, without involvement of the hematopoietic system, liver, lungs, or spleen, have 100% probability of survival.

Patients with systemic involvement have a higher mortality rate, especially children diagnosed before age 2 years with liver, lungs, spleen, or hematopoietic involvement. Even with aggressive treatment, mortality ranges from 38% to 54%. Of note, patients with leukemia (acute lymphoblastic leukemia or acute nonlymphoblastic leukemia) or solid tumors may have an increased incidence of LCH and vice versa.

Management

The management and treatment of LCH is dependent upon the severity and extent of involvement. Mild skin-only LCH can be treated with topical steroids, antibacterial agents, psoralen ultraviolet A (PUVA), and topical nitrogen mustard. Localized bony lesions can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), intralesional steroids, curette with, or without, bony chip packing, or low-dose (300–600 rads) irradiation.

Multisystem LCH can be systemically treated with corticosteroids, vinblastine, methotrexate, or epipodophyllotoxin (etoposide). Failure to respond to treatment after 6 weeks of these drugs is a poor prognostic indicator. Even in responsive patients, there is a high (58%) rate of LCH reactivity. Reactive disease can be treated with etanercept, cyclosporine, 2-chlorodeoxyadenosine, or imatinib mesylate. Finally, in recalcitrant cases, bone marrow, stem cell liver or lung transplantation may be necessary.

Non-LCH encompasses a spectrum of disorders with a benign, cutaneous self-resolving proliferation of mononuclear phagocytes other than Langerhans cells. Clinical forms include juvenile xanthogranulomas (JXGs), benign cephalic histiocytosis, generalized eruptive histiocytosis, and indeterminate cell histiocytosis, which may represent different expressions of the same pathologic process.

Synonyms Class II histiocytosis, non-X histiocytosis.

Juvenile Xanthogranuloma

JXGs are common, benign, self-healing lesions of infancy and childhood characterized by one or several red to yellow papules and nodules on the skin and rarely in other organs.

Synonyms Nevoxanthoendothelioma (a misnomer).

Epidemiology

Age Birth (15%) to before age 1 year (75%).

Gender M > F, 1.5:1.

Incidence Most common form histiocytosis.

Etiology Unclear. Possibly reactive granuloma to unknown cause.

Pathophysiology

Reactive histiocyte proliferation to unknown traumatic or infectious stimulus

History

Asymptomatic cutaneous JXGs are present at or soon after birth, may proliferate in number and size for 1 to 2 years, and then both cutaneous and rare visceral lesions involute spontaneously within 3 to 6 years.

Physical Examination

Skin Findings

Type Papules to nodules.

Color Red–brown (Fig. 19-3), transitioning to yellow quickly.

Size 2 to 20 mm in diameter.

Number Solitary or multiple (can be hundreds; Fig. 19-4).

Palpation Firm or rubbery.

Distribution Face, scalp, neck > upper trunk > UEs > lower extremities > mucous membranes.

General Findings

Ocular Ocular JXG (0.5%).

Other Rarely associated with systemic lesions (lungs, bones, kidneys, pericardium, colon, ovaries, testes), café au lait macules, necrosis factor 1, leukemia.

Differential Diagnosis

The differential for JXG includes UP, benign cephalic histiocytosis, generalized eruptive histiocytosis, self-healing reticulohistiocytosis, xanthomas, histiocytosis X, and nevi.

Laboratory Examinations

Dermatopathology Monomorphous, non-lipid-containing histiocytic infiltrate, may have foamy cells, foreign body giant cells, and Touton giant cells in the superficial dermis and periphery of the infiltrate. Fat stains are positive. Electron microscopy shows histiocytes with comma-shaped bodies, lipid vacuoles, cholesterol clefts, and myeloid bodies. Immunohistochemical stains are HAM56+, CD68+, factor XIIIa+.

Course and Prognosis

JXG skin lesions are often present at birth or during the first 9 months of life, run a benign course, often increasing in number until age 1 to 1.5 years, and then spontaneously involute. Rarely, systemic lesions involving the eyes, lung, pericardium, meninges, liver, spleen, and testes also occur. The patient’s general health is not affected and development progresses normally.

Ocular JXGs are the most worrisome because of complications such as glaucoma, hemorrhage, and blindness. In rare instances, JXG may be associated with necrosis factor 1, and these patients have an increased risk of juvenile myelomonocytic leukemia.

Management

No treatment is necessary for the cutaneous lesions because they will involute without intervention.

Ocular lesions may require radiation and/or topical or systemic steroids to avert complications of glaucoma, hemorrhage, or blindness.

