Skin and Adnexal Structures

Clinical Features

• Acquired, possibly autoimmune disease with a strong familial association

• Characterized by patches of pigment loss (“hypopigmentation”) in skin

• Localized disease may show linear, segmental pattern; generalized disease involves face, upper trunk, dorsa of hands, periorificial areas, and genitalia; scalp and eyelashes not typically affected

• Stable patches of vitiligo are sharply demarcated and may be surrounded by a zone of hyperpigmentation; in active lesions, areas of total depigmentation may be surrounded by a zone of partial depigmentation and have a slight rim of erythema at the border

Histopathology

• Sparse/mild superficial perivascular inflammation with scattered melanophages

• Complete loss of melanin from the basal layer and total absence of melanocytes only seen in well-established lesions and in the depigmented center of expanding lesions

• Advancing border-enlarged melanocytes with increased dendritic processes and a mild superficial perivascular inflammation

• Normal-appearing skin (adjacent to the vitiliginous patches)—patchy interface change and a mild superficial perivascular and lichenoid lymphocytic infiltrate

• Active lesions—lymphocyte aggregates (“Pautrier-like” microabscesses) in the basal layer

Special Stains and Immunohistochemistry

• Silver stains or the dopa reaction (Fontana-Masson) highlight loss of basal layer melanin pigment ( Figures 2.2A and B )

  

• Immunohistochemical stains for SOX10 or Melan-A are useful in confirming decreased density/absence of basal melanocytes

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• On routine H&E-stained sections, other diseases manifesting with minimal histologic alterations (normal-appearing skin), such as tinea versicolor, urticaria, and urticaria pigmentosa (macular variant), should be considered.

• Mycosis fungoides-epidermotropism and Pautrier microabscesses in all epidermal layers composed of lymphocytes with hyperchromatic and convoluted nuclei diagnostic

Selected References

Attili VR, Attili SK. Lichenoid inflammation in vitiligo: a clinical and histopathologic review of 210 cases. Int J Dermatol . 2008;47:663–669.

Le Poole IC, Das PK. Microscopic changes in vitiligo. Clin Dermatol . 1997;15:863–873.

Silverberg JI, Silverberg NB. Clinical features of vitiligo associated with comorbid autoimmune disease: a prospective survey. J Am Acad Dermatol . 2013;69:824–826.

Clinical Features

• Typically, presents with pruritic, raised, erythematous, and edematous areas ( wheals or hives )

• Acute urticaria lasts <6 weeks, more common in the pediatric age group; chronic urticaria lasts >6 weeks, more common in adults

• An underlying predisposing condition can be identified in only up to 25% of patients; certain foods, drugs, contact allergens, and physical stimuli such as pressure, cold temperature, and occult infections may be factors

• Urticarial vasculitis is a syndrome consisting of recurrent urticaria, arthralgia, and abdominal pain; individual cutaneous lesions persist for >24 hours

• In angioedema, dermal edema extends into subcutaneous fat and presents with large wheals

Histopathology

• Interstitial edema, telangiectases, and a sparse/mild superficial perivascular mixed inflammatory cell infiltrate composed of lymphocytes, eosinophils, and neutrophils ( Figure 2.3 )

  

• Urticarial vasculitis—features of early leukocytoclastic vasculitis characterized by mild perivascular infiltrate of neutrophils, neutrophilic nuclear dust, and extravasated red blood cells; minimal or absent fibrin deposits in the vessel walls

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Hypocomplementemia, seen in 32% of patients with urticarial vasculitis; measurements of CH50 and C1q binding assays are helpful

• Patients with hereditary angioedema have a low serum level of C1 esterase inhibitor during the attack

• Direct immunofluorescence (DIF) studies: vascular deposits of immunoglobulins, complement, or fibrin are seen in one third of patients with urticarial vasculitis

Differential Diagnosis

• Macular Variant of Urticaria Pigmentosa (Telangiectasia Macularis Eruptiva Perstans)

  • Generally occurs as an extensive eruption of brownish-red macules

  • Dilated blood vessels in the upper dermis and a mild superficial perivascular mononuclear cell infiltrate composed mostly of mast cells are characteristic( Figure 2.4A )

    

  • Eosinophils are generally absent; dermal edema is not prominent

  • Giemsa, toluidine blue, Leder, or immunohistochemical stain for mast cell tryptase and CD117 can help demonstrate the increased number of mast cells ( Figure 2.4B )

• Leukocytoclastic Vasculitis Due to Other Causes

  • Fibrinoid necrosis of vessels, leukocytoclasia, and an abundance of extravasated erythrocytes

Selected References

Barzilai A, Sagi L, Baum S, Trau H, et al. The histopathology of urticaria revisited-clinical pathological study. Am J Dermatopathol . 2017;39:753–759.

Cugno M, Castelli R, Cicardi M. Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and lymphoproliferation. Autoimmun Rev . 2008;8:156–159.

Wisnieski JJ. Urticarial vasculitis. Curr Opin Rheumatol . 2000;12:24–31.

Clinical Features

• Disorder of unknown etiology involving skin, mucous membranes, hair, and nails

• Typically presents as pruritic, polygonal, violaceous, flat-topped papules with a fine scale

• Predilection for flexor surfaces of extremities, lower back, and glans penis

• Surface of lesions may show a network of white lines ( Wickham striae )

• Oral lesions (lacy, reticular network of papules involving buccal mucosa or the tongue) may be the sole manifestation

• Association with hepatitis C

Histopathology

• Compact hyperkeratosis, irregular epidermal hyperplasia (“saw-toothed”) with wedge-shaped hypergranulosis that corresponds to the openings of follicles and acrosyringia ( Figure 2.5A )

  

• Bandlike, predominantly lymphocytic infiltrate in the superficial dermis that obscures the dermoepidermal junction

• Eosinophilic colloid bodies (“Civatte bodies”), representing damage to the basal cell layer, are present at the dermoepidermal junction

• Small clefts known as Max-Joseph/Caspary-Joseph spaces may be seen at the dermo-epidermal junction

• Hypertrophic lichen planus—typically characterized by irregular acanthosis and interface change with an underlying inflammatory infiltrate confined only to the tips of the rete ridges

• Oral lesions—typically show parakeratosis, less acanthosis, and are frequently ulcerated

