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BENIGN LYMPHOCYTIC INFILTRATES

Several dermatologic disorders are characterized by a predominantly lymphocytic skin infiltrate. Some of these are generalized processes, such as eczemas, psoriasis (which may have significant neutrophil infiltrate also), lichen planus, alopecia areata, and many others. These are not considered here, as they are not usually a source of problems for differential diagnosis. It is, however, worth being aware that many lesions alter over time; for example, most insect bites have a significant eosinophil component in their infiltrate, but more chronic bite reactions may be predominantly lymphocytic and thus enter the pathologic differential diagnosis of some of the disorders discussed in this section. The main disorders that are usually considered to fit into the category of cutaneous lymphocytic infiltrates are:

•	Jessner lymphocytic infiltrate,
•	lupus erythematosus (see Ch.13),
•	polymorphic light eruption (see Ch.17),
•	lymphocytoma cutis,
•	erythema annulare centrifugum and other annular (figurate) erythemas,
•	erythema multiforme, and
•	cutaneous lymphoma (see Ch.33).

Jessner lymphocytic infiltrate, Jessner–Kanof disease

Etiology and pathogenesis

This is a benign lymphocytic infiltrate that most closely resembles lupus erythematosus (LE), and is considered by some to be a variant of it. Like LE, provocation by sunlight is a common feature. There are, however, some immunopathologic differences from LE.

Clinical features

Lesions consist of (usually multiple) erythematous plaques and papules, which are most frequent on the head and upper trunk or upper arms (Fig. 11.4 and Fig. 11.5). In some instances, they may be markedly annular. They do not have the follicular plugging or atrophic changes seen in discoid LE. Premenstrual exacerbation is prominent in some cases.

Differential diagnosis

This includes the following.

•	Lupus erythematosis—the distinction from LE can be both clinically and histologically difficult, and may require passage of time for the situation to become clear (see also Fig.13.5).
•	Polymorphic light eruption—this is usually much more obviously related to sunlight, although some patients with Jessner lymphocytic infiltrate do report photoaggravation
•	Rosacea—occasionally very difficult to distinguish clinically, although pustules are usually present in rosacea (cutaneous demodicosis enters the same differential).
•	Lymphocytoma cutis—usually a problem only if there are few and rather nodular lesions.
•	Sweet syndrome—often affects the face, and usually more acute and pustular; histology will differentiate.
•	Annular erythemas—may be histologically similar, but usually do not affect the face, which is a common site for Jessner lymphocytic infiltrate.
•	Other annular eruptions that may affect the face—such as sarcoidosis, and annular lesions in Sjögren syndrome; these are usually distinguished by histology or by other clinical or laboratory features.
•	Cutaneous lymphoma and potential lymphoma precursors such as follicular mucinosis.

Fig. 11.4 Jessner lymphocytic infiltrate. A slightly tumid plaque on the cheek, which clinically may resemble an early lesion of discoid lupus erythematosus (LE), but which lacks the epidermal component of LE.

Fig. 11.5 Multiple lesions of Jessner lymphocytic infiltrate. Annular and arciform lesions are common in this condition, and may be difficult to distinguish from the group of ‘annular and figurate erythemas’, such as erythema annulare centrifugum.

Treatment

Response to treatment is unpredictable. Sunscreens may be useful prophylaxis. Topical steroids and systemic antimalarials or dapsone can be helpful.

Lymphocytoma cutis (Spiegler–Fendt sarcoid)

Etiology and pathogenesis

This term is used for a reactive B-lymphocyte proliferation that may resemble a cutaneous lymphoma (Ch.33) but has benign behavior. Some cases may follow insect bites, scabies nodules, and inoculations or tattoos.

Clinical features

Lesions may be solitary or multiple, and consist of firm purplish-colored dermal nodules (Fig. 11.6 – 11.8). The face and upper trunk are common sites; lesions may affect the nipple.

