Diagnostic clues

In the previous chapter, an orderly approach to the diagnosis of inflammatory skin lesions was discussed. This chapter records in list form some useful points that may assist in reaching a correct diagnosis. Many of the clues that follow produce diagnostic lists that are not necessarily related to tissue reaction, etiology, or pathogenesis.

Some of the clues that follow are original observations; many have been around for decades. An acknowledgment should be made here of the work of A. Bernard Ackerman, who has contributed more “clues” to diagnostic dermatopathology than anyone else.

Like all “shortcuts,” the following “clues” must be used with caution. They are not absolute criteria for diagnosis, and they are not invariably present at all stages of a disease. An attempt has been made to group the clues into several sections.

Features of Particular Processes

Signs of Photosensitivity ( Fig. 3.1 )

  • Dilated vessels in the upper dermis

  • Stellate fibroblasts/dendrocytes

  • Deep elastotic fibers

  • Deep extension of the infiltrate

  • Epidermal “sunburn” cells

Note: The duration of the process and the underlying nature of the light reaction will influence the response. Only one or two features may be present; for example, sunburn cells (apoptotic keratinocytes) are confined to phototoxic and photosensitive drug eruptions.

Fig. 3.1, Photosensitivity reaction.

Signs of Rubbing/Scratching ( Fig. 3.2 )

  • Acute, severe : Pale pink epidermis, sometimes with loss of cell borders; pinpoint erosions or larger ulcers; fibrin below the epidermis

  • Chronic, persistent : Psoriasiform epidermal hyperplasia; vertical streaks of collagen in the papillary dermis; stellate fibroblasts/dendrocytes; fibroplasia of varying amounts; enlarged follicular infundibula (as prurigo nodularis commences); compact orthokeratosis

Fig. 3.2, Chronic rubbing leading to vertical collagen in the papillary dermis and psoriasiform hyperplasia of the epidermis. (H&E)

Subtle Clues to Drug Reactions

  • Superficial dermal edema

  • Activated lymphocytes

  • Eosinophils and/or plasma cells

  • Red cell extravasation

  • Endothelial swelling of vessels

  • Exocytosis of lymphocytes

  • Apoptotic keratinocytes.

The changes present will mirror the clinical types of reaction. In morbilliform reactions, lymphocytes extend into the lower epidermis and the apoptotic keratinocytes are in the basal layer.

Clues to Elastic Tissue Alterations

  • Small blue coiled/clumped fibers (pseudoxanthoma elasticum)

  • Wavy epidermis (particularly in children)

  • Elastophagocytosis

  • Dispersed neutrophils (early cutis laxa)

  • Unusually thickened collagen (connective tissue nevus).

Clues to Deficiency States

  • Confluent parakeratosis

  • Superficial epidermal necrosis and/or pallor

  • Mild psoriasiform hyperplasia

  • Hemorrhage (in pellagra and mixed deficiencies).

Clues to Fungal Infections ( Fig. 3.3 )

Basically, these features should prompt the performance of a periodic acid–Schiff (PAS) stain. Many simulants exist.

  • Compact orthokeratosis with no other explanation

  • Layering of epidermal cornification (“sandwich sign”)

  • Neutrophils in the epidermis/stratum corneum

  • Spongiosis, particularly palmoplantar

  • Suppurative folliculitis.

Fig. 3.3, Dermatophyte.

Subtle Clues to a Folliculitis ( Fig. 3.4 )

These signs refer to a likely folliculitis at deeper levels of the biopsy.

  • Neutrophils on top of the stratum corneum

  • Neutrophils at the edge of the tissue section

  • Uneven vasculitis (centered in one small area)—miliaria may do the same

  • Focal splaying of neutrophils and dust in mid dermis.

Fig. 3.4, Folliculitis.

“Last Week's Sign” ( Fig. 3.5 )

Last week's sign refers to a dermatosis, no longer active, that is “playing itself out.” It was presumably more active some days earlier.

  • Parakeratosis overlying basket-weave orthokeratin (the key feature)

  • Mild hyperplasia of the epidermis

  • Mild dermal inflammation.

Fig. 3.5, “Last week's sign.”

Lagging Histology

Lagging history refers to several conditions in which the clinical appearances may be striking in comparison to the histology.