• Lichen planus of hair follicles (lichen planopilaris)—active lesions typically show a dense lymphocytic infiltrate surrounding the infundibulum of the follicle ; in later stages, there is perifollicular fibrosis with loss of follicles with advanced stages resulting in scarring alopecia

Special Stains and Immunohistochemistry

• PAS stain confirms interface change

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Lichenoid Drug Eruption

  • Focal parakeratosis and necrotic keratinocytes particularly at and above the dermoepidermal junction

  • Presence of eosinophils in the inflammatory cell infiltrate

• Lichen Planus–Like Keratosis (Benign Lichenoid Keratosis)

  • Solitary lesion

  • Absence of epidermal hyperplasia with hypergranulosis and presence of parakeratosis in addition to lichenoid pattern of inflammation

  • Adjacent areas may show changes of solar lentigo

• Lichenoid Graft-Versus-Host Disease (GVHD)

  • Generally the inflammatory cell infiltrate is sparse

  • Foci of parakeratosis and thinning of epidermis may be present

• Lichen Striatus

  • More common in children than adults and presents as a unilateral eruption along Blaschko lines on extremities, trunk, or neck

  • Lichenoid inflammatory cell infiltrate similar to lichen planus; however, the infiltrate extends deep in the reticular dermis around hair follicles and sweat glands

  • Epidermal spongiosis and an admixture of histiocytes in the inflammatory cell infiltrate

• Lichen Nitidus

  • Asymptomatic dermatosis of childhood, characterized by round, flat-topped papules that measure only a few millimeters

  • Histologically, the inflammatory cell infiltrate is bandlike but the lesion is small and discrete; infiltrate is confined to widened dermal papillae and enclosed by elongated rete on either side (“ball and claw”) ( Figure 2.5B )

  • Frequent histiocytes in the infiltrate, epidermal atrophy, and focal parakeratosis are helpful in differentiating lichen nitidus from lichen planus

Selected References

Shai A, Halevy S. Lichen planus and lichen planus-like eruptions: pathogenesis and associated diseases. Int J Dermatol . 1992;31:379–384.

Shiohara T. The lichenoid tissue reaction: an immunological perspective. Am J Dermatopathol . 1998;10:252–256.

Tziotzios C, Lee JYW, Brier T, et al. Lichen planus and lichenoid dermatoses: clinical overview and molecular basis. J Am Acad Dermatol . 2018;79(5):789–804.

Clinical Features

• Acute cytotoxic cell-mediated hypersensitivity reaction to infections, most commonly herpes simplex virus infection, and drugs, in particular sulfonamides

• The eruption is multiform and consists of macules, papules, vesicles, and occasionally large flaccid bullae; often associated with fever

• Herpesvirus-associated erythema multiforme (EM) involves the extremities and presents with typical target-like lesions, whereas drug-associated EM shows truncal involvement and a purpuric type of macular eruption; mucosal involvement (Stevens-Johnson syndrome) is characteristic

• The most severe form, toxic epidermal necrolysis (a widespread blotchy erythema) is characterized by large flaccid bullae with “sloughing” of the skin and is most often caused by drugs, including sulfonamides, β-lactam antibiotics, and nonsteroidal anti-inflammatory drugs; associated with a high mortality rate

Histopathology

• Cornified layer is unaltered, attesting to the acute nature of the disease

• Confluent interface change/vacuolar alteration of the basal cell layer and a sparse superficial perivascular lymphocytic infiltrate that may focally obscure the dermoepidermal junction ( Figure 2.6A )

  

• The hallmark of EM is the presence of necrotic keratinocytes, initially as single cells and later as small clusters; the necrosis is more widespread in drug-induced EM

• In toxic epidermal necrolysis, there is full-thickness epidermal necrosis resulting in subepidermal bullae ( Figure 2.6B )

• In late lesions, the papillary dermis may contain melanophages (a sign of damage to the basal cell layer)

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• DIF studies of lesional skin <48 hours old will show immunoglobulin M (IgM) and C3 in the walls of superficial dermal vessels

• Herpes simplex virus DNA has been detected within lesions of EM using PCR and in situ hybridization (ISH)

Differential Diagnosis

• Staphylococcal Scalded-Skin Syndrome

  • Clinical appearance may be similar to toxic epidermal necrolysis

  • Microscopically, staphylococcal scalded-skin syndrome shows a split in the granular layer diagnostic (in contrast to toxic epidermal necrolysis where there is separation at the dermoepidermal junction)

• Acute GVHD

  • May be histopathologically indistinguishable from early EM

• Fixed Drug Eruption

  • Interface dermatitis with necrotic keratinocytes similar to EM

  • Deeper extension of inflammatory cell infiltrate containing eosinophils

  • Prominent pigment incontinence

Selected References

Ackerman AB, Ragaz A. Erythema multiforme. Am J Dermatopathol . 1985;7:133–139.

Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol . 1997;24:726–729.

Samim F, Auluck A, Zed C, Williams PM. Erythema multiforme: a review of epidemiology, pathogenesis, clinical features, and treatment. Dent Clin North Am . 2013;57(4):583–596.

Clinical Features

• Occurs most frequently in bone marrow transplant recipients and less commonly in recipients of blood products and solid organ transplants

• Incidence is 30% to 40% in related donor-recipient versus 60% to 80% when unrelated; risk increases with age

• Acute phase

  • Presents with the triad of skin lesions, hepatic dysfunction, and diarrhea; develops within 3 months after transplant

  • Skin lesions are characterized by extensive erythematous macules, purpuric to violaceous papules and plaques, and, in severe cases, toxic epidermal necrolysis–like eruption; oral lesions may be present

• Chronic phase

  • Occurs >3 months to a year after transplantation

  • In the early lichenoid stage, the eruption is similar to lichen planus

  • Late sclerotic stage is characterized by skin induration and tightening

Histopathology

• Acute phase—4 grades

  • Grade I: vacuolar alteration of the basal cell layer, which may be focal or diffuse

  • Grade II: intraepidermal necrotic keratinocytes occasionally surrounded by lymphocytes (satellite necrosis) ( Figure 2.7 )

    

  • Grade III: widespread necrosis of keratinocytes with separation at the dermoepidermal junction

  • Grade IV: full-thickness necrosis and loss of epidermis

  • Sparse superficial perivascular lymphocytic infiltrate is usually present in acute GVHD

  • Follicular papules when evident clinically exhibit histopathologic changes in follicular epithelium similar to those evident in the epidermis

• Chronic phase

  • Early lichenoid phase-histopathologic features of lichen planus; satellite necrosis may still be seen in GVHD

  • Late sclerotic phase-histopathologic changes similar to scleroderma with dermal sclerosis extending into the subcutis plus epidermal atrophy

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Erythema Multiforme

  • May be histopathologically indistinguishable from acute GVHD

• Lichen Planus

  • May be histopathologically indistinguishable from lichenoid phase of GVHD

• Scleroderma

  • May be histopathologically indistinguishable from sclerotic phase of GVHD

  • Epidermal atrophy, if present, helps in differentiating sclerotic phase of GVHD from scleroderma

Selected References

Aractingi S, Chosidow O. Cutaneous graft-versus-host disease. Arch Dermatol . 1998;134:602–612.

