Degenerative and metabolic diseases

Clinical features

Eruptive xanthomata are small (1–4 mm) yellowish papules with a red halo that have a predilection for the buttocks, shoulders, and extensor surfaces of the limbs ( Fig. 13.3 ). They may also present in the antecubital and popliteal fossae, axillae, lips, eyelids, and ears. They often appear in crops and may wax and wane with plasma lipoprotein levels. Lesions usually resolve spontaneously over a period of weeks. Pruritus is frequently present and the papules are sometimes tender. Eruptive xanthomata may rarely display a Koebner phenomenon. Healing is occasionally associated with the development of hyperpigmented scars. Cutaneous lesions of Langerhans cell histiocytosis and cutaneous involvement by adenocarcinoma may mimic eruptive xanthoma.

Eruptive xanthomata are associated with hypertriglyceridemia and most often occur in hyperchylomicronemic states. Sometimes their presence correlates with increased levels of VLDL. The most common cause, however, is secondary hyperlipoproteinemia (HPL), especially in those cases associated with diabetes mellitus and alcohol ingestion, or in those that are drug induced (e.g., due to exogenous estrogens, corticosteroids or retinoids). They may also develop as a consequence of decreased lipoprotein lipase activity, ApoCII deficiency or increased synthesis of VLDL, which effectively blocks chylomicron access to lipoprotein lipase. Eruptive xanthomata are therefore often accompanied by other features of hyperlipidemia, including lipemia retinalis, hepatosplenomegaly, abdominal pain, and pancreatitis. They may also rarely develop as a manifestation of primary hyperlipoproteinemia (HPL), particularly autosomal recessive lipoprotein lipase deficiency (HPL type I) in children and familial HPL type V in adults. An exceptional association with β-sitosterolemia, a condition usually presenting with tuberous or tendinous xanthomata, has been documented. Much rarer associations include familial hypertriglyceridemia, the nephrotic syndrome, chronic pancreatitis, von Gierke disease, and hypothyroidism. An association with acanthosis nigricans (AN) has also been reported. Dystrophic xanthomatization resulting in eruptive xanthomas at the site of prior herpes zoster as a manifestation of Wolf isotopic response has also been reported. There are also reports of eruptive xanthomas developing in tattoos.

Histologic features

The histologic features are seen predominantly within the superficial reticular dermis. In early lesions histiocytes are numerous and the fully developed ‘foam cells’, which characterize xanthomata, are sometimes few in number. The infiltrate may also contain an admixture of lymphocytes and neutrophils. In an established papule, xanthoma cells with characteristic clear or foamy cytoplasm form the predominant cell type ( Figs 13.4–13.6 ). Occasional cases show a palisading appearance at low magnification and urate-like crystals.

Eruptive xanthomata often develop rapidly over the course of several days and occasionally are associated with spontaneous resolution. The quantity of intracytoplasmic lipid (predominantly triglyceride in contrast to other xanthomata, which contain mostly cholesterol) is in a state of flux and may be associated with extracellular deposition, a phenomenon that is rare or absent in the other types of xanthomata. In all xanthomata the lipid within the macrophage stains positively with fat stains such as oil red O, scarlet or Sudan red ( Fig. 13.7 ).

Differential diagnosis

There can be confusion with granuloma annulare histologically as both conditions have certain features in common, namely a dermal interstitial histiocytic infiltrate with variably increased mucin. Although extracellular lipid may disrupt dermal collagen, necrobiosis is not characteristic of eruptive xanthoma and palisading is not a feature of the latter. Additionally, it contains few giant cells and the perivascular infiltrate is histiocytic, in contrast to the perivascular lymphocytes seen in granuloma annulare. Cases of eruptive xanthoma with urate-like crystals have been misdiagnosed as gout. Immunohistochemical studies of these urate-like crystals suggest that they are, not surprisingly, composed of chylomicrons.

Clinical features

Tendinous xanthomata, which are associated with raised LDL levels, are slowly enlarging subcutaneous tumors that occur in tendons (especially those of the hands, knees, elbows, and the Achilles tendon), ligaments, fascia, and periosteum ( Figs 13.8 and 13.9 ). The overlying skin, which appears normal, is freely moveable over the surface and small tendon xanthomata may be difficult to palpate. The lesions characteristically ‘move with the tendons’ and are thought to be trauma related. The presence of these xanthomata is most frequently a feature of heterozygous familial (LDL receptor deficiency) hypercholesterolemia. There is a high risk of associated coronary atherosclerosis. A meta-analysis demonstrated a threefold increased risk of cardiovascular disease in patients with familial hypercholesterolemia and tendinous xanthomata compared to those without cutaneous lesions. Tendinous xanthomata are also seen in familial combined hyperlipidemia, normocholesterolemic states such as cerebrotendinous xanthomatosis (cholestanolosis) and β-sitosterolemia, and the nephrotic syndrome. Cerebrotendinous xanthomatosis is an autosomal recessive disease caused by a mutation in CYP27A1 , the sterol 27-hydroxylase gene that is an important regulator of brain cholesterol homoestasis. This results in xanthoma in the brain as well as tendons.

Clinically, the lesions, which may be mistaken for gouty tophi and rheumatoid nodules, are sometimes found in association with tuberous xanthomata and xanthelasmata.

Histologic features

Tendinous xanthomata are composed of multiple nodules containing xanthoma cells, accompanied in early lesions by an admixture of inflammatory cells including non-lipidized histiocytes, lymphocytes, and neutrophil polymorphs. The deposits in tendinous xanthoma are doubly refractile to polarized light ( Fig. 13.10 ). Older lesions are characteristically associated with fibrosis.

Clinical features

Tuberous xanthomata are firm yellow–red papules and nodules, which are found most frequently on the extensor aspect of the knees, elbows, and buttocks ( Figs 13.11–13.13 ). Lesions sometimes also occur on the hands and palms. Rare cases involve cheeks and nose. They are most characteristically seen in familial dysbetalipoproteinemia type III, and there is a particular risk of peripheral vascular disease. Four other conditions may also be characterized by tuberous xanthomatosis:

• homozygous familial hypercholesterolemia,

• cerebrotendinous xanthomatosis,

• β-sitosterolemia,

• type IV HPL.

Tuberous xanthomata also occur in secondary hyperlipidemia (e.g., due to the nephrotic syndrome or hypothyroidism). Protease inhibitors may cause hyperlipidemia, and ritonavir has been reported to induce tuberous and tendinous xanthoma lesions. Clinically, tuberous xanthomata occasionally resemble the lesions of erythema elevatum diutinum. Tuberous and tendinous normolipemic xanthomata have been described but it seems that, with adequate follow-up, patients usually develop some form of hyperlipidemia. Cholesterotic fibrous histiocytomas may be associated with hyperlipidemia and often simulate a tuberous xanthoma clinically and histologically. A rare case of undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma) clinically presenting as a tuberous xanthoma in a patient with type IIA HPL has been documented.

Histologic features

Tuberous xanthomata consist of multiple nodules in the reticular dermis and sometimes the subcutaneous fat ( Fig. 13.14 ). Their appearance varies, depending upon their stage of evolution ( Fig. 13.15 ). Xanthoma cells predominate in early lesions, but with maturity fibrosis supervenes ( Fig. 13.16 ). On occasion, foreign body giant cell granulomata containing cholesterol clefts are seen and a perivascular chronic inflammatory cell infiltrate is sometimes evident ( Fig. 13.17 ).

Differential diagnosis

Heavily lipidized fibrous histiocytomas that tend to occur mainly around the ankle may histologically mimic tuberous xanthoma. The latter lesions lack the architecture of fibrous histiocytomas, have a nodular/multinodular growth pattern with variable fibrosis and lack epidermal hyperplasia and the hyalinization of collagen pattern seen at the periphery of fibrous histiocytomas.

Clinical features

Planar xanthomata are typically soft yellow dermal macules or plaques that occur most frequently around the eyes, where they are known as xanthelasmata ( Fig. 13.18 ). About 50% of patients with xanthelasmata have associated hyperlipidemia (hypercholesterolemia or HPL type III) which is often accompanied by a cholesterol corneal arcus. Many of those who appear biochemically normal on routine testing, however, are shown to have subtle abnormalities of lipid metabolism on more detailed analysis. There is a particularly increased risk of coronary artery atherosclerosis in younger patients. When very extensive (diffuse or generalized plane xanthomatosis) and associated with orange–yellow planar xanthomata around the head and neck, and occasionally the upper trunk and arms, there may be an associated systemic disorder such as multiple myeloma with paraproteinemia, cryoglobulinemia, benign paraproteinemia or, less commonly, leukemia and rheumatoid arthritis (necrobiotic xanthogranuloma) ( Fig. 13.19 ). More exceptional associations include idiopathic Bence Jones proteinuria, Sézary syndrome, Castleman disease, relapsing polychondritis, acquired palmoplantar keratoderma, adult T-cell leukemia/lymphoma, and Takayasu disease. A patient with monoclonal gammopathy and cutaneous lesions with features of both plane xanthoma and amyloidosis has been documented. The latter case was also associated with myeloma.