Differential diagnosis

The main differential diagnoses are insect bite reactions, cutaneous sarcoidosis, and cutaneous lymphoma. On the face in particular, skin tumors such as basal cell carcinoma are in the differential (as well as less common but typically firm purple-colored tumors such as cylindromas; see Ch.23). Cutaneous metastases occasionally need to be considered and, especially in the case of more widespread lesions, the other lymphocytic infiltrates discussed in this section.

Fig. 11.6 Solitary lesion of lymphocytoma cutis on the forehead. At this site, the differential diagnosis might include basal cell carcinoma, sarcoidosis, Jessner lymphocytic infiltrate, and LE.

Fig. 11.7 A lesion of lymphocytoma cutis on the trunk. This patient developed several similar lesions, and clinically was thought likely to have a B-cell lymphoma, although the histologic and immunocytochemical features strongly favored a benign process. Some such cases may be very difficult to characterize with confidence.

Fig. 11.8 Multiple small lesions of lymphocytoma cutis, known as a miliary pattern.

Treatment

Some lesions regress spontaneously. Intralesional steroid injection is a useful therapy.

Erythema annulare centrifugum and the ‘annular (figurate) erythemas’

Etiology and pathogenesis

The annular or figurate erythemas are a poorly defined and poorly understood group of disorders, which are felt to be a reactive dermatosis. The most characteristic is erythema annulare centrifugum (EAC; (Fig. 11.9 –11.11), which is usually idiopathic, although cases have occasionally been documented to be caused by a wide range of triggers, such as infections (dermatophytes and Candida), drugs (chloroquine and penicillin), foods (blue cheese), and tumors (Hodgkin disease). It may also rarely occur as a familial disorder.

    Erythema chronicum migrans due to borreliosis (Ch.24), erythema marginatum (a transient migratory rash in patients with rheumatic fever), and erythema gyratum repens due to gastrointestinal malignancy (Ch.12) are usually included under the heading of annular erythemas. Neonatal LE is also often listed in this group but should probably be viewed as separate, as there is usually diagnostic serology (Ch.13).

Fig. 11.9 Erythema annulare centrifugum. Arciform lesions (a) and sometimes multiple concentric annular areas (b) are common. This type of eruption is commonly confused with fungal infections unless samples are taken for mycologic examination.

 

Fig. 11.10 Some lesions of erythema annulare centrifugum have a well-developed scaling component. This is typically inward-pointing and proximal to the inflammatory advancing edge of the lesion, giving the impression that the scale is trailing the active lesion.

 

Fig. 11.11 Erythema annulare centrifugum. (a,b) Evolution of lesions, which typically move and enlarge over a period of days or weeks. They do not have the day-to-day variability in size and site that occurs in urticaria, but enlarge more rapidly than most fungal infections.

Clinical features

Erythema annulare centrifugum is an annular dermatosis with central clearing. It starts as a small macule with radial enlargement, occasionally over days but more typically over weeks or months. The edge is often urticated but with a trailing edge of scaling, and the central area clears, hence most lesions are erroneously diagnosed as ringworm dermatophyte infection (Ch.26).

Differential diagnosis

This includes the following.

•	Ringworm—a frequent and reasonable initial diagnosis, best excluded by mycology testing of skin scrapings.
•	Lupus erythematosus—especially neonatal and subacute cutaneous forms, generally distinguished by positive serology for anti-SSA.
•	Erythema multiforme—more acute, lesions expand but do not migrate or centrally clear, and different histology.
•	Granuloma annulare—there is no scaling, the (slowly) expanding edge of the lesion has a cobblestoned feel, and often more acrally sited.
•	Lyme borreliosis—usually larger, more rapidly spreading, and more inflammatory; serology may differentiate.
•	Jessner lymphocytic infiltrate—usually on the face, and lesions do not tend to migrate.
•	Sarcoidosis—annular lesions may occur but are more fixed; different histology.
•	Cutaneous lymphoma—annular lesions may occur but are more fixed; histology will differentiate.
•	Sjögren syndrome—annular lesions are usually on the face and are uncommon in non-Japanese.