Hillen U, Hausermann P, Massi D, et al. Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease. J Eur Acad Dermatol Venereol . 2015;29:948–954.

Zhou Y, Barnett MJ, Rivers JK. Clinical significance of skin biopsies in the diagnosis and management of graft-vs-host disease in early post-allogeneic bone marrow transplantation. Arch Dermatol . 2000;136:717–721.

Clinical Features

• Chronic multisystem autoimmune disease that affects the connective tissue and vasculature of various organs

• Three classic cutaneous forms: discoid, subacute, and systemic lupus

  • Discoid lupus erythematosus (DLE)—clinically, mildly scaling, erythematous, edematous, sharply demarcated plaques measuring up to 15 cm, involving the scalp, face, upper trunk, and upper extremities (photosensitive distribution); follicular plugging may be seen

  • Older lesions—atrophic with variable pigmentation

    • Subacute lupus erythematosus—presents as a symmetric photodistributed eruption of psoriasiform/annular plaques

    • Tumid lupus—indurated plaques and nodules without overlying erythema or atrophy

    • Verrucous lesions—seen in 2% of patients with chronic cutaneous lupus erythematosus

    • Panniculitis—seen in select patients with chronic cutaneous or systemic forms of lupus erythematosus

Histopathology

• DLE—epidermal atrophy, hyperkeratosis with follicular plugging and confluent interface change that involves follicular epithelia and marked thickening of the basement membrane ( Figure 2.8A )

  

• A moderate perivascular and periadnexal lymphocytic infiltrate and a mild increase in dermal mucin

• Subacute cutaneous lupus erythematosus (SCLE) and neonatal lupus erythematosus-prominent interface change with numerous individually necrotic dyskeratotic keratinocytes, less prominent hyperkeratosis and inflammatory cell infiltrate than DLE

• SLE—may show interface change with involvement of follicular epithelia, periadnexal and perivascular lymphocytic infiltrate, and increased dermal mucin similar to discoid lupus but more often the histologic changes are subtle

• Tumid lupus erythematosus—superficial and deep perivascular and periadnexal lymphocytic infiltrate and increased dermal mucin but no epidermal changes

• Lupus panniculitis/lupus profundus—lobular lymphocytic panniculitis with hyaline fat necrosis, superficial and deep perivascular and periadnexal lymphocytic infiltrate, interstitial mucin, with or without epidermal changes ( Figure 2.8B ), reactive lymphoid follicles not uncommon in the subcutis

• Verrucous lupus—verrucous epidermal hyperplasia, interface change involving follicular epithelia, superficial and deep perivascular and periadnexal lymphocytic infiltrate and increased dermal mucin

Special Stains and Immunohistochemistry

• PAS stain—helpful in demonstrating interface change and thickened basement membrane ( Figure 2.8C )

• Colloidal iron stain—highlights interstitial mucin deposits

Other Techniques for Diagnosis

• DIF—continuous granular deposition of immunoglobulin G (IgG), IgM, and C3 in a band along the dermoepidermal junction ( Figure 2.8D )

Differential Diagnosis

• Dermatomyositis

  • Interface change, pauci-inflammatory, minimal increase in dermal mucin, and lupus band test is generally negative

• Lichen Planus

  • Irregular epidermal hyperplasia with hypergranulosis, and lichenoid lymphoid cell infiltrate with pigment incontinence

• Polymorphous Light Eruption

  • Superficial and deep perivascular lymphocytic infiltrates of lupus (especially tumid form) must be differentiated from polymorphous light eruption, which usually shows marked edema of papillary dermis

• Subcutaneous Panniculitis-Like T-Cell Lymphoma

  • Can mimic lupus profundus

  • Rimming of the subcutaneous fat cells by neoplastic T lymphocytes and presence of lymphocyte nuclei within the cytoplasm of histiocytes (emperipolesis) are characteristic features

Selected References

Arps DP, Patel RM. Lupus profundus (panniculitis): a potential mimic of subcutaneous panniculitis-like T-cell lymphoma. Arch Pathol Lab Med . 2013;137:1211–1215.

Biazar C, Sigges J, Patsinakidis N, Ruland V, et al. Cutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Autoimmun Rev . 2013;12:444–454.

Jerdan MS, Hood AF, Moore GW, et al. Histopathologic comparison of the subsets of lupus erythematosus. Arch Dermatol . 1990;126:52–55.

Clinical Features

• Connective tissue disease characterized by inflammatory myositis involving the proximal muscles and cutaneous lesions consisting of a heliotrope rash (violaceous, slightly edematous periorbital patches involving the eyelids), Gottron papules (discrete red-purple papules over bony prominences of knuckles, knees, and elbows), and photodistributed erythematous-edematous lesions over the upper chest and back

• The disease has two peaks, one in childhood and one between the ages of 45 and 65 years

Histopathology

• Histopathologic changes of the erythematous-edematous lesions of the skin include epidermal atrophy, vacuolar interface change with scattered individually necrotic keratinocytes, a sparse superficial perivascular lymphocytic infiltrate ( Figure 2.9 )

  

• Mild increase in interstitial mucin

• Subepidermal fibrin deposits can be seen

• Gottron papules—epidermal hyperplasia in addition to mild interface change

• Panniculitis and calcification of the subcutaneous tissue may be seen at a later stage

Special Stains and Immunohistochemistry

• PAS stain confirms interface change and a thickened basement membrane zone

Other Techniques for Diagnosis

• DIF—may show complement (C5b-C9) around blood vessels

Differential Diagnosis

• Subacute Cutaneous Lupus Erythematosus

  • Histopathologic features identical to those of dermatomyositis, clinical correlation including evaluation for myositis critical

  • Positive lupus band test helpful (especially in early stages of dermatomyositis when the muscular weakness is not apparent)

Selected References

Callen JP. Dermatomyositis. Lancet . 2000;355:53–57.