In cases of myeloma and plane xanthoma, it has been demonstrated that complexes form between serum lipoproteins and paraprotein, suggesting that this interaction may induce a hyperlipidemia and xanthoma formation. The serum lipid levels of patients with diffuse plane xanthomata are normal or raised. Plane xanthomata may present in the gingiva and, in this location, are usually associated with hyperlipidemia. An exceptional case has been described in an infant presenting with normolipemic papular and nodular lesions progressing to plane xanthomata and resulting in spontaneous resolution. Diffuse plane normolipemic xanthomata with mucosal and conjunctival involvement and aortic valve xanthomatosis may occur exceptionally. Lesions have been reported that clinically resembled plane xanthomata in a patient with systemic lupus erythematosus but histologically showed degeneration of collagen bundles with secondary fat deposition.

Intertriginous xanthomata seen in patients with raised LDLs and pathognomonic of homozygous familial hypercholesterolemia present as yellow papules and plaques, often with a cobblestone appearance. These occur in the finger webspaces and to a lesser extent in the axillae and antecubital and popliteal fossae. They have a particularly high association with early and severe atherosclerosis. Intertriginous xanthomata may also rarely be seen in heterozygous familial hypercholesterolemia.

Planar xanthomata presenting as yellow-orange macules in the skin creases of the palm and fingers (xanthoma striatum palmare) are diagnostic of familial dysbetalipoproteinemia (HPL type III, broad beta disease) ( Fig. 13.20 ), which is due to an abnormality of the apoprotein ApoE (homozygous ApoE2/E2). This results in impaired uptake of lipoprotein remnant particles by the liver and macrophages with resultant HPL and increased atherogenesis. Interestingly, the tendency to familial dysbetalipoproteinemia is present in 1% of the population, but a second lipid abnormality appears to be necessary to induce symptoms.

Plane xanthomata of cholestasis, for example due to primary biliary cirrhosis and biliary atresia, present as well-demarcated, beige–orange plaques that are particularly found on the hands and feet, but may occur elsewhere. They can also develop in patients with diabetes mellitus and have been described in the setting of cholestasis resulting from chronic graft-versus-host disease.

Planar xanthomata have also been described as a feature of HDL deficiency.

Histologic features

In planar xanthomata, the characteristic lipid-laden foam cells are situated within the superficial dermis ( Figs 13.21–13.23 ). There is minimal fibrosis. In rare cases, the histology may overlap with that of necrobiotic xanthogranuloma. ^.

Clinical features

The verruciform xanthoma is an uncommon, asymptomatic lesion, which occurs predominantly in the oral cavity of adults in their fifth or sixth decade and shows a male predilection (1.7 : 1). It is most often found on the premolar gingiva of the mandible or maxilla. At this site it usually produces a solitary, well-circumscribed, asymptomatic, erythematous or yellow–tan lesion, 3–20 mm in diameter, which may be papillomatous or ulcerated. The patients are normolipidemic. The clinical differential diagnosis includes viral warts, leukoplakia, and squamous cell carcinoma.

Verruciform xanthomata of the skin, which are extremely rare, have been described at a variety of sites including the ear, nose, lip, digits, and arm. Most cases described, however, have arisen on anogenital skin ( Fig. 13.24 ). It may also develop as a reactive phenomenon within epidermolytic acanthoma, seborrheic keratoses, epidermal nevi (including patients with inflammatory linear verrucous epidermal nevus or with the epidermal nevus syndrome), lymphangioma circumscriptum, and has been recorded as a complication of lymphedema. It has been described in association with longstanding discoid lupus erythematosus, lichen sclerosus, lichen planus, complicating ulceration in epidermolysis bullosa, congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome (CHILD syndrome) and in association with squamous cell carcinoma of the penis. Occasionally, verruciform xanthomata are multifocal. Such a case has been described as multiple lesions in the upper aerodigestive tract of a child with a systemic lipid storage disease. Multiple verruciform xanthomata have also been reported in the anogenital region several years following necrotizing fasciitis of the perineum and in the oral mucosa in a patient with chronic graft-versus-host disease. A rare case of disseminated lesions has been described on the hands, feet, and anogenital region and another with similar widespread disease that also included the oral cavity.

In the skin, verruciform xanthoma usually presents as a gray or pink nodule or as a plaque with a variably warty surface. Untreated, the lesions have a long duration and behave in a benign fashion, recurrence being very uncommon after local excision.

Pathogenesis and histologic features

The etiology and pathogenesis of the verruciform xanthoma are unknown. Originally, a viral infection by human papillomavirus (HPV) was suspected. Although most studies have not demonstrated definitive evidence to support this hypothesis, there are isolated reports demonstrating HPV DNA by polymerase chain reaction (PCR) in the lesions. Additionally, it has been suggested that keratinocyte necrosis may lead to the release of intracellular lipids, with resultant macrophage influx and xanthomatization. The inciting event leading to keratinocyte necrosis has not been identified. Immunohistochemical and electron microscopic studies give some credence to support to this latter hypothesis (see below). More recently, it has been proposed that localized lymphedema is a critical factor in some cases, as the same types of lipid-laden macrophages are seen in other conditions associated with chronic lymphedema.

Verruciform xanthoma is an exophytic lesion characterized by massive but regular acanthosis, variable papillomatosis, parakeratosis, and hyperkeratosis ( Fig. 13.25 ). Neutrophils, and neutrophilic debris are frequently observed at the level of the stratum corneum. Bacterial colonies may also be evident in the parakeratotic stratum corneum. The acanthosis is associated with uniform, bulbous epidermal ridges, all of which penetrate to the same depth, giving a characteristically level lower border. The expanded ridges are associated with marked central keratinocyte necrosis and a heavy neutrophil polymorph inflammatory cell infiltrate ( Fig. 13.26 ). There is no epithelial atypia and viral inclusions are invariably absent. The accentuated papillary dermis between the elongated epidermal ridges contains large numbers of eosinophilic foamy to granular xanthoma cells, which stain positively with lipid stains, but not usually with the diastase–periodic acid-Schiff (PAS) technique ( Fig. 13.27 ). No foreign body or Touton giant cells are present. At the base of the lesion the epidermis may show focal basal cell hydropic degeneration associated with patchy loss of basement membrane. The reticular dermis deep to the lesion often contains a moderately dense lymphocyte–plasma cell infiltrate, which at the edge of the lesion sometimes adopts a lichenoid distribution. Typically, vascular ectasia is seen beneath the lesion, possibly giving support to the lymphedema hypothesis. Oral examples are similar to their cutaneous counterparts, but they lack compact hyperkeratosis.

Older studies showed that the fully formed foamy cells are negative for histiocytic markers including factor XIIIa, Mac 387, Ham-56, and KP1 (CD68) while the incompletely lipidized cells are diffusely positive for KP1 and weakly positive for FXIIIa and keratin. Nonlipidized cells located in the periphery of the infiltrate are diffusely positive for FXIIIa only. This staining pattern has led to the suggestion that FXIIIa-positive dermal dendritic cells in the setting of damaged keratinocytes play an active role in the formation of the lipid cells seen in this condition. The mechanism of keratinocyte damage is not fully elucidated. One theory proposes that the macrophages play an active role in keratinocyte cleavage and keratinolysis with secondary release of epithelial lipid. Macrophage recruitment is postulated to occur as a consequence of CD8-positive T cells present in the submucosa. A more recent study of oral verruciform xanthomas showed diffuse, strong immunoreactivity for CD68 in all of the xanthoma cells and moderate immunoreactivity for CD163 and CD63 regardless of the degree of lipidization.

Ultrastructural studies have revealed histiocytes containing numerous nonmembrane-bound lipid droplets, lysosomes, and myelin figures. Smaller numbers of these lipid inclusions may be found in the overlying keratinocytes and in the intercellular space. In one report, basal melanocytes were found to contain conspicuous lipid droplets. This was accompanied by evidence that the latter had been released into the basal intercellular space in association with disruption of the basal lamina, thereby providing a source for the lipid within the dermal macrophages.

Differential diagnosis

Verruciform xanthoma must be distinguished from viral warts, granular cell tumor, and verrucous carcinoma:

• Viral warts : verruciform xanthoma lacks the vacuolation, clumped keratohyalin granules and tiers of parakeratosis seen in a viral wart. Inclusions are not a feature.