Rare cases of systemic JXGs will also spontaneously involute, but severe symptomatic cases can be treated with systemic chemotherapy, radiotherapy, corticosteroids, or cyclosporine.

The mastocytosis syndromes are a spectrum of clinical disorders associated with a proliferation of mast cells within the skin and, rarely, other organs (the liver, spleen, and lymph nodes).

Classification

Childhood mastocytosis is distinct from adult mastocytosis and has three clinical forms:

1. 1. Solitary mastocytoma (20%): individual lesion(s) typically on distal extremities

   2. UP: generalized lesions over trunk

   3. Diffuse cutaneous mastocytosis: erythrodermic infant with a boggy or doughy skin

Synonyms Bullous mastocytoma, bullous UP, bullous mastocytosis.

Epidemiology

Age By age 2 years (55%), 2 to 15 years (10%).

Gender M = F.

Incidence 1 in 8000 children.

Prevalence 20000 cases estimated in the United States.

Genetics Reported familial cases, but majority are sporadic.

Pathophysiology

Alterations in the tyrosine kinase KIT (CD117) structure and activity has been implicated in adult mastocytosis and some cases of extensive skin/systemic childhood mastocytosis. But some other mast cell growth promoting mechanism (such as increased soluble stem cell factor) is likely responsible for the majority of childhood mastocytosis syndromes. Mast cell concentrations are 150-fold higher in childhood mastocytomas and 40-fold higher in childhood UP than normal skin. Degranulated mast cells release vasoactive substances such as histamine (leading to urticaria and gastrointestinal [GI] symptoms), prostaglandin D2 (leading to flushing and cardiac and GI symptoms), heparin, and neutral protease/acid hydrolases.

History

In children, mastocytosis typically begins before age 2 with one to many scattered cutaneous lesions. The lesions may be flat or slightly raised but have a tendency to become red and form an urticarial wheal or bullae with gentle rubbing, exercise, hot baths, or histamine-releasing drugs (NSAIDs, alcohol, dextran, polymyxin B, morphine, codeine). Children rarely have systemic symptoms, but with extensive cutaneous involvement, a flushing episode may be accompanied by headache, diarrhea, wheezing, or syncope. Diffuse cutaneous mastocytosis presents as a diffusely erythrodermic infant with a boggy or doughy appearance.

Physical Examination

Skin Findings

Type Macule/papule, urticarial wheals/ plaques or bullae when gently stroked (Darier’s sign; Fig. 19-5).

Color Reddish-brown hyperpigmented color.

Size 1 mm to several centimeters.

Number Solitary lesions or multiple (hundreds; Fig. 19-6).

Distribution Trunk, extremities, neck > scalp, face, palms, soles, mucous membranes (Fig. 19-7).

Differential Diagnosis

The differential diagnosis for mastocytosis includes urticaria, insect bites, bullous impetigo, viral infection, lentigines, café au lait macules, JXG, nevi, linear IgA disease, other autoimmune bullous dermatoses.

Laboratory Examinations

Dermatopathology Accumulation of mast cells in the dermis. Mast cell infiltrates may be sparse (spindle-shaped mast cells) or dense (cube-shaped mast cells). Toluidine blue, Giemsa and Leder stains, or monoclonal antibodies to tryptase and CD117 (KIT) can help identify tissue mast cells.

Serum α-Tryptase levels are elevated in symptomatic or asymptomatic patients with systemic mastocytosis. β-Tryptase is elevated in patients with anaphylaxis related or unrelated to mastocytosis. Total (α- and β-) serum tryptase levels can be correlated with the extent of mast cell disease in patients. More than 75 ng/mL total serum tryptase indicates definite systemic involvement, whereas only 50% of patients with levels between 20 and 75 ng/mL have systemic disease.

Urine Patients with systemic mastocytosis or extensive cutaneous involvement may have increased 24-hour urinary histamine or histamine metabolite excretion. Of note, foods with high histamine content (spinach, eggplant, cheese, red wine) will artificially elevate urinary histamine.

Bone Marrow Biopsy In bone marrow biopsies of children with UP, 18% can have mast cell infiltration.

Course and Prognosis

When seen in children younger than 10 years, all forms of mastocytosis have a good prognosis. Most childhood disease has limited cutaneous involvement; 50% of cases spontaneously remit by adolescence and another 25% of cases resolve by adulthood. Systemic involvement appears to affect <5% of children with mastocytosis. This percentage is much higher in adults with mastocytosis and their prognosis is much worse. When systemic involvement occurs, mast cells infiltrate the bones, liver, spleen, and lymph nodes. The presence of mast cells in the peripheral blood of patients with mastocytosis is a poor prognostic sign.