Mendese G, Mahalingam M. Histopathology of Gottron’s papules-utility in diagnosing dermatomyositis. J Cutan Pathol . 2007;34:793–798.

Sontheimer RD. Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis. Curr Opin Rheumatol . 1999;11:475–482.

Clinical Features

• • Spongiotic dermatitis refers to reaction pattern characterized histologically by the presence of intercellular edema (spongiosis) in the epidermis

  • Group includes allergic contact dermatitis, photoallergic dermatitis, nummular dermatitis, atopic dermatitis, dyshidrotic dermatitis, and Id reaction

• Allergic Contact Dermatitis

  • Most commonly caused by poison ivy, nickel, and rubber compounds, presents with pruritic, edematous, erythematous papules and occasional vesicles usually within 1-3 days of exposure

• Photoallergic Dermatitis

  • Due to topical application (photocontact) or ingestion of an allergen

  • Presents with pruritic and erythematous papulovesicular lesions on sun-exposed skin; usually on face, arms, and neck

• Nummular Dermatitis

  • Disease of unknown etiology characterized by coin-shaped, pruritic, erythematous, scaly, crusted plaques on the exterior aspects of extremities

• Atopic Dermatitis

  • Inherited chronic, pruritic, scaly eruption affecting face and extensor aspects of extremities in children

• Dyshidrotic Dermatitis

  • Characterized by numerous pruritic vesicles along sides of fingers and toes and palms and soles

• Autoeczematization or Id Reaction

  • Sudden localized or generalized eruption of pinhead-sized vesicles developing in association with a defined local dermatitis or with infection

  • Most common cause is a remote dermatophyte infection

Histopathology

• Three distinct reaction patterns— acute , subacute , and chronic

• Acute spongiotic dermatitis

  • Spongiotic vesicles with minimal acanthosis ( Figure 2.10A )

    

  • In allergic contact dermatitis, eosinophils may be present in the vesicles ( Figure 2.10B )

  • Mild papillary dermal edema and a superficial perivascular lymphohistiocytic inflammation are present

• Subacute spongiotic dermatitis

  • Parakeratosis with plasma, mild to moderate spongiosis, epidermal hyperplasia, and superficial perivascular lymphohistiocytic infiltrate

• Chronic Spongiotic Dermatitis

  • Hyperkeratosis, acanthosis with hypergranulosis, minimal spongiosis, and papillary dermal fibrosis

Special Stains and Immunohistochemistry

• PAS stain useful in excluding dermatophytosis with spongiosis

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Seborrheic Dermatitis

  • Histopathology varies with age of the lesion, follicle-centered, “shoulder” parakeratosis ( Figure 2.10C ) and a mild superficial perivascular lymphoid cell infiltrate with admixed neutrophils

• Pityriasis Rosea

  • “Moundlike” parakeratosis ( Figure 2.10D ), mild spongiosis ( only in the “herald patch” ), mild superficial perivascular lymphoid cell infiltrate, and extravasated red cells

  • Identical changes may be seen in superficial form of erythema annulare centrifugum

• Spongiotic Drug Eruptions and Insect Bite Reactions

  • Deeper extension of the inflammatory infiltrate with admixed eosinophils

• Psoriasis

  • Chronic spongiotic dermatitis (lichen simplex chronicus) may resemble psoriasis but lacks confluent parakeratosis with neutrophils and thinning of suprapapillary plates

Selected References

Ackerman AB, Chongchitnant N, Sanchez J, et al. Histologic Diagnosis of Inflammatory Skin Diseases . Baltimore: Williams & Wilkins; 1997.

Ackerman AB, Ragaz A. A plea to expunge the word “eczema” from the lexicon of dermatology and dermatopathology. Am J Dermatopathol . 1982;4:315.

Weedon D. Skin Pathology . 2nd ed. New York: Churchill Livingstone; 2002:112.

Clinical Features

• An X-linked–dominant dermatosis that affects mostly females

• Characteristic cutaneous manifestations seen at birth include crops of vesicles and bullae on extremities arranged in a linear or whorled pattern

• Lesions heal with hyperkeratosis and verrucous epidermal hyperplasia; the verrucous lesions heal with streaks and whorls of hyperpigmentation that are later replaced by faint hypochromic patches

Histopathology

• Vesicular stage—characterized by marked epidermal spongiosis with eosinophils, individually dyskeratotic keratinocytes, and whorls of squamous cells with central keratinization ( Figure 2.11 )

  

• Verrucous stage—characterized by hyperkeratosis, verrucous epidermal hyperplasia, individually dyskeratotic keratinocytes, and occasional eosinophils

• Hyperpigmented stage—characterized by numerous melanophages in the superficial dermis

• Hypopigmented stage—characterized by epidermal atrophy, decreased melanin in the basal cell layer, and absence of adnexae

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Eosinophilic Spongiosis

  • Seen in a spectrum of unrelated entities that include allergic contact dermatitis, precursor lesions of pemphigus and bullous pemphigoid; clinical history essential in differentiation

• Epidermal Nevus

  • Verrucous stage of incontinentia pigmenti may resemble epidermal nevus

• Postinflammatory Pigmentary Alterations

  • Hyper- and hypopigmented stages of incontinentia pigmenti resemble postinflammatory pigmentary changes

Selected References

Ackerman AB, Chongchitnant N, Sanchez J, et al. Histologic Diagnosis of Inflammatory Skin Diseases . Baltimore: Williams & Wilkins; 1997.

Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol . 2002;47:169–187.

Ehrenreich M, Tarlow MM, Godlewska-Janusz E, Schwartz RA. Incontinentia pigmenti (Bloch-Sulzberger syndrome): a systemic disorder. Cutis . 2007;79:355–362.