• In granular cell tumor the hyperplastic overlying squamous epithelium often shows an infiltrative growth pattern, in contrast to the exophytic nature of verruciform xanthoma. The granular cells are larger, often have a syncytial appearance, and typically stain positively with the PAS reaction.

• Verrucous carcinoma has both exophytic and endophytic components, the latter appearing as deeply penetrating bulbous epithelial processes. The epithelium often has a ‘watery’ appearance and xanthoma cells are not a feature.

Clinical features

Angiokeratoma corporis diffusum (Anderson-Fabry disease) is a sex-linked recessive disorder of glycosphingolipid metabolism with a high mortality. It is very rare with an approximate incidence of 1 in 200 000. Deficiency of the lysosomal enzyme α-galactosidase A leads to the widespread accumulation of neutral glycolipids, mainly globotriaosylceramide (GB3, ceramide trihexoside), and elevated urinary trihexoxylceramide levels.

Globotriaosylceramide is normally broken down by α-galactosidase A to produce galactose and lactosylceramide. The full-blown syndrome is normally seen only in men, since female carriers have 15% to 40% greater enzyme activity than their male siblings or offspring. Heterozygotes, however, usually display abnormal ophthalmological and ultrastructural features. Occasionally, heterozygous females may manifest signs and symptoms due to extreme X inactivation (lyonization) of the healthy X-chromosome. Cutaneous lesions are believed to occur in about 20% of heterozygous females.

In males, the disease normally presents in childhood as episodes of excruciating intermittent pain, frequently in the fingers and toes. The attacks may be accompanied by fever, edema, and malaise. Patients may also have hypohidrosis, lymphedema, acroparesthesia, and peripheral vasomotor disturbance affecting the heart, kidney, and central nervous system (CNS). Heat intolerance and telangiectases of the ears are often present early in the course of the disease.

The characteristic angiokeratomata develop after puberty and present as tiny red–black bilaterally symmetrical papules, 0.5–2 mm in diameter, with slight hyperkeratosis. Lesions are typically seen in the bathing trunk distribution including the thighs, buttocks, lower back, penis, and scrotum, although occasional lesions may also be seen on the trunk or buccal mucosa ( Figs 13.28 and 13.29 ). The number of angiokeratomata is highly variable. Atypical cases can present with an oligosymptomatic phenotype which includes only very few cutaneous angiokeratomata and asymptomatic involvement of organs such as the kidney and the heart. A female heterozygote with multiple nonkeratotic cutaneous angiomas has also been described. Nonvascular proliferations have been reported in patients with Fabry disease, including polyarteritis nodosa and leg ulcers. Telangiectasias develop in up to one-fourth of affected males. The presence of angiokeratomas and telangiectasias has been correlated with disease severity.

In a patient in whom the diagnosis is suspected, confirmation can usually be obtained by an ophthalmic examination. The conjunctival vessels may be tortuous or aneurysmal, as may the retinal vessels, and slit-lamp examination of the eyes reveals characteristic whorled, corneal linear opacities (verticillate cornea) ( Fig. 13.30 ). Enzyme assay of α-galactosidase A can be performed using peripheral leukocytes or cutaneous fibroblasts. Hair root analysis has been recommended for the detection of heterozygotes.

Affected males can develop transient cerebrovascular accidents, but one of the most common causes of death is renal failure. In the early stages, proteinuria is seen and microscopy of the urinary sediment sometimes reveals characteristic lipid-laden cells even before proteinuria develops ( Fig. 13.31 ). Electron microscopy may reveal the typical inclusions ( Fig. 13.32 ).

Cardiac involvement is found in approximately 20% of patients. Glycosphingolipid deposits in the conducting system, myocardium, endocardium, and valves may give rise to angina, electrocardiographic abnormalities, hypertrophic cardiomyopathy, hypertension, mitral valve incompetence, and aortic medial degeneration. Cardiovascular disease was found to be the most common cause of death in patients in a study of the Fabry registry, but cardiovascular outcomes are linked to coexisting severe chronic renal disease.

Oral and dental abnormalities are more common than previously realized and include the presence of cysts/pseudocysts of the maxillary sinuses and maxillary prognathism.

Pathogenesis and histologic features

A variety of genetic defects has been identified including point mutations, gene rearrangements, and deletions resulting in defects of α-galactosidase A. However, rare patients with angiokeratoma corporis diffusum but without detectable mutation in the α-galactosidase gene have been described. Patients with Fabry disease have elevated serum levels of vascular endothelial growth factor (VEGF-a), which could account for the vascular proliferation seen in this disease.

The skin lesions are composed of ectatic blood-filled vessels in the papillary dermis, associated with slight hyperkeratosis ( Figs 13.33 and 13.34 ). A characteristic feature is vacuolation of endothelial cells due to lipid deposits. The latter are doubly refractile and can usually be demonstrated in frozen material tissue sections. They may also be identified in toluidine blue-stained material. On electron microscopy, lamellar electron-dense inclusion bodies are present within endothelial cells, pericytes, smooth muscle cells, fibroblasts, sweat gland epithelium, and macrophages. It is believed that these are due to lipid deposition within lysosomes ( Fig. 13.35 ). Lamellar bodies have also been identified in the endothelial cells of affected vessels with polyarteritis nodosa in a patient with Fabry disease.

Differential diagnosis

Other forms of angiokeratomata, for example those of Mibelli or Fordyce, should be clinically distinguishable by their site and distribution although their histopathological appearances are identical. It should be noted, however, that diffuse angiokeratomata may also be seen in fucosidosis, α-galactosidosis, sialidosis, aspartylglycosaminuria, α-N-acetylgalactosaminidase deficiency (Kanzaki disease), human beta-mannosidosis, adult-onset GM1 gangliosidosis, and indeed, diffuse angiokeratomata of a benign type may occur in patients with normal enzyme activities. Widespread angiokeratomata have also been described as an exceptional finding in tuberous sclerosis and in a patient with Hodgkin lymphoma as a possible paraneoplastic syndrome.

Clinical features

Primary and myeloma-associated systemic amyloidoses predominantly affect the elderly (mean onset at 65 years of age) and show a slight predilection for males. Up to 15% of patients with myeloma have coexisting primary amyloidosis. Occasional patients present with primary systemic amyloidosis and only develop multiple myeloma later.

The early clinical changes, which are often mild, non-specific, and very difficult to diagnose, include weight loss, hoarseness, dyspnea, fatigue, paresthesia, and lightheadedness. Subsequently, the most frequent features are development of the carpal tunnel syndrome and edema due to renal and cardiac involvement. Bilateral carpal tunnel syndrome may be the first symptom of the disease.

The commonest cutaneous manifestation is hemorrhage (purpura, petechiae, and frank ecchymoses) due to deposition of amyloid within blood vessel walls, with resultant fragility ( Figs 13.39–13.42 ). It occurs most typically on the hands (often posttraumatic) and around the eyes, when the purpura may follow proctoscopy or vomiting ( Fig. 13.43 ). Lesions are sometimes also evident in the nasolabial folds, the neck, axillae, umbilicus, anogenital region, and within the oral cavity. Prominent hemorrhagic bullae may be present. Rarely, systemic amyloidosis presents with solitary vulval lesions which may mimic a condyloma acuminatum.

Blistering is sometimes an additional feature, which occurs due to cleavage developing within the amyloid deposits as a consequence of shearing stresses. The blisters are often hemorrhagic, and occur most often on the tongue, buccal or labial mucosa although they may be more widespread and thus mimic those of bullous pemphigoid. Blisters can sometimes arise on the dorsal surfaces of the hands and fingers and the extensor aspect of the forearms and epidermolysis bullosa acquisita then enters the differential diagnosis ( Fig. 13.44 ). Healed lesions are sometimes associated with the development of milia. Bullous amyloidosis most often develops in patients with systemic disease, particularly myeloma associated. Rarely, however, it may complicate primary cutaneous amyloidosis. Rare cases present an elastolytic appearance and development of cordlike indurations associated with intermittent claudication. Prominent perivascular deposition of amyloid has been documented in these patients.

In more advanced cases, waxy, smooth, shiny papules, plaques, and even nodules develop. Cystic nodular lesions have also been reported. The papules are skin-colored or yellow and have a dome-shaped appearance. They are found predominantly on the face (especially the eyelids), head and neck, axillae, umbilicus, inguinal region, and the perineum. In severely affected patients the clinical appearances with taut skin, particularly affecting the face, hands, and digits, may mimic scleroderma. Alopecia and nail dystrophy are sometimes evident ( Fig. 13.45 ). Chronic paronychia, palmodigital erythematous swelling, and induration of the hands have been described. The presence of these features in conjunction with macroglossia and the carpal tunnel syndrome is highly suggestive of primary or myeloma-associated systemic amyloidosis ( Fig. 13.46 ). In addition to macroglossia, the tongue may be covered with waxy papules, nodules, and plaques and occasionally it is ulcerated or fissured. As a consequence, speaking and swallowing difficulties are not infrequently encountered. The sicca syndrome may also be a manifestation of primary systemic amyloidosis. Exceptionally, association with normolipemic xanthoma has also been documented.