Management

Solitary mastocytosis and UP cutaneous lesions self-resolve and need no treatment. Moderate sunlight exposure can help diffuse skin lesions resolve. Patients with numerous lesions or diffuse cutaneous mastocytosis should be counseled to avoid potential mast cell degranulating agents: aspirin, NSAIDs, codeine, opiates, procaine, alcohol, polymyxin B sulfate, radiographic dyes, ketorolac, Toradol, scopolamine, systemic lidocaine, d-tubocurarine, metocurine, etomidate, thiopental, succinylcholine hydrochloride, enflurane, isoflurane, gallamine, decamethonium, pancuronium, hot baths, vigorous rubbing after baths or showers, tight clothing, and extremes of temperature.

Antihistamines may be helpful in mastocytosis. Second-generation H1-blockers (cetirizine, loratadine, and fexofenadine) may work better than first-generation H1-blockers (diphenhydramine, hydroxyzine HCl). Ketotifen fumarate or doxepin can be potent H1-blockers used in conjunction with H2-blockers. In resistant cases, H2-blockers (cimetidine, ranitidine, famotidine, or nizatidine) can be used in combination with H1-blockers.

Other medications that have been helpful for mastocytosis include oral cromolyn sodium, PUVA, topical, intralesional or systemic steroids, cyclosporine, or interferon-α-2b.

Symptomatic patients with mastocytosis should carry an epinephrine pen because severe allergic reactions with anaphylaxis and hypotension can occur. Additional diagnostic evaluation should be performed in patients with evidence of further organ system involvement, such as, GI bleeding, abdominal pain, enlarged liver or spleen, bone pain, or blood abnormalities.

Lymphomatoid papulosis (LyP) is a recurrent self-healing papulovesicular dermatosis of the trunk and extremities with histologic features ` of lymphocytic atypia, but a low risk of malignant transformation.

Classification

LyP is part of a spectrum of CD30 (Ki-1)-positive cutaneous lymphoproliferative diseases (CD30+ lymphoproliferative disorders), including LyP, primary cutaneous anaplastic large cell lymphoma (pcALCL), and borderline CD30+ lesions.

Synonyms Macaulay disease, lymphoproliferative disorder.

Epidemiology

Age Any age. Peak: 50 years.

Gender F > M.

Incidence 1 to 2/million.

Race Blacks less frequently affected.

Etiology Unclear. Possible activated T cells responding to external or internal stimuli or an indolent skin T-cell malignancy held in check by the host immune system.

Pathophysiology

The pathophysiology of LyP is unknown. CD30 signaling is important for the growth and survival of lymphoid cells; thus, accumulated genetic defects may have a role in the development of LyP. Clinically, LyP spontaneously regresses, and Bax (a proapoptotic protein) or FADD (Fas-associating protein with death domain) may mediate the apoptosis of tumor cells.

History

LyP begins as asymptomatic or mildly pruritic macules and papules that appear in crops within 1 to 4 weeks. Lesions may resolve within 2 to 8 weeks or recur and persist for decades. Constitutional symptoms (low-grade fever, malaise, night sweats) rarely occur.

Physical Examination

Skin Findings

Type Papules, vesiculopapules, scale, crust, ulcers, scars.

Color Red-brown, hemorrhagic, hypo- or hyperpigmented (Fig. 19-8).

Size 2 to 30 mm in diameter.

Distribution Trunk, proximal extremities > hands, feet, scalp.

Mucous Membranes Oral, genital mucosa rarely affected.

General Findings

Lymphadenopathy (LAD) Regional or generalized lymphadenopathy may be present.

Differential Diagnosis

The differential for LyP includes folliculitis, insect bites, LCH, milia, miliaria, scabies, pityriasis lichenoides et varioliformis acuta, cutaneous Hodgkin’s lymphoma, or cutaneous T-cell lymphoma (CTCL).

Laboratory Examinations

Dermatopathology Dense mixed cell infiltrate with a wedge- or band-like distribution on the upper dermis. The infiltrate is composed of histiocytes, eosinophils, plasma cells, and strikingly atypical lymphocytes with convoluted nuclei. According to the principal morphologic type, LyP is classified into type A, which consists of large atypical lymphocytes with multinucleated variants and cells resembling Sternberg–Reed cells, type B, composed of cerebriform lymphocytes similar to cells in CTCL and type C, with sheets of anaplastic large cells indistinguishable from ALCL.

Immunohistology Dominant cells in LyP express CD30 (Ki-1) antigen. Tumor cells may express CD56, TIA-1, granzyme B, or CXCR3. Clonality in LyP is controversial.