Clinical Features

• Chronic dermatosis of unknown etiology affecting up to 2% of the population

• Males and females affected equally

• Variably sized, well-demarcated plaques covered by thick, silvery white scale that have a predilection for areas with trauma, including scalp, lumbosacral skin, and extensor surfaces of elbows and knees

• Several manifestations that include localized or generalized pustular psoriasis, eruptive or guttate psoriasis, and erythrodermic psoriasis

• Involvement of nails, oral mucosa, and tongue can occur

Histopathology

• Confluent parakeratosis with neutrophils and neutrophilic microabscesses (intracorneal-Munro microabscesses and intraspinous-spongiform pustule of Kogoj)

• Hypogranulosis corresponding to zones of parakeratosis

• Regular (psoriasiform) epidermal hyperplasia with elongation of rete ridges and thinning of suprapapillary plates ( Figure 2.12A )

  

• Dilated tortuous blood vessels in the dermal papillae

• Mild superficial perivascular lymphocytic infiltrate

• Pustular psoriasis—Exhibits the above but has in addition prominent Munro microabscesses and spongiform pustules of Kogoj ( Figure 2.12B )

• Guttate psoriasis—psoriasiform epidermal hyperplasia not as pronounced

• Erythrodermic psoriasis-histopathologic changes may be nonspecific

• AIDS-associated psoriasiform dermatitis

• Distinguishing features from psoriasis include individually necrotic/dyskeratotic keratinocytes, absence of thinning of the suprapapillary plates, and presence of plasma cells ( Figure 2.12C-a,b )

Special Stains and Immunohistochemistry

• PAS stain helpful in excluding dermatophytic infections (which also exhibit neutrophils in the stratum corneum)

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Subacute/Chronic Spongiotic Dermatitis Such As Allergic Contact or Nummular Dermatitis

  • Presence of spongiosis and eosinophils helpful in differentiation

• Dermatophyte Infection

  • Presence of superficial fungal spores and hyphal forms diagnostic (typically evident in PAS stained sections)

• Bacterial Impetigo

  • Subcorneal pustule diagnostic of an early lesion (rarely biopsied)

  • Gram stain may demonstrate the bacteria

• Pityriasis Rubra Pilaris

  • Alternating ortho and para-keratotic scale, psoriasiform epidermal hyperplasia, follicular plugging with “shoulder” parakeratosis diagnostic

  • Contrasting features with psoriasis include absence of neutrophils in the stratum corneum and retention of the granular cell layer

Selected References

De Mozzi P, Johnston GA, Alexandroff AB. Psoriasis. An evidence-based update. Report of the 9th evidence-based update meeting, 12 May 2011, Loughborough, UK. Br J Dermatol . 2012;166:252–260.

Nestle FO. Psoriasis. Curr Dir Autoimmun . 2008;10:65–75.

Ragaz A, Ackerman AB. Evolution, maturation, and regression of lesions of psoriasis. Am J Dermatopathol . 1979;1:199.

Clinical Features

• Chronic follicular-based erythematous papular eruption of unknown etiology that progresses to form orange-red scaly plaques containing islands of normal-appearing skin

• Generalized erythroderma may occur with progression

• Palmoplantar keratoderma and scales on the face and scalp not uncommon

Histopathology

• Alternating orthokeratosis and parakeratosis in horizontal and vertical directions (“checkerboard pattern”) ( Figure 2.13A and B )

  

• Psoriasiform epidermal hyperplasia with short rete and thick suprapapillary plates

• Follicular papules demonstrate “shoulder” parakeratosis and dilated follicular infundibula with follicular plugging

• Acantholysis restricted to adnexal epithelium

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Psoriasis

  • Confluent parakeratosis with neutrophils and neutrophilic microabscesses, psoriasiform epidermal hyperplasia with hypogranulosis ( granular cell layer is retained in pityriasis rubra pilaris ) and basal keratinocyte atypia, thinning of suprapapillary plates ( suprapapillary plates are thick in pityriasis rubra pilaris ), and papillary dermal telangiectases are diagnostic features

Selected References

Barr RJ, Young EM Jr. Psoriasiform and related papulosquamous disorders. J Cutan Pathol . 1985;12:412–425.

Mobini N, Toussaint S, Kamino H. Noninfectious erythematous, papular, and squamous diseases. In: Elder DE, Elenitsas R, Johnson BL Jr, et al., eds. Lever’s Histopathology of Skin . 10th ed. Philadelphia; Lippincott Williams & Wilkins; 2008:169.

Piamphongsant T, Akaraphant R. Pityriasis rubra pilaris: a new proposed classification. Clin Exp Dermatol . 1994;19:134–138.

Insect Bite Reaction (Papular Urticaria)

Selected References

Ackerman AB, Chongchitnant N, Sanchez J, et al. Histologic Diagnosis of Inflammatory Skin Diseases: An Algorithmic Method Based on Pattern Analysis . 2nd ed. Baltimore: Williams & Wilkins; 1997:202.

Gilliam AC, Wood GS. Cutaneous lymphoid hyperplasias. Semin Cutan Med Surg . 2000;19:133–141.

Howard R, Frieden IJ. Papular urticaria in children. Pediatr Dermatol . 1996;13:246–249.

Clinical Features

• Self-limited cutaneous eruption of unknown cause that affects young adults and children

• Two forms:

  • Acute or pityriasis lichenoides et varioliformis acuta (PLEVA), more severe form common in children and young adults

  • Chronic or pityriasis lichenoides chronica (PLC), the milder form more common in adults

  • Transitional forms with changes between the two extremes occur

• In PLEVA, a papular, papulonecrotic, and occasionally vesiculopustular eruption occurs on the trunk and proximal extremities, usually resolves in a few weeks; crops of new lesions can continue to appear, and the disease process itself may have a chronic course

• In PLC, recurrent crops of reddish-brown papules with adherent scales occur on the trunk and extremities and resolve in a few weeks

Histopathology

• PLEVA

  • Parakeratosis and scale crust with neutrophils, vacuolar interface change, and individually necrotic keratinocytes ( Figure 2.16A )

    

  • Superficial and deep perivascular and lichenoid, predominantly lymphocytic infiltrate with atypical CD30+ lymphocytes

  • Lymphocytic vasculitis (especially in the ulceronecrotic variant)

  • Papillary dermal edema and extravasated erythrocytes

• PLC

  • Hyperkeratosis, parakeratosis, mild epidermal hyperplasia, interface change

  • Superficial perivascular lymphohistiocytic infiltrate with extravasated erythrocytes ( Figure 2.16B )

Special Stains and Immunohistochemistry

• Lymphocytes predominantly of the cytotoxic/suppressor T-cell phenotype, presence of CD8+ T lymphocytes confirmed by immunohistochemistry

• Immunohistochemical stain for CD30 may reveal scattered CD30+ cells in PLEVA

Other Techniques for Diagnosis

• DIF may reveal IgM and C3 deposits along the basement membrane zone

Differential Diagnosis

• Lymphomatoid Papulosis

  • Histopathologic features overlap with PLEVA

  • Wedge-shaped inflammatory cell infiltrate composed of clusters of atypical CD30+ lymphocytes with admixed eosinophils

• Vesicular Insect Bite Reactions

  • Superficial and deep dermal infiltrate with numerous eosinophils, papillary dermal edema and extravasated erythrocytes helpful histopathologic clues

Selected References

Bowers S, Warshaw EM. Pityriasis lichenoides and its subtypes. J Am Acad Dermatol . 2006;55:557–572.