Hepatomegaly is found in about 50% of cases and there may also be evidence of cardiomyopathy with arrhythmia or heart failure, peripheral neuropathy, and renal failure or the nephrotic syndrome. Splenomegaly is a feature in less than 10% of cases. Intestinal involvement can lead to malabsorption or an ulcerative colitis-like picture, sometimes with hemorrhage. Pseudo-obstruction, diarrhea, and constipation can also occur. There is no effective treatment for systemic primary amyloidosis and the prognosis is therefore grave. Mortality relates primarily to cardiac and renal involvement.

Histologic features

Masses of eosinophilic, amorphous, fissured material are present in the dermis and subcutaneous tissues. The overlying epidermis is often stretched and flattened, but – in contrast to the macular and lichenoid variants – shows no evidence of amyloid deposition. In mild cases the changes may be limited to the perivascular tissues, but in more extensive disease large aggregates are usually evident. Involvement of blood vessel walls, arrector pili muscles, skin adnexa, and subcutaneous fat (amyloid rings) is frequently present ( Figs 13.47 and 13.48 ). Amyloid deposits around the pilosebaceous units may be accompanied by follicular atrophy with resultant hair loss. There is usually little secondary inflammatory cell infiltration.

In those cases associated with blistering, the vesicle appears in an intradermal or less commonly subepidermal location. The dermis, in addition to showing amyloid deposits, often in association with blood vessel walls, also shows a fragmented appearance due to the presence of cleft like spaces. Purpura is frequently marked.

Clinically normal skin shows histologic evidence of amyloid deposition in up to 50% of patients.

An exceptional case of reactive eccrine syringofibroadenomatosis secondary to primary cutaneous amyloidosis has been reported.

Clinical features

This variant of amyloidosis, induced by beta-2-microglobulin, occurs in patients on long-term hemodialysis. Exceptionally, cases may present after short-term hemodialysis. The most commonly involved organs are the heart, gastrointestinal tract, and lungs. Interestingly, the disease does not seem to involve the spleen. Carpal tunnel syndrome, polyarthralgia, and destructive spondyloarthropathy have also been documented. The walls of blood vessels are often involved, whereas bone lesions are relatively rare, although pathological fractures may occur. Cutaneous involvement, which is very uncommon, has been reported to present as subcutaneous masses in the buttocks and shoulder, lichenoid papules and a wrinkled appearance of the skin of the palmar aspect of the fingers. Rare cases of amyloidoma of the tongue and external auditory canal have been reported.

Histologic features

In cases with skin involvement, the amyloid deposits have been found either in the subcutaneous tissue or in the papillary and reticular dermis, around sweat glands and hair follicles. Occasionally, special stains are unhelpful in demonstrating amyloid and confirmation of the diagnosis by electron microscopy or, mass spectroscopy can confirm the diagnosis.

Familial Mediterranean fever

Pathogenesis and histologic features

Familial Mediterranean fever is cause by mutations in MEFV on chromosome 16p13 , a gene that encodes pyrin, a protein involved in deactivating the immune response. Defects in pyrin lead to over production of interleukin-1, resulting in a proinflammatory state contributing to the formation of amyloid. In familial Mediterranean fever, a serum precursor protein forms the amyloid in this condition. This precursor is a HDL known as serum amyloid A.

The erysipelas-like lesions are characterized by a perivascular mixed infiltrate of lymphocytes, histiocytes, and neutrophils with leukocytoclasia. Vasculitis is not seen, although on direct immunofluorescence perivascular C3 and, less consistently IgM and fibrinogen, have been reported. However, as noted above, leukocytoclastic vasculitis may be seen in this disease.

Familial amyloidotic polyneuropathy

Histologic features

Histologically, biopsies from clinically normal skin reveal the presence of amyloid in blood vessel walls, sweat glands, and arrector pili muscle.

Clinical features

Amyloid elastosis is a very rare disease, characterized by cutaneous deposits of amyloid in association with elastic fibers of the skin. Only a handful of cases have been reported to date, all in the setting of systemic amyloidosis, except for one in the setting of primary cutaneous amyloidosis. The clinical manifestations are variable. Most have skin-colored to yellow cobblestoned papules and plaques. Some patients had a pseudoxanthoma-like lesions on the neck and/or intertriginous areas. One patient had widespread skin-colored papules and a whitish cobblestone plaque around the urethral meatus. Some patients had cordlike thickening of superficial blood vessels, livedo reticularis-like changes on the trunk, Raynaud phenomenon, venous and arterial thrombosis, and the nephrotic syndrome. The patient with primary cutaneous amyloidosis presented a plaque with prominent skin folds and peripheral erythema involving his left axilla. The causes of the systemic amyloidosis included lambda light chain paraprotein and myeloma.

Histologic features

Amyloid is seen in the dermis, around adnexal structures, surrounding elastic fibers, sometimes forming small globules, and in blood vessel walls, together with striking deposits in the dermal, subcutaneous, and serosal elastic tissue.

Clinical features

Lichen and macular amyloidoses (skin-limited amyloidoses) represent different manifestations of the same process and both entities may coexist (biphasic amyloidosis) or one may transform into the other. A large study of primary localized cutaneous amyloidosis found that 67% of cases represented lichen amyloidosis, 8% macular amyloidosis, and 25% biphasic variants. Although most cases are sporadic, up to 10% of patients demonstrate an autosomal dominant inheritance pattern (see familial primary cutaneous amyloidosis ).

Macular primary cutaneous amyloidosis.

This is most commonly seen in patients from the Middle East, Asia, and Central and South America. It affects females more often than males (3 : 1), is seen in younger age groups, and is usually a chronic condition. Patients present with a macular, dark brown or grayish, symmetrical pigmentation, which occurs most frequently on the upper chest and back, although the extremities and face may also be affected ( Fig. 13.49 ). The lesions sometimes have a very characteristic reticulated or rippled appearance, which can be quite subtle, and they are usually moderately pruritic ( Fig. 13.50 ). More commonly, however, macular amyloid appears as small, 2–3 mm diameter lesions or else as confluent macular foci, which sometimes have superimposed micropapules. Lesions sometimes follow Blaschko lines, resembling incontinentia pigmenti. Exceptionally, widespread diffuse pigmentation occurs. Predominantly hypopigmented macules have been described, mimicking guttate morphea and vitiligo.

Papular or lichen amyloidosis.

In papular or lichen amyloidosis, discrete papules and/or plaques occur, which are often scaly, persistent, and pigmented ( Fig. 13.51 ). They are usually severely pruritic. Excoriations, lichenification, and nodular prurigo-like lesions due to chronic scratching are sometimes evident. Lesions are especially common on the front of the shins and extensor aspect of the forearms ( Figs 13.52 and 13.53 ). The calves, ankles, dorsa of the feet, thighs, and trunk may also be affected. Presentation is most often in young adults. The sex incidence is equal. Lichen amyloidosis shows a predilection for the Chinese race and familial cases have been recorded. An association with Epstein-Barr virus infection has been reported in a single case, but this was not confirmed in a larger study.

Association with systemic disease is probably coincidental but there have been a number of cases described with progressive systemic sclerosis.

Other primary cutaneous amyloidoses.

These include anosacral and poikilodermatous variants:

• Anosacral amyloidosis presents as scaly hyperpigmented macules and lichenoid papules spreading out from the perianal skin. It is seen in patients from Japan and China and is very rare. The disease may present early in life and its cause has not been established, although a relationship to keratinocyte apoptosis has been suggested. Clinically, lesions can be confused with lichen simplex chronicus, a dermatophyte infection or even postinflammatory hyperpigmentation.

• Poikiloderma-like cutaneous amyloidosis is an extremely rare manifestation of localized cutaneous amyloidosis. Patients present with poikilodermatous skin lesions and lichenoid papules. It may be associated with photosensitivity, short stature, and palmoplantar keratoderma. Blisters are rarely seen. The condition presents early in life or in young adults. Confusion with other conditions associated with poikiloderma, including poikiloderma atrophicans vasculare, is possible. A single case of poikiloderma-like amyloidosis associated with lichen, dyschromic, and bullous variants has been described.