Fig. 11.12 Target lesions of erythema multiforme. Although ‘classical’, neat concentric circles of this type are relatively uncommon; the trigger is almost always herpes simplex when the lesions are palmar and with this pattern.

Treatment

Most cases gradually subside, and response to treatment is variable. Topical steroids and oral antimalarials are used if required.

Erythema multiforme

Etiology and pathogenesis

Erythema multiforme (EM) is an abused term that is applied by non-dermatologists to many rashes with mixed morphology. It is best defined by the clinicopathologic correlation of appropriate skin lesions (described here) and consistent histologic features, which include an upper dermal lymphocytic infiltrate with (usually) exocytosis into the epidermis, upper dermal edema and erythrocyte extravasation, and epidermal cell death.

    Causes of EM include drugs, infections, and others (Table 11.2). About a third of cases are clearly linked to herpes simplex infection, and the 30% of cases that are idiopathic probably include a large proportion in which herpes simplex is the trigger but has been clinically unapparent. The disease spectrum includes mucosal lesions (Stevens–Johnson syndrome), and features overlap with those of toxic epidermal necrolysis (Ch.18)

    Erythema multiforme is more common than the other conditions discussed in this section.

Clinical features

Onset is relatively acute and may be preceded or accompanied by fever, malaise, and arthralgia. The characteristic clinical lesion of EM is the target lesion (Fig. 11.12– 11.16), which is usually most typical on the palms, especially in EM secondary to herpes simplex infection. Lesions may expand initially, classically producing concentric rings of pallor, erythema, or duskiness, and there may be central necrosis or blistering. They do not migrate or centrally clear in the manner seen in EAC. Often the eruption consists of papules and plaques with grayish central epidermal necrosis, rather than the multiple concentric circles of ‘classic’ target lesions. Crops of lesions may occur over a week or two.

Fig. 11.13 Target lesions of erythema multiforme. In (a) the cause was herpes simplex; in (b), with identical morphology, the lesions were drug-induced. The patient in (a) also had mucosal features of Stevens–Johnson syndrome.

 

Fig. 11.14 Nodular lesions of erythema multiforme (EM). This pattern, which usually affects the dorsal aspect of hands and forearms, is the typical morphology of EM related to orf infection. There is often associated swelling of the hands and general malaise.

 

Fig. 11.15 Stevens–Johnson syndrome affecting the lips, with confluent erosion. Occasionally, it can be difficult to distinguish between lip lesions of herpes simplex and those of Stevens–Johnson syndrome, but this may be important therapeutically.

 

Fig. 11.16 (a) Ocular involvement in Stevens–Johnson syndrome. Note that there is a lesion of erythema multiforme (EM) on the nose in (b). Conjunctivitis can occur in cases of EM without other mucous membrane involvement.

    Mucous membranes may be affected, including erosions of the lips (Fig. 11.15), oral vesicles, conjunctivitis (Fig. 11.16), and genital lesions. These may also occur in isolation, particularly in EM due to mycoplasma infection. In severe cases, esophageal or bronchial mucosae may be involved.

Differential diagnosis

Erythema multiforme is usually readily differentiated from the other lymphocytic infiltrates by its rapid onset, multiplicity and predominantly acral distribution of lesions, morphologic appearance, strong association with herpes simplex, and tendency to spontaneous resolution.

    Vasculitis does, however, need to be considered in the differential in some patients, especially if lesions are purpuric.     It may be difficult clinically to decide whether oral lesions are those of EM or those of a causative herpes simplex infection.

    Some patients get frequent premenstrual episodes of EM (probably caused by herpes simplex reactivation in most cases); this may be difficult to distinguish from progesterone dermatitis (Ch.12).

Treatment

The