Ersoy-Evans S., Greco MF, Mancini AJ, et al. Pityriasis lichenoides in childhood: a retrospective review of 124 patients. J Am Acad Dermatol . 2007;56:205–210.

Kempf W, Kazakov DV, Palmedo G, et al. Pityriasis lichenoides et varioliformis acuta with numerous CD30(+) cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. A clinicopathologic, immunohistochemical, and molecular biological study of 13 cases. Am J Surg Pathol . 2012;36:1021–1029.

Clinical Features

• Well-defined, circumscribed patches occur at the same site in response to repeated intake of the drug

• Lesions are slightly edematous and erythematous and may develop dusky centers and become bullous and heal with pigmentation

• Increasing number of lesions can occur with each successive administration of the offending drug

Histopathology

• Interface dermatitis with scattered individually necrotic keratinocytes, (changes identical to those seen in EM) ( Figure 2.17A )

  

• Superficial and deep perivascular and lichenoid inflammatory cell infiltrate composed of lymphocytes, eosinophils, and occasional neutrophils

• Prominent pigment incontinence

• Bullous variant resulting from more extensive epidermal necrosis has been described

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Erythema Multiforme

  • Interface dermatitis with scattered individually necrotic keratinocytes and a predominantly superficial perivascular and patchy lichenoid lymphoid cell infiltrate

• Erythema Dyschromicum Perstans/Lichen Planus Pigmentosus

  • Interface dermatitis with scattered individually necrotic keratinocytes; prominent pigment incontinence may be the only feature in older lesions( Figure 2.17B )

Selected References

Crowson AN, Magro CM. Recent advances in the pathology of cutaneous drug eruptions. Dermatol Clin . 1999;17:537–560, viii.

Gru AA, Salavaggione AL. Lichenoid and interface dermatoses. Semin Diagn Pathol . 2017;34:237–249.

Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol . 2006;45:897–908.

Clinical Features

• Multiple, small papules that are most often short lived, heal leaving oval scars, and are usually recurrent

Histopathology

• Wedge-shaped superficial and deep perivascular and lichenoid lymphoid cell infiltrate with admixed eosinophils and scattered large and small atypical lymphocytes

• Surface ulceration may be present

• Reed Sternberg–like cells (in type A) and atypical lymphocytes with cerebriform nuclei resembling mycosis fungoides (in type B) are occasionally seen

• Rarely, a dense monomorphous infiltrate of atypical lymphocytes resembling anaplastic large cell lymphoma (type C) can be seen in association with typical clinical features of lymphomatoid papulosis ( Figure 2.18 )

  

Special Stains and Immunohistochemistry

• Immunohistochemical stain CD30 highlights the presence of clusters of CD30+ atypical lymphocytes

Other Techniques for Diagnosis

• Clonal rearrangement of T-cell receptor gene may be present

Differential Diagnosis

• Insect Bite Reaction

  • Superficial and deep perivascular and interstitial lymphoid cell infiltrate with numerous eosinophils

  • While reactive CD30+ lymphocytes can be seen these are typically single cells and not clustered

• PLEVA

  • Histologic pattern of interface and lichenoid dermatitis similar to lymphomatoid papulosis

  • Reactive CD30+ lymphocytes can be seen, however, these are typically scattered single cells and not clustered

Selected References

Cerroni L. Lymphomatoid papulosis, pityriasis lichenoides et varioliformis acuta, and anaplastic large-cell (Ki-1+) lymphoma. J Am Acad Dermatol . 1997;37:287.

Guitart J, Querfeld C. Cutaneous CD30 lymphoproliferative disorders and similar conditions: a clinical and pathologic prospective on a complex issue. Semin Diagn Pathol . 2009;26:131–140.

LeBoit PE. Lymphomatoid papulosis and cutaneous CD30+ lymphoma. Am J Dermatopathol . 1996;18:221–235.

Werner B, Massone C, Kerl H, Cerroni L. Large CD30-positive cells in benign, atypical lymphoid infiltrates of the skin. J Cutan Pathol . 2008;35:1100–1107.

Clinical Features

• Hematogenous dissemination of causative organism, Treponema pallidum , results in a cutaneous eruption that can be macular, papular, papulosquamous, or, rarely, pustular

• Associated constitutional symptoms such as fever and lymphadenopathy may be present; other manifestations include condyloma lata, syphilis cornee, lues maligna, and alopecia

Histopathology

• Patchy/confluent parakeratosis containing neutrophils

• Regular psoriasiform epidermal hyperplasia (minimal in macular lesions, prominent in condylomata lata) with focal spongiosis ( Figure 2.19A )

  

• Interface change with scattered individually necrotic keratinocytes and papillary dermal edema

• Superficial and deep perivascular, periadnexal, and lichenoid lymphoplasmacytic infiltrate; plasma cells may be present around nerves ( Figure 2.19B )

• Infiltrate can be lymphocytic, lymphoplasmacytic, or lymphohistiocytic with rare granuloma formation

Special Stains and Immunohistochemistry

• Silver stain (Warthin-Starry) may show spirochetes within the epidermis in one third of cases ( not used anymore because of high background associated with this stain )

• Immunohistochemistry with a monoclonal antibody to T. pallidum yields better detection rates (organisms are more often found in the dermis compared to the epidermis)

Other Techniques for Diagnosis

• Molecular detection of T. pallidum using PCR the gold standard

Differential Diagnosis

• Mycosis Fungoides

  • Shows psoriasiform lichenoid pattern similar to syphilis; however, in mycosis fungoides, atypical lymphoid cells are present within the dermal infiltrate and in the mildly spongiotic epidermis