Pathogenesis and histologic features

Chronic irritation to the skin has been proposed as the cause of amyloid deposition in the macular and lichenoid variants, although this has never been proven. The documentation, however, of friction amyloidosis due to nylon brush skin massage and towels does offer some support to this hypothesis. It may be that chronic trauma in a susceptible or ‘primed’ individual may be associated with an increased risk of developing cutaneous amyloidosis. It has been suggested that amyloid deposition in lichen amyloidosis is a consequence of scratching, as pruritus tends to be the presenting symptom even before amyloid is detected in skin biopsies. The chronic damage to the epidermis induces apoptosis of keratinocytes and this leads to amyloid deposition in the papillary dermis. A similar mechanism has been proposed in notalgia paresthetica. This is a condition characterized by pruritus, a burning sensation, and paresthesia or hyperesthesia in an area of the back between dermatomes D2 and D6. The resultant irritation and scratching induce cutaneous hyperpigmentation and amyloid deposition. It has even been suggested that the cutaneous amyloidosis observed in patients with multiple endocrine neoplasia type 2A is secondary to notalgia paresthetica (see below).

In both variants the amyloid is deposited high in the papillary dermis, often immediately adjacent to the epidermis.

In the macular type, the amount of amyloid present is often very small and focally distributed. It frequently has a faceted appearance ( Figs 13.54–13.56 ). Special stains and/or immunocytochemistry are sometimes necessary as the deposits can easily be missed. Intraepidermal cytoid bodies are present in about 33% of cases. Typically, there is associated pigmentary incontinence, but only minor epidermal changes of hyperkeratosis and acanthosis are generally evident. Melanin pigment may be present in the stratum corneum. A slight perivascular chronic inflammatory cell infiltrate is often found in the superficial dermis. Mild vacuolar interface alteration can be present.

In papular or lichen amyloidosis, the histopathological changes are similar and cannot be reliably distinguished from those of the macular variant, except that the quantities deposited are greater and there is often more marked epidermal acanthosis, hypergranulosis, and hyperkeratosis. Basal cell hydropic degeneration may be evident and colloid bodies are usually visible ( Figs 13.57 and 13.58 ). Satellite cell necrosis is sometimes a feature. A superficial perivascular chronic inflammatory cell infiltrate is typically present.

When special stains fail to demonstrate the presence of amyloid, ultrastructural studies are usually successful in detecting the presence of the protein.

In contrast to skin involvement in systemic disease, blood vessel deposits are not a feature of primary cutaneous localized lesions.

In earlier literature it was postulated that the amyloid might have been derived from mast cells or fibroblasts. The application of newer technology, however, has shown that it is indisputably of keratinocyte derivation, and amyloid deposits have been shown to contain disulfide bonds and bullous pemphigoid antigen. Numerous recent publications confirm the presence of epidermal keratin in the deposits in both macular and lichenoid forms using monoclonal immunocytochemistry. The amyloid of the skin-limited variants, so-called amyloid-K, has been shown to contain 50 and 67 kD keratin filaments. Apolipoprotein E, one of the proteins found in the amyloid plaque of Alzheimer disease and in systemic amyloidosis, has also been demonstrated in the amyloid present in localized cutaneous amyloidosis. Electron microscopic studies have provided further evidence that amyloid-K is of keratinocyte origin by showing tonofilament filamentous (apoptotic) degeneration into amyloid filaments both within the epidermis and in the immediately adjacent dermis. Under normal circumstances, apoptotic keratinocytes (cytoid bodies) are either shed as a consequence of epidermal upward migration or are released into the dermis where they are removed by an inflammatory response as is seen, for example, in lichen planus. In macular and lichenoid cutaneous amyloidosis it appears that the above disposal mechanism is either overwhelmed or nonfunctioning.

Early ultrastructural changes consist of loss of tonofilament electron density and development of a wavy morphology accompanied by internalization of desmosomes, thickening of the keratinocyte cell membrane, and the acquisition of hemidesmosome-like attachments to neighboring cells. Cytoplasmic and nuclear remnants are frequently present in the more superficial deposits. It is thought that on entering the dermis, fibroblasts and macrophages convert the degenerate keratin into amyloid filaments ( Fig. 13.59 ). The precise mechanism is unknown, but it must involve the conversion of the normal alpha tertiary structure of tonofilaments into the beta-pleated configuration of amyloid. The filaments of amyloid and cytoid bodies show ultrastructural differences. Amyloid fibrils are irregularly distributed whereas the filaments in cytoid bodies are arranged in bundles or whorls.

It is postulated that the development of localized cutaneous amyloidosis is dependent upon mild chronic trauma resulting in excessive production of cytoid bodies and their subsequent conversion into amyloid deposits. It would seem that despite a normal humoral response as shown by the presence of IgM and IgG in association with complement fixation, the normal cellular response whereby apoptotic keratinocytes are removed is lacking.

Amyloid deposits are frequently found in intimate association with dermal elastic fibers and the deposits in macular amyloidosis have been shown to contain fibrillin. Whether this is of pathogenetic significance or is merely a secondary phenomenon is uncertain.

The apoptotic theory of amyloidogenesis in the cutaneous variants has, however, been challenged. On the basis of finding amyloid deposits immediately below the basal keratinocyte, separating its cell membrane from the lamina densa in the absence of any evidence of filamentous degeneration, it has been suggested that cutaneous amyloid deposits may also be a direct secretory product of keratinocytes. It could be that both mechanisms are in operation.

Clinical features

In this rare variant, which is more common in females, pink–brown single or multiple nodules develop on the trunk, extremities, genitalia, face or scalp ( Fig. 13.61 ). Bilateral nodular amyloidosis of the eyelids in the absence of systemic amyloidosis has rarely been documented. The lesions often have a waxy appearance and the surface may be atrophic or ulcerated. Most cases of nodular amyloidosis are limited to skin and only 7% show progression to systemic amyloidosis. Occasional reports have documented monoclonal paraproteinemia, lymphoplasmacytoid lymphoma, marginal zone lymphoma, Sjögren syndrome, proteinuria, bone marrow abnormalities, and a positive rectal biopsy. It has also been reported in association with psoriasis, eczema, and cirrhosis. Nodular cutaneous amyloidosis has also been described in association with carpal tunnel syndrome induced by the amyloidogenic transthyretin His 114 variant. An unusual variant of nodular amyloidosis with bilateral plantar involvement is very occasionally encountered.

Histologic features

The histologic appearances cannot be distinguished from those of systemic amyloidosis and, indeed, as in primary amyloidosis, the amyloid consists of light chain-derived AL protein. It is thought likely that this nodular variant results from local production of light chains by a localized group of plasma cells. PCR studies have demonstrated that the infiltrating plasma cells in cases of nodular amyloidosis are usually monoclonal. Polyclonality, however, has also been reported. In all patients with nodular amyloidosis, it is important to exclude systemic disease. A rare case of nodular amyloidosis secondary to keratin derived amyloid has been described.

The deposits of amyloid are present in both the papillary and reticular dermis and may involve the subcutaneous fat ( Figs 13.62–13.64 ). Sometimes the vasculature and nerve sheaths are affected ( Figs 13.65–13.67 ). Characteristically, plasma cells are seen around blood vessels and at the margin of the amyloid deposits ( Fig. 13.68 ). Rarely, an associated foreign body giant cell reaction with phagocytosis of amyloid and/or calcification are evident.

Clinical features

The juvenile variant, which is exceedingly rare, develops in children before puberty and sometimes has a familial incidence. Patients present with discrete, or sometimes confluent, papules measuring 0.2–1.5 cm in diameter. An unusual periocular and perioral linear pattern has been reported. Lesions, which are yellow–brown in color, appear translucent and when punctured characteristically express gelatinous material. The underlying tissues often feel indurated. Juvenile colloid milium predominantly affects the face, in particular the cheeks, nose, and around the mouth ( Figs 13.69–13.71 ). Induction of purpura after stroking has been described in both juvenile and adult colloid milium. This phenomenon has been attributed to vascular fragility due to infiltration of the blood vessel walls by colloid material. Exceptionally, juvenile colloid milia may present with gingival deposits and ligneous conjunctivitis as a result of infiltration of these tissues by colloid-like material.

Pathogenesis and histologic features

Although the etiology remains unknown, in some cases at least, sunlight plays an important role. The pathogenesis, however, shows considerable overlap with macular and lichenoid amyloidosis. Juvenile colloid milium represents a primary degenerative disorder of epidermal keratinocytes, which through the process of apoptosis are transformed into colloid bodies within the superficial dermis.

The initial change is one of filamentous transformation whereby the relatively straight electron-dense keratin filaments are converted into shortened, curved 8–10 nm filaments arranged in weaved or whorled fascicles ( Fig. 13.72 ). Occasionally, both types of filament may be identified simultaneously within the cytoplasm of basal keratinocytes. With progression, filamentous transformation comes to affect the entire cell, and nuclear, cytoplasmic, and desmosomal remnants may be identified within the filamentous mass ( Fig. 13.73 ). Residual desmosomes are sometimes present around the border of the colloid deposit. Finally, the apoptotic cell is extruded into the adjacent dermis. In addition to the transformed filaments characteristic of all cytoid bodies, amyloid filaments have also been identified in juvenile colloid milium, thereby prompting the authors to classify this entity along with other amyloid-K dermatoses. Positive labeling of the deposits for epidermal keratin gives support to this hypothesis.