  • Sclerodermoid graft-versus-host disease (GVHD) may have “rock-hard skin” but only subtle collagen deposition.

  • Cicatricial alopecia can be similar.

  • Urticaria: Histology underestimates the edema because of dehydration during tissue processing.

  • Prurigo nodularis: There may be clinical nodules but no histological swollen infundibula, only psoriasiform hyperplasia of lichen simplex chronicus.

  • Pauci-cellular photodermatoses: There may be striking clinical changes but only telangiectasia and sparse inflammatory cells on histology.

Histological Features—What Do They Suggest?

Superficial and Deep Inflammation ( Fig. 3.6 )

The presence of a superficial and deep inflammatory cell infiltrate within the dermis should trigger the mnemonic “8Ls + DRUGS.”

Fig. 3.6, A superficial and deep dermal infiltrate.


  • Light reactions

  • Lymphoma

  • Leprosy

  • Lues

  • Lichen striatus

  • Lupus erythematosus

  • Lipoidica (necrobiosis)

  • Lepidoptera (and other arthropods)


  • Dermatophyte

  • Reticular erythematous mucinosis

  • Urticarial stages (bullous pemphigoid)

  • Gyrate erythemas

  • Scleroderma (localized)

  • And, of course, drug reactions

A “Busy” Dermis ( Fig. 3.7 )

Busy refers to a dermis that appears focally hypercellular on scanning magnification and is not usually due to the usual inflammatory infiltrates.

  • Incomplete form of granuloma annulare

  • Interstitial granulomatous dermatitis

  • Interstitial granulomatous drug reaction

  • Resolving vasculitis (increased mucin also)

  • Chronic photodermatoses

  • Folliculitis—at deeper levels (cells are neutrophils and dust)

  • Subtle breast carcinoma recurrence

  • Desmoplastic melanoma (also perivascular lymphocytes)

  • Kaposi's sarcoma (early stage)

Fig. 3.7, A “busy” dermis.

Absent Stratum Corneum

  • Staphylococcal scalded skin syndrome

  • Pemphigus foliaceus

  • Peeling skin syndrome

  • Psoriatic erythroderma (psoriasiform hyperplasia present)

  • Artifacts

Filled Papillary Dermis ( Fig. 3.8 )

The low power impression is that of a variably hypercellular papillary dermis. Excluded from consideration are nodular and diffuse infiltrates also involving the reticular dermis. The “LUMP” mnemonic covers most cases: l ichenoid, u rticaria pigmentosa, m ycosis fungoides, p igmented purpuric dermatoses. Expressed differently they are as follows:

  • Most of the lichenoid tissue reactions

  • Pigmented purpuric dermatoses

  • Cutaneous T-cell lymphoma

  • Parapsoriasis (if not included earlier)

  • Some mastocytomas

  • Early lichen sclerosus et atrophicus.

Fig. 3.8, The papillary dermis is filled.

Papillary Microabscesses ( Fig. 3.9 )

  • Dermatitis herpetiformis

  • Linear immunoglobulin A (IgA) disease

  • Cicatricial pemphigoid

  • Localized cicatricial pemphigoid

  • Bullous lupus erythematosus

  • Epidermolysis bullosa acquisita

  • Drugs

  • Hypersensitivity vasculitis (rare)

  • Rheumatoid neutrophilic dermatosis

  • Pemphigoid gestationis (eosinophils)

  • Deep lamina lucida pemphigoid

  • Generalized exanthematous pustulosis (rare)

Fig. 3.9, Dermal papillary microabscess.

Sparse Perivascular Neutrophils

In some conditions, neutrophils are relatively sparse or less conspicuous than in vasculitis, a neutrophilic dermatosis, or cellulitis.

  • Erythema marginatum

  • Still's disease

  • Neutrophilic urticaria

  • Mild periodic fever syndromes

  • Early or subsiding neutrophilic dermatoses

  • Neutrophilic erythemas of infancy

  • Some flea bites

Thickened Basement Membrane ( Fig. 3.10 )

  • Lupus erythematosus

  • Dermatomyositis (less so)

  • Lichen sclerosus et atrophicus

Fig. 3.10, Thickened basement membrane and mild basal vacuolar change.