  • Plasma cells are not frequent

• Subacute and Chronic Spongiotic Dermatitis, Including Photoallergic Dermatitis

  • May show some psoriasiform hyperplasia and spongiosis

  • In general, plasma cells are not prominent

• Pityriasis Lichenoides

  • Can simulate secondary syphilis but shows predominantly a lymphocytic infiltrate without plasma cells

• Psoriasis and Psoriasiform Drug Eruption and AIDS-Associated Psoriasiform Dermatitis

  • Inflammatory infiltrate is typically not deep as in secondary syphilis and plasma cells not prominent

  • Suprapapillary plate thinning is not a feature of secondary syphilis

• Sarcoid and Other Conditions With a Prominent Granulomatous Pattern

  • May appear similar to the granulomatous pattern of secondary syphilis

  • Clinical correlation and serologic studies are necessary

Selected References

Hoang MP, High WA, Molberg KH. Secondary syphilis: a histologic and immunohistochemical evaluation. J Cutan Pathol. 2004;31:595-599.

Jeerapaet P, Ackerman AS. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373.

Muller H, Eisendle K, Brauninger W, et al. Comparative analysis of immunohistochemistry, PCR and focus-floating microscopy for the detection of T. pallidum in mucocutaneous lesions of primary, secondary and tertiary syphilis. Br J Dermatol. 2011;165:50-60.

Clinical Features

• Idiopathic ulceronecrotic skin disease that begins as follicular papules and pustules that eventually ulcerate

• Lower extremities and trunk are often involved

• Fully developed lesions show a necrotic center with a raised, undermined border with a dusky-purple hue

• Pyoderma gangrenosum may be the cutaneous manifestation of underlying systemic diseases such as inflammatory bowel disease, connective tissue disease, hematopoietic malignancies, and liver diseases

Histopathology

• Histologic features are nonspecific and not diagnostic—vary according to the age of the lesion and the area biopsied

• Area biopsied:

  • Center of the lesion shows ulcer with necrosis, dense diffuse neutrophilic infiltrate, and occasionally secondary vasculitis ( Figure 2.21 )

    

  • Undermined border shows a mixed inflammatory cell infiltrate in addition to neutrophils

  • Periphery of the ulcer shows a lymphocytic and histiocytic inflammatory infiltrate

• Age of the lesion

  • Early lesions show an intradermal microabscess

  • Advanced lesions show a perivascular lymphoplasmacytic infiltrate, reactive endothelial cell atypia and secondary vasculitis

Special Stains and Immunohistochemistry

• Special stains and microbiologic cultures help exclude an infectious etiology

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Sweet Syndrome

  • Neutrophilic infiltrate that is typically more superficial, leukocytoclasia and marked papillary dermal edema

• Bacterial Cellulitis

  • Requires demonstration of bacteria by Gram stain or microbiologic cultures

Selected References

Binus AM, Qureshi AA, Li VW, Winterfield LS. Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in 103 patients. Br J Dermatol . 2011;165:1244.

Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol . 2009;23:1008.

Su WP, Schroeter AL, Perry HO, et al. Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Pathol . 1983;13:323.

Eosinophilic Cellulitis/Wells syndrome

Selected References

Brasileiro LG, Abreu MAMM, Paschoal RS. Wells’ syndrome: the importance of differential diagnosis. An Bras Dermatol . 2019;94:370–372.

Caputo R, Marzano AV, Vezzoli P, Lunardon L. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol . 2006;142:1157.

Fujii K, Tanabe H, Kanno Y, et al. Eosinophilic cellulitis as a cutaneous manifestation of idiopathic hypereosinophilic syndrome. J Am Acad Dermatol . 2003;49:1174–1177.

Clinical Features

• Contagious, pruritic, papulovesicular, and pustular eruption most pronounced on the abdomen, buttocks, and anterior axillary folds caused by the mite Sarcoptes scabiei

• Eruption believed to be a hypersensitivity reaction

• Burrows, produced by the female mite, typically involve the palms, web spaces between fingers, and male genitalia

• Persistent pruritic nodules/nodular scabies involving most commonly the scrotum can be seen up to several months after treatment

Histopathology

• Sections taken from the burrow show a tunnel-like space (“molting pouches”) between layers of parakeratosis containing the mite/larvae/ova/feces ( Figure 2.22 ).

  

• Spongiosis and vesiculation may be present in the epidermis

• Superficial and deep dermal infiltrate containing varying numbers of eosinophils

• Persistent nodular lesions show dense, diffuse, mixed inflammatory cell infiltrate containing eosinophils, thick-walled blood vessels, and occasionally atypical mononuclear cells, “pseudolymphomatous” pattern may also be seen. Mite is generally absent in these lesions

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• A suspected burrow can be shaved, placed on a glass slide, and examined under oil immersion

Differential Diagnosis

• In the absence of the mite or its products in the cornified layer, the histologic changes cannot be distinguished from other hypersensitivity reactions such as those caused by arthropod bites

Selected References

Brites C, Weyll M, Pedroso C, et al. Severe and Norwegian scabies are strongly associated with retroviral (HIV-1/HTLV-1) infection in Bahia, Brazil. AIDS . 2002;16:1292.

Chosidow O. Scabies and pediculosis. Lancet . 2000;355:819–826.

Fernandez N, Torres A, Ackerman AB. Pathological findings in human scabies. Arch Dermatol . 1977;113:320.

Clinical Features

• Benign non-Langerhans cell histiocytosis that most commonly occurs during infancy (within first 6 months of life) but can be seen occasionally in adults (adult xanthogranuloma)

• About 20% are congenital

• Usually presents as single or multiple tan to pink-red nodules that almost always regress over time to a tan macule or depression

• Occasionally found in the deep soft tissue

• Eye, particularly the uveal tract, most frequent site of extracutaneous involvement

Histopathology

• Distinctive architecture—exophytic lesion with a well-defined epidermal collarette

• Lesional cells—uniform-appearing histiocytes with an eosinophilic, vacuolated, or xanthomatous cytoplasm,

• Touton giant cells are typically seen ( Figure 2.23 )

  

• Admixture of neutrophils, eosinophils, and lymphocytes

• Resolving lesion resembles dermatofibroma

Special Stains and Immunohistochemistry

• Oil red O highlights intracytoplasmic neutral lipids

• CD68 and factor XIIIa positive

• CD1a negative; S-100 protein usually negative

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Langerhans Cell Histiocytosis (Eosinophilic Granuloma)

  • Presence of histiocytes positive for CD1a and S-100 protein and admixed eosinophils, electron microscopy demonstrates Birbeck granules

• Fibrous Histiocytoma (Dermatofibroma)

  • Spindled fibroblasts and histiocytic cells arranged in a storiform pattern

  • Peripheral collagen entrapment and overlying epidermal hyperplasia with pigmentation of basal keratinocytes

• Xanthoma

  • Composed of sheets of histiocytes containing abundant intracytoplasmic lipid

  • Cholesterol clefts and multinucleate giant cells are typical

Selected References

Burgdorf WH, Zelger B. JXG, NF1, and JMML: alphabet soup or a clinical issue? Pediatr Dermatol . 2004;21:174.