Juvenile colloid milium has also been shown by direct immunofluorescence to be accompanied by immunoglobulin, complement, and fibrin deposits. Whether this represents an autoimmune-mediated reaction as is seen in macular-lichenoid amyloidosis or a secondary non-specific reactive phenomenon has yet to be determined.

Histologically, the deposits are present in the superficial dermis where they impinge on the overlying and often somewhat frayed epidermis ( Figs 13.74–13.77 ). The colloid is composed of eosinophilic amorphous aggregates, often showing a fractured appearance. The overlying epithelium shows prominent cytoid bodies, while laterally, acanthosis associated with downward and inward growth results in cuffing or even encirclement of the colloid islands by an epidermal collarette. An admixture of fibroblasts and mast cells may be evident and pigmentary incontinence is sometimes present. Juvenile colloid milium is histochemically indistinguishable from amyloid: it is diastase-resistant, PAS positive, thioflavine-T positive, and shows positive staining with Congo red with apple-green birefringence.

Clinical features

This variant, which is much commoner than the childhood form, affects middle-aged patients and shows a predilection for males. Outdoor workers are most often affected and lesions seen on sun-exposed skin are often accompanied by the features of solar elastosis, giving rise to the synonym of papular elastosis.

Adult colloid milium presents as dome-shaped yellowish translucent papules measuring 0.1–0.5 cm in diameter and, in common with juvenile colloid milium, they contain gelatinous material. Lesions are most often seen on the face, ears, neck, and the dorsum of the hands ( Fig. 13.78 ) and may be skin-colored to brown. Adult colloid milium affects fair-skinned patients and follows excessive sun exposure. This has been dramatically illustrated in patients whose lesions are limited to sun-exposed areas of the body. Adult colloid milium has also been reported following the excessive use of cosmetic ultraviolet A (UVA) sunbed exposure. A rare association with multiple myeloma has been described. A further report described a patient who developed lesions of adult colloid milia in areas exposed to mineral oils. A single case has also been described in a patient with beta thalassemia major. Rare cases of pigmented colloid milium have been documented as a consequence of exogenous ochronosis due to bleaching creams and fertilizers.

Pathogenesis and histologic features

In contrast to the keratinocyte changes seen in the juvenile variant, adult colloid milium represents an extreme degree of actinic damage centered upon the upper dermal elastic fibers. Although earlier studies suggested that the colloid might have represented abnormal collagen or a fibroblast secretory product, more recent studies suggest that it derives from actinic elastoid.

Ultrastructural studies have shown that there is direct continuity between actinic elastoid and the colloid deposits and that, within the electron-dense colloid, remnants of both normal and elastotic fibers may sometimes be identified. Amyloid filaments are not present. Further support for this hypothesis is given by the identification of SAP component within the colloid deposits. Although this protein is characteristically present within amyloid, it is also a constant component of normal elastic tissue and has also been identified in actinic elastoid. Adult colloid milium does not label with antikeratin antibodies, and immunoglobulins and complement are absent.

Histologically, the eosinophilic amorphous, autofluorescent clefted deposits are typically separated from the epidermis by a grenz zone containing normal collagen ( Figs 13.79 and 13.80 ). Fibroblasts often occupy the fissures between the fragmented deposits.

Histochemically, adult colloid milium is diastase-resistant, PAS positive, thioflavine-T positive, and demonstrates apple-green birefringence with Congo red. It is also Dylon positive. Colloid milium can be difficult to distinguish from amyloidosis, and electron microscopy may be necessary.

Clinical features

Hyalinosis cutis et mucosae (Urbach-Wiethe disease, lipoid proteinosis), is a very rare, autosomal recessive condition first described in 1929 in which hyaline material is deposited in virtually any organ in the body, but particularly the skin, the pharyngeal mucosa, and the larynx. It has been reported most frequently in South Africa (descendants of German and Dutch immigrants) and Sweden, and it has been suggested that up to 35% of documented cases have had South African lineage.

The gene for lipoid proteinosis has been mapped to chromosome 1q21 and the disease is caused by mutations in the extracellular matrix protein 1 gene ( ECM1 ) which lead to partial or complete loss of function of the protein. ECM1 is thought to play a critical role in dermal structure and organization by binding to dermal ground substance (molecules such as perlecan and matrix metalloproteinases), in the formation and maintenance of the basement membrane, and in stromal signaling. It has been called ‘biological super-glue’. It is also overexpressed in cancers, influencing tumor growth and metastasis. Over 40 different mutations in this gene have been reported in association with lipoid proteinosis, and studies thus far have not demonstrated a relationship between the specific type of mutation and clinical phenotype. Interestingly, patients with lichen sclerosus have autoantibodies to ECM1.

The initial symptom, a hoarse cry, develops in infancy and results from incomplete closure of the vocal cords, which are thickened and irregular due to the hyaline deposits. Induration of the oral mucosa (including the inner aspect of the lips, the gingivae, uvula, palate, and floor of the mouth) begins in childhood and is progressive, so that adults have extensive yellow infiltration ( Fig. 13.81 ). The lower lip often assumes a cobblestone appearance. The tongue also tends to be thick and immobile with sublingual frenulum thickening and ankyloglossia. Recurrent ulcers on the tongue have been described. Nail growth is frequently abnormal and the upper incisors, premolars or molars can be hypoplastic or aplastic.

Early inflammatory skin lesions (bullae, pustules, and crusts) are followed by acneiform infiltrated scars on the face and limbs ( Fig. 13.82 ). Papulonodular lesions develop on the face, fingers, and around the eyelashes, where they produce the pathognomonic ‘string of beads’ appearance (moniliform blepharosis) ( Fig. 13.83 ). Thicker xanthoma-like plaques, which sometimes become verrucous, later develop on the areas of trauma including the knees, elbows, feet, and hands. With chronicity in severely affected patients the entire skin becomes yellow, waxy, and thickened, particularly the flexures. Similar lesions in the scalp may produce alopecia, which can be patchy or diffuse.

Intracranial disease sometimes occurs, associated with calcification, which is thought to complicate deposition of hyaline material around cerebral blood vessels and basal ganglia. Epilepsy is a not uncommon result. Other neurological manifestations include memory loss, rage attacks, and mild mental retardation.

Involvement of the small bowel by the disease may lead to intestinal bleeding.

The disease is usually associated with normal life expectancy although there might be some increase in the mortality rate during childhood due to respiratory insufficiency.

Pathogenesis and histologic features

The epidermis is acanthotic and occasionally papillomatous, with overlying hyperkeratosis. Homogeneous eosinophilic material is distributed in a very characteristic pattern in the dermis. Initially, it is found around capillaries and concentrically around sweat coils ( Figs 13.84 and 13.85 ); later, more extensive deposits are seen, which tend to be vertically orientated within the dermis. The hair follicles and arrector pili muscles are often surrounded by a hyaline mantle. In advanced cases, the perineurium of nerves can also be affected. This material stains very strongly with PAS (diastase-resistant) and only very weakly with Congo red and thioflavine-T ( Fig. 13.86 ). The name lipoid is used because the hyaline material usually has a lipid component.

Ultrastructurally, the deposit is amorphous, electron-dense, and may contain ill-defined, anastomosing amyloid-like (5–10 nm) filaments and delicate collagen fibers ( Figs 13.87 and 13.88 ). Reduplication of basal lamina is evident around blood vessels, hair follicles, and sweat glands, and excess type IV collagen has been demonstrated immunohistochemically. The fibroblasts contain abundant rough endoplasmic reticulum and numerous mitochondria. Intracytoplasmic inclusions, probably lysosomal in nature, have also been described.

The etiology of bullous lesions in lipoid proteinosis is unclear. A recent report sheds light on a possible pathogenesis. It describes subcorneal and intraepidermal acantholysis without dyskeratosis in a child with lipoid proteinosis. Subepidermal clefting was also noted but thought to be artifactual. Direct immunofluorescence studies were negative.

Despite considerable research, the precise pathogenesis of lipoid proteinosis remains an enigma. Quantitative abnormalities of dermal collagen have been clearly demonstrated, but little is known about the nature of the hyaline deposits other than that they are probably composed of an admixture of glycoproteins, glycosaminoglycans, and lipids, as may be determined by special staining techniques.