Mid-Dermal Infiltrate and Mucin ( Fig. 3.11 )

  • Cutaneous lupus erythematosus

  • Reticular erythematous mucinosis (REM)

  • Jessner's lymphocytic infiltrate

Other signs will usually allow these diagnoses, but sometimes REM will present with very little deep infiltrate. Biopsies appear to have a “mid-dermal plexus.” Dermatomyositis can have mucin, but the infiltrate is only superficial. Perifollicular mucin can be seen in Carney's complex. REM and Jessner's infiltrate (no longer used) are both patterns of expression of cutaneous lupus erythematosus.

Fig. 3.11, A “mid-dermal plexus” with perivascular inflammation is present.

Epidermotropism and Exocytosis ( Fig. 3.12 )

The terms epidermotropism and exocytosis are often used interchangeably. It is best to restrict them as follows:

  • Exocytosis : Random emigration of inflammatory cells through the epidermis; some cells will reach the surface. It is common in inflammatory dermatoses. In the spongiotic tissue reaction, it may be a striking feature in nummular dermatitis and spongiotic drug reactions.

  • Epidermotropism : Refers to directed emigration of lymphocytes; it usually involves only the lower one-third to half of the epidermis. The cells tend to aggregate. There is little, if any, accompanying spongiosis. It is a feature of mycosis fungoides.

Fig. 3.12, Epidermotropism.

The Epidermal/Follicular “Vacuum Cleaner” ( Fig. 3.13 )

The epidermal/follicular “vacuum cleaner” is the author's term for the irregular epidermal hyperplasia ± enlarged follicular infundibula, associated with the transepidermal elimination of material from the dermis. It can be subtle after cryotherapy to sun-damaged skin; it may be the cause of a persistent lesion at the site, often mistaken as a clinical recurrence.

Fig. 3.13, Epidermal “vacuum cleaner.”

Parakeratosis as a Helpful Sign

  • Lipping : See later

  • Spongiosis : Pityriasis rosea, erythema annulare centrifugum, seborrheic dermatitis, other spongiotic diseases

  • Neutrophils : Psoriasis (neutrophils in “summits” of mounds), seborrheic dermatitis, dermatophyte infection, necrolytic erythema, secondary bacterial infection

  • In tiers : Porokeratosis, verruca vulgaris, palmoplantar psoriasis

  • With interface change : Lichenoid drug, lichen planus–like keratosis, pityriasis lichenoides, lupus erythematosus (more often orthokeratosis)

  • Overlying orthokeratosis : Healing lesion or intermittent activity, particularly a spongiotic process

  • Alternating : Alternating orthokeratosis and parakeratosis in a horizontal direction is seen in ILVEN, and actinic keratosis, and in a horizontal and vertical direction in pityriasis rubra pilaris

  • Broad thick zones : Psoriasis, glucagonoma and deficiency states (epidermal pallor is not invariable), pityriasis lichenoides, granular parakeratosis.

Parakeratotic Follicular Lipping

  • Seborrheic dermatitis

  • Pityriasis rubra pilaris (follicular lesions)

  • Spongiotic processes, or psoriasis, on the face. The large number of follicles on the face means that they are more likely to be involved incidentally in any condition with parakeratosis.

“Chunks of Coal” ( Fig. 3.14 )

Large atypical lymphoid cells within a heavy mixed infiltrate occur in lymphomatoid papulosis. The cells have been likened to “chunks of coal.”

Fig. 3.14, “Chunks of coal.”

Interstitial Eosinophils ( Fig. 3.15 )

Interstitial eosinophils refers to the presence of eosinophils between collagen bundles and away from vessels. Perivascular eosinophils are also present.

  • Arthropod bites

  • Cnidarian contact

  • Other parasite infestations

  • Drug reactions

  • Toxic erythema of pregnancy

  • Annular erythemas of infancy

  • Wells’ syndrome

  • Dermal hypersensitivity

  • Hypereosinophilic syndrome

  • Urticaria

  • Urticarial stages of bullous pemphigoid, pemphigoid gestationis

  • Internal malignancy (rare)

Large numbers of eosinophils in suspected bite reactions suggest scabies or a hypersensitive state to the arthropod. Prebullous pemphigoid also has numerous eosinophils.

Fig. 3.15, Interstitial eosinophils in an insect bite reaction.

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