Dehner LP. Juvenile xanthogranulomas in the first two decades of life: a clinicopathologic study of 174 cases with cutaneous and extracutaneous manifestations. Am J Surg Pathol . 2003;27:579.

Freyer DR, Kennedy R, Bostrom BC, et al. Juvenile xanthogranuloma: forms of systemic disease and their clinical implications. J Pediatr . 1996;129:227–237.

Clinical Features

• Typically occurs in adults

• Most frequently presents as a well-circumscribed red-brown cutaneous nodule with a red-brown to yellow cut surface

• May present as localized (giant cell reticulohistiocytoma) or systemic disease (multicentric reticulohistiocytosis)

• Cutaneous reticulohistiocytoma (localized form)—may present as single or multiple skin lesions with clinical features similar to xanthogranuloma

• Multicentric reticulohistiocytosis (systemic form)—rare, may involve lymph nodes, heart, bone, and joints in addition to widespread skin involvement, may present with progressive erosive arthritis, fever, and weight loss, association with hyperlipidemia, internal malignancies, and autoimmune diseases

Histopathology

• Essentially similar features in both localized and systemic forms

• Well-defined infiltrate of multinucleate, uniform epithelioid histiocytes with abundant eosinophilic (“oncocytic”) cytoplasm, multinucleate giant cells with “ground-glass” cytoplasm ( Figure 2.24 )

  

• Infrequent mitotic activity

• Scattered chronic inflammatory cells

Special Stains and Immunohistochemistry

• Lesional cells are CD68 positive and S-100 protein and CD1a negative

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

• Langerhans Cell Histiocytosis

  • Infiltrate of large histiocytoid CD1a and S100 protein positive cells with nuclear grooves

• Juvenile Xanthogranuloma

  • Distinctive architecture, polymorphous infiltrate, presence of Touton giant cells diagnostic

Selected References

Jung HD, Kim HS, Lee JY, et al. Multicentric reticulohistiocytosis. Acta Derm Venereol . 2013;93:124–125.

Miettinen M, Fetsch JF. Reticulohistiocytoma (solitary epithelioid histiocytoma): a clinicopathologic and immunohistochemical study of 44 cases. Am J Surg Pathol . 2006;30:521.

Snow JL, Muller SA. Malignancy-associated multicentric reticulohistiocytosis: a clinical, histological, and immunophenotypic study. Br J Dermatol . 1995;133:71–76.

Granuloma Annulare

Selected References

Barren DF, Cootauco MH, Cohen BA. Granuloma annulare: a clinical review. Prim Care Pract . 1997;1:33–39.

Gunes P, Goktay F, Mansur AT, et al. Collagen-elastic tissue changes and vascular involvement in granuloma annulare: a review of 35 cases. J Cutan Pathol . 2009;36:838.

Magro CM, Crowson AN, Regauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease. Hum Pathol . 1996;27:50–56.

Clinical Features

• Degenerative cutaneous disease of unknown etiology

• More common in women than men

• Characteristically affects the anterior tibial surface but also has a predilection for the thighs, popliteal areas, and dorsum of the feet and arms

• Indurated yellow-brown oval plaques with a violaceous border

• Center of the plaque may later become atrophic with a distinctive yellow waxy hue

• Very small proportion occur in patients with diabetes mellitus

Histopathology

• Rectangular contour of biopsy sample, alternating horizontal layers of basophilic degeneration of collagen and an inflammatory infiltrate of histiocytes, lymphocytes, and plasma cells ( Figure 2.26 ) diagnostic (“sandwich” or tiered appearance at scanning magnification)

  

• Vascular changes (reactive endothelial cell atypia and thickened vessel walls) are features shared with diabetic microangiopathy

• Zones of dermal sclerosis

• Sarcoidal type granulomas are seen on occasion

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• DIF may reveal IgM, IgA, C3 and fibrinogen in thickened vessels

Differential Diagnosis

• Rheumatoid Nodule

  • Deeply eosinophilic homogenous foci of fibrinoid degeneration of collagen surrounded by a palisade of lymphohistiocytic infiltrate typically seen in the deep dermis or subcutis

• Granuloma Annulare

  • Demarcated zones of necrobiosis with mucin surrounded by a palisade of lymphohistiocytic infiltrate, typically involving the upper half of the dermis

• Necrobiotic Xanthogranuloma

  • Atrophic epidermis, granulomatous inflammation with Touton giant cells of the deep dermis and subcutis, necrobiosis with cholesterol clefts

Selected References

Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol . 1991;25:735–748.

Magro CM, Crowson AN, Regauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease. Hum Pathol . 1996;27:50–56.

O’Toole EA, Kennedy U, Nolan JJ, et al. Necrobiosis lipoidica: only a minority of patients have diabetes mellitus. Br J Dermatol . 1999;140:283–286.

Clinical Features

• Chronic deep-seated inflammatory nodule that occurs in patients with rheumatoid arthritis and occasionally in patients with SLE

• Seen during the course of the disease in 30% to 40% of patients with rheumatoid arthritis

• Predilection for areas subject to mechanical trauma, typically in para-articular locations, including metacarpophalangeal and proximal interphalangeal joints

• Solitary or multiple, firm, nontender, freely mobile, large subcutaneous nodules

Histopathology

• Central areas of homogeneous eosinophilic degeneration of collagen surrounded by a peripheral palisade of histiocytes and lymphocytes ( Figure 2.27 ), located in the subcutaneous tissue and deep dermis

  

• Classified as a “red granuloma” because of the central homogenous eosinophilic areas

Special Stains and Immunohistochemistry

• Noncontributory