Numerous mechanisms have been hypothesized, but none has satisfactorily unraveled the nature of the primary disturbance in this disease. The identification of lipid droplets within the hyaline deposits therefore led to the suggestion that lipoid proteinosis might represent a systemic lipoidosis. However, the lipid deposition is very variable and lesional chemical analyses have not demonstrated any consistent abnormalities. Fibroblast tissue culture experiments have not supported this concept. It probably denotes a secondary phenomenon. The ultrastructural finding of intracytoplasmic inclusions – including myelin figures and lysosomes accompanied by an increased fibroblast hexuronic acid content – has raised the possibility of a lysosomal storage disorder. This has recently been given further support by the demonstration of abnormal lysosomes in eccrine cells and histiocytes in two patients with this disease. These lysosomes were found to contain amorphous granular material, zebra bodies, and curved tubular profiles. The curved tubular profiles are similar to those found in Farber disease and it has been suggested that lipoid proteinosis represents a disease with not only impaired production of collagen but also with alterations in ceramide metabolism.

A number of publications have described a variety of changes in the dermal collagen content. The reduplicated basement membrane laminae noted ultrastructurally have been shown to be composed of laminin accompanied by collagen types III and IV. This feature, however, is of doubtful significance as similar appearances have been described in a wide variety of conditions including psoriasis, systemic lupus erythematosus, and diabetes mellitus. Basement membrane replication most likely represents a non-specific secondary response to a range of stimuli.

Dry weight studies of lipoid proteinosis dermis have shown an apparent decrease in collagen content, although there appears to be a relative increase in collagen types III and V compared with collagen type I. Immunofluorescence data, however, suggest that there are reduced absolute levels of both type I and type III collagen. In vitro studies of fibroblast collagen synthesis, as determined by radioactive hydroxyproline synthesis, have revealed no significant abnormality. Fibroblasts, however, have reduced replicative capacity. Investigations have disclosed reduced fibroblast type I procollagen mRNA and a diminished type I:III procollagen mRNA ratio. Type IV procollagen mRNA levels have been shown to be raised. No DNA abnormalities or chromosomal alternations have yet been identified in lipoid proteinosis.

It is likely that the collagen changes are not directly responsible for the accumulation of the granular hyaline material so characteristic of this disorder. It is, however, most probably of fibroblast derivation.

Clinical features

Cutaneous macroglobulinosis (IgM storage papules) is a rarely documented manifestation of Waldenström macroglobulinemia. The latter is a chronic lymphoproliferative condition that typically presents in the fifth and sixth decades and shows a slight predilection for males. It is characterized by proliferation of lymphoplasmacytoid cells in the bone marrow, lymph node, and spleen and IgM paraproteinemia. Patients present with weakness, fatigue, weight loss, anemia, mucous membrane bleeding, retinal hemorrhages, lymphadenopathy, hepatosplenomegaly, peripheral neuropathy, and the hyperviscosity syndrome. Skin involvement is very uncommon and includes papules, nodules, tumors, plaques, and macroglobulinosis cutis. Additional features that are sometimes encountered include purpura, xanthomata, cryoglobulinemia, and Raynaud phenomenon.

Clinically, macroglobulinosis presents as sometimes pruritic, skin-colored, erythematous or translucent papules measuring up to 1.0 cm in diameter distributed predominantly on extensor sites including knees, elbows, buttocks, and the arms and legs. Umbilication, erosion, and crusting and hyperkeratosis are commonly seen. Cutaneous tumor deposits present as violaceous nodules and plaques.

Histologic features

The papules are characterized by homogeneous eosinophilic material in the papillary and reticular dermis ( Fig. 13.89 ). Hair follicles and eccrine glands may be encased. The deposits are PAS positive but are Congo red negative ( Fig. 13.90 ). Vessels may also show occlusion by the same material. A lymphoplasmacytoid infiltrate is variably present. The plasma cells may contain intracytoplasmic IgM-rich vacuoles.

Direct immunofluorescence and immunohistochemistry show that the deposits stain strongly for IgM.

Ultrastructurally, the deposits are composed of amorphous or granular and sometimes filamentous material which by immunoelectron microscopy consists of IgM. The periodicity of amyloid is absent in the filamentous component.

The plaques and tumor nodules are composed of lymphoplasmacytoid infiltrates.

Clinical features

Congenital erythropoietic porphyria (Gunther disease) is the most severe and mutilating of the erythropoietic porphyrias. It is inherited as an autosomal recessive and develops as a consequence of deficiency of the fourth enzyme of the heme pathway (uroporphyrinogen III synthase) resulting in excessive production of uroporphyrin I and coproporphyrin I, which give the urine a pink–burgundy color. Patients with the more severe form of the disease may present with fetal hydrops. The diapers of affected children usually show a characteristic pink stain. Uroporphyrin I accumulates in the bone marrow, peripheral blood, and other organs. It has been demonstrated that there is a clear correlation between the degree of porphyrin excess and disease severity. There is increased production of uroporphyrins and coproporphyrins in the urine and coproporphyrins in the feces.

Affected patients develop intense photosensitivity to sunlight as well as to fluorescent light, typically in infancy ( Fig. 13.92 ). Symptoms include painful and pruritic erythema and swelling, which occurs within minutes of sun exposure. Vesicles and bullae are supervened by a mutilating scarring process on the face and hands, where autoamputation may occur ( Figs 13.93 and 13.94 ). A rare case of metastatic squamous cell carcinoma has been reported in an amputation stump. Sclerodermoid change is sometimes seen. A case resembling pseudoxanthoma elasticum (PXE) has also been reported. Coarse hair may be found on the face, and lanugo hair develops on the limbs. Pigmentary changes are sometimes evident. In addition, patients develop cicatricial alopecia of the scalp, nail changes, conjunctivitis, ectropion, keratoconjunctivitis, symblepharon, blepharitis, necrotizing scleritis, or brown staining of the teeth (erythrodontia). The teeth characteristically fluoresce intense orange–red with Wood light (400 nm). The sclera also demonstrates pink fluorescence under Wood light.

Hemolytic anemia and splenomegaly occur in a large proportion of the patients and hypersplenism is sometimes a feature. Patients with congenital erythropoietic porphyria have an increased risk of bone fragility with resultant fractures and developmental defects. Acro-osteolysis, soft tissue calcifications, and widening of the diploic space have also been documented. Early death may result, often in the third decade. Rare cases are associated with the nephrotic syndrome, probably secondary to renal siderosis. A delayed late-onset variant has rarely been described. Some of these patients present with thrombocytopenia and others with myelodysplasia.

The URO-synthase gene has been mapped to chromosome 10q25.3-q26. The molecular defects in this disease are very heterogeneous and greater than 38 mutations in the URO-synthase gene have already been described. These include single base substitutions, insertions and deletions, and splicing defects. By far the most common mutation is C73R, which has been found in up to 40% of patients with the disease. Two other relatively common mutations include L4F and T228M, seen in 8% and 7% of patients, respectively. Prenatal diagnosis of the disease is possible not only by measurement of uroporphyrin I levels in amniotic fluid, but also by DNA mutation analysis.

Clinical features

Although this condition was not recognized until 1961, it is now known to be the second commonest type of porphyria. It results from increased production of protoporphyrin due to diminished ferrochelatase (heme synthase) activity. Ferrochelatase is the enzyme responsible for the combination between protoporphyrin IX and iron to form heme. Urinary porphyrins are normal because protoporphyrins are insoluble in water. Protoporphyrin is elevated in plasma, erythrocytes, and occasionally in the feces. Coproporphyrins may be found in erythrocytes and feces. The mode of inheritance is predominantly autosomal dominant with incomplete penetrance although an autosomal recessive inheritance has also rarely been reported. The gene for ferrochelatase has been mapped to the long arm of chromosome 18 (18q21.3). A less common genetic variant is the X-linked dominant form caused by a gain of function mutation in erythroid-specific 5-aminolevulinate synthase on the X-chromosome. This form appears to be more common in North Africa.

The variable clinical manifestations of this disease are probably the result of heterogeneity of the ferrochelatase gene defects. Acute photosensitivity usually presents in early childhood. A painful burning erythema with edema occurs immediately after exposure to sunlight. Petechiae can occur, particularly with prolonged exposure. Vesicles are uncommon, but a scaly, erythematous reaction may be seen, leading to circular or linear depressed scars on the face (particularly on the bridge of the nose and around the mouth) and over the knuckles ( Figs 13.95–13.99 ). Purpura and urticaria are sometimes seen. There may also be a waxlike thickening of the skin, particularly of the dorsum of the hands and, more rarely, the face ( Fig. 13.100 ). Bullae and milia have been documented exceptionally. A further case presented with pseudoainhum. An association with lupus erythematosus is very rare. Hypertrichosis and hyperpigmentation are not typically seen.