Course and Prognosis

In 90% of childhood LyP cases, the lesions usually resolve after 3 to 8 weeks or may have a slightly prolonged course. Ten to twenty percent of adult patients may progress to malignant lymphoma (ALCL, Hodgkin disease, or MF) but no patients with LyP died of the disease. Development of nodules or tumors may be a useful clinical sign for malignant transformation of the disease and patients with such lesions should have a systemic workup.

Management

No treatments have been proven to be consistently effective. Many childhood cases resolve spontaneously or with sunlight exposure. Symptomatic, pruritic lesions can be treated with topical steroids or phototherapy. Because of the risk of malignant transformation, especially in adults, careful long-term follow-up is recommended.

For more severe or refractory and extensive disease in adults, topical treatments such as carmustine; nitrogen mustard; MTX; imiquimod; intralesional interferon; systemic treatments such as steroids, antibiotics (tetracycline, erythromycin), sulfones, PUVA, UVA-1, electron beam, excimer laser, low-dose methotrexate, acyclovir, retinoids, chlorambucil, cyclophosphamide, cyclosporine, or dapsone have been reportedly effective.

CTCL applies to T-cell lymphoma, which first manifests in the skin and slowly progresses to lymph nodes and internal organs, terminating as a malignant lymphoma.

Synonyms MF, large plaque parapsoriasis.

Epidemiology

Age All ages. Peak: 50 to 70 years.

Gender M > F, 2:1.

Race African American > Caucasian.

Incidence Incidence 5/million. Causes 1% of deaths from lymphoma (about 200 deaths/year in the United States).

Etiology Unknown. Chemical, physical, and microbial irritants may lead to an accumulation of mutations in oncogenes, suppressor genes, and signal-transducing genes.

Pathophysiology

The pathophysiology of CTCL is unknown. Genetic instability followed by T-cell proliferation may produce numerous clonal chromosomal aberrations.

History

Skin symptoms are the presenting symptom of CTCL and last for months to years with nonspecific diagnoses such as psoriasis, nummular dermatitis, or eczema. The skin lesions wax and wane and are asymptomatic or mildly pruritic. Systemically, the patient feels well until the visceral organs become involved.

Physical Examination

Skin Findings

Type Plaques, scale, “infiltrated” (Fig. 19-9), nodules, tumors, ulcers.

Color Red, pink, purple.

Shape Round, oval, arciform, annular, concentric, or bizarre configurations.

Size >3 cm.

Arrangement Discrete plaques, nodules, and tumors, or diffuse erythroderma (Sézary’s syndrome) and palmoplantar keratoderma.

Distribution Buttocks, sun-protected areas > exposed areas.

General Findings

Lymphadenopathy/Hepatosplenomegaly In late disease, lymphadenopathy and/or splenomegaly may be present.

Sézary’s Syndrome Leukemic form of CTCL consisting of (1) erythroderma, (2) lymphadenopathy, (3) elevated WBC (>20000) with a high proportion of so-called Sézary cells, (4) hair loss, and (5) pruritus.

Differential Diagnosis

In the early stages, the diagnosis of CTCL is difficult to recognize and may be mistaken for refractory psoriasis, eczema, contact dermatitis, irritant dermatitis tinea corporis, or poikiloderma atrophicans vasculare.

Laboratory Examinations

Repeated and multiple (three) biopsies are often necessary.

Dermatopathology Dermal band-like, patchy infiltrate of atypical lymphocytes extending to skin appendages. Epidermal T cells with hyperchromatic, irregularly shaped nuclei and mitoses may be present. Intraepidermal collections of atypical cells (Pautrier microabscesses) are highly characteristic. Monoclonal antibody techniques identify most atypical cells as helper/inducer T cells. A dominant T-cell clone can be demonstrated by molecular assays (i.e., Southern blot, polymerase chain reaction).

Course and Prognosis

Children typically live for 10 to 15 years before CTCL ever progresses to any worrisome degree.

Management

Children with CTCL need conservative symptomatic treatment with sunlight exposure, antipruritic creams or topical steroids, and routine long-term follow-up.

For histologically proven plaque-stage CTCL, treatment possibilities include PUVA, topical nitrogen mustard, topical carmustine, bexarotene gel, tazarotene gel, total skin electron beam therapy, radiotherapy, interferon, bexarotene, methotrexate, etoposide, interferon-α, interleukin-2, receptor-targeted cytotoxic fusion proteins, alemtuzumab, or extracorporeal PUVA photochemotherapy.