In the majority of cases the disease is limited to the skin, but some affected patients develop protoporphyrin-rich gallstones, and 5% to 10% of patients develop liver disease, which may progress to liver failure in fewer than 5% of patients and rarely to cirrhosis. Patients who develop liver failure typically have the autosomal recessive or X-linked dominant forms of transmission. Neurological manifestations are not common. Anemia is rare and if present is very mild.

Recently, a late-onset variant has been described, which is more commonly associated with hematological malignancy, where the disease occurs secondary to an acquired somatic mutation in the malignant clone within the bone marrow. Exacerbation of the disease by blood transfusion and by iron ingestion has been described.

Clinical features

This very rare autosomal dominant form of porphyria develops as a result of a deficiency of coproporphyrinogen oxidase. This enzyme catalyzes the sixth step in the heme biosynthetic pathway. It has been mapped to the long arm of chromosome 3 (3q11.2). A number of different mutations have been documented. Heterozygous patients often do not manifest symptoms of the disease. In those who develop symptoms, these usually appear after puberty. Affected patients develop intermittent attacks of abdominal pain in association with neurological and psychiatric manifestations. About 30% of cases develop photosensitivity, usually at the time of the acute attacks. The cutaneous changes are similar to those described for porphyria cutanea tarda. The disease may be precipitated by pregnancy, the contraceptive pill, fasting, infections, and the anabolic steroid methandrostenolone. Diagnosis is confirmed by the presence of increased excretion of coproporphyrinogen III in urine and feces. Porphobilinogen and aminolevulinic acid are increased during the episodic attacks.

Harderoporphyria is regarded as a variant form of hereditary coproporphyria in which hematological alterations predominate. Patients present with jaundice, severe chronic hemolytic anemia starting in the neonatal period, hepatosplenomegaly, and photosensitivity. Neuropsychiatric symptoms or abdominal pain are not seen. These patients usually have a specific mutation (K404E) on one or both alleles of the coproporphyrinogen gene.

Clinical features

This is the commonest type of porphyria and usually manifests in middle age. It shows a marked male predominance. The highest incidence is found in the South African Bantu. Cases are also often seen in Europe and North America.

There are two main forms of porphyria cutanea tarda: familial and sporadic. Both variants have in common a reduced activity of uroporphyrinogen decarboxylase (URO-D), which catalyzes the decarboxylation of uroporphyrinogen to coproporphyrinogen. In the familial variant there is decreased URO-D activity in erythrocytes and most other tissues while in the sporadic form there is decreased URO-D activity restricted to the liver. In rare familial cases, normal URO-D activity has been reported in erythrocytes.

The rare familial form exhibits an autosomal dominant inheritance. The onset tends to be earlier than that of the sporadic form and the exceptional cases occurring in childhood are usually familial. The disease is related to many different mutations in the UROD gene. There is no clear correlation between disease severity and the type of mutation. Porphyria cutanea tarda may be precipitated by many exogenous factors, including alcohol abuse, iron overload, childbirth, and sun exposure. Pregnancy may exacerbate the symptoms of the disease during the first trimester. Multiple factors often contribute to precipitate the disease in a given patient. Rare cases of familial porphyria cutanea tarda present with constrictive pericarditis.

The second much more common form is sporadic or acquired. Up to 80% of patients with porphyria cutanea tarda have the sporadic form of the disease. It has been demonstrated that sporadic porphyria cutanea tarda is a multifactorial disorder involving a combination of genetic and environmental factors. Recent studies have demonstrated that the hemochromatosis gene mutations C282Y and H63D represent a susceptibility factor in Western European and Australian patients affected by this form of the disease. These mutations probably induce the disease through iron overload. It has also been suggested that the IVS4+198 T allele in the human transferrin receptor-1 may play an independent role in the development of the disease. However, this has not been substantiated in other studies. Coinheritance of mutations in the uroporphyrinogen decarboxylase and in the hemochromatosis genes appears to accelerate the onset of porphyria cutanea tarda. Sporadic cases mainly occur in patients exposed to a variety of hepatotoxic chemicals, such as ethanol, estrogens, griseofulvin, vitamin B ₁₂ , sulfonamides, tamoxifen, pravastatin, barbiturates, hydantoins, and chlorinated hydrocarbons: for example, an epidemic form occurred in Turkey due to exposure to the fungicide hexachlorobenzene. Rare associations include diabetes mellitus, Wilson disease, myelofibrosis, the CREST syndrome, and hepatocellular carcinoma.

Increased hepatic iron stores are a major predisposing factor. The mechanism by which this happens is not well understood. Iron catalyzes the formation of reactive oxygen species and this may enhance uroporphyrin formation by increasing the rate at which uroporphyrinogen is oxidized to uroporphyrin, leading to the manifestations of the disease. A second possible proposed mechanism considers the indirect inhibition of uroporphyrinogen decarboxylase by iron. Whatever the mechanism, the iron overload has important therapeutic implications as venesection can induce a remission.

Hepatitis C virus infection is often associated with porphyria cutanea tarda. A frequent association is also the acquired immunodeficiency syndrome (AIDS). AIDS patients with porphyria cutanea tarda are often hepatitis C virus-positive. Patients who have had both acquired and familial variants have developed the typical features of increased skin fragility, blistering, hyperpigmentation, and hypertrichosis, but scarring and milia have rarely been evident. Often, the development of porphyria has preceded the diagnosis of HIV infection. In many instances this has been related to excessive alcohol consumption and/or infectious hepatitis, particularly hepatitis C. The association has been reported too often to be merely fortuitous and liver damage seems to be the common denominator. The causal agent (be it hepatitis C virus or HIV) seems to have a direct effect upon hepatocyte porphyrin metabolism. It has been demonstrated that elevated serum porphyrin levels occur in early-stage HIV infection and hepatitis C infection. Porphyria cutanea tarda has also been described in association with nonalcoholic liver disease, chronic hemodialysis, noninsulin dependent diabetes mellitus and lupus erythematosus. An autoantibody study in a large series of patients with lupus erythematosus suggests that the association is fortuitous. The association with hematological malignancies, including leukemia and lymphoma, is usually related to the treatment, particularly repeated blood transfusions.

Typically, blisters occur on light-exposed skin and are traumatic or actinically induced ( Figs 13.101–13.103 ). Cutaneous fragility is usually marked. The blisters are slow to heal and leave superficial atrophic scars with milia. Although they are most often seen on the backs of the hands, they may also be found on the palms, face, scalp, forearms, trunk, and under the finger nails. Hypertrichosis and premature aging with chronic actinic damage are usual and sclerodermatous changes may be marked ( Fig. 13.104 ). The hypertrichosis is characterized by long dark lanugo hair developing about the cheeks and temples, the eyebrows, ears, and arms ( Fig. 13.105 ). The sclerodermatous features, which are more common in females, are found on both light-exposed and unexposed skin. Sites that are particularly affected include the face, neck, scalp, chest, and backs of hands, and often there is hyper- or hypopigmentation or both. In rare cases, patients may clinically present as scleroderma without other manifestations of porphyria cutanea tarda. Hyperpigmentation, if present, may be diffuse, reticulate or spotty. Preauricular calcification is a common complication. The dermal fibrosis appears to be related particularly to high uroporphyrin levels. Uroporphyrin has been shown to stimulate fibroblast collagen synthesis independent of ultraviolet light.

Uncommon cutaneous manifestations of porphyria cutanea tarda include alopecia affecting the frontoparietal, temporal, and occipital regions of the scalp, and centrofacial papular lymphangiectasis. Hair darkening has also been reported. Very rare cases have been documented presenting with plaques or simulating solar urticaria.

Acute attacks are not a feature of this variant. Biochemical evidence of liver involvement is common, but clinical manifestations are unusual. Urinary porphyrin levels are increased and result in pink–red fluorescence with a Wood lamp.

The diagnosis is confirmed by the presence of uroporphyrin and heptacarboxylic porphyrins in urine and plasma and by the presence of isocoproporphyrin in feces.

Clinical features

Hepatoerythropoietic porphyria is very rare and, in fact, represents the homozygous form of familial porphyria cutanea tarda. Both diseases share some of the mutations that have been described. This form of porphyria is also heterogeneous and different mutations in the UROD gene may occur. The activity of uroporphyrinogen decarboxylase is much lower than in porphyria cutanea tarda. As a consequence, disease manifestations are typically severe. Mild variants have been reported in association with certain genetic mutations. Extreme immediate photosensitivity occurs in infancy. Erythema, edema, and vesicles lead to severe scarring, with hypertrichosis and sclerodermatous changes in exposed areas. Ocular features include photophobia, conjunctivitis, and scleromalacia perforans. Hepatitis, cirrhosis, and normochromic anemia may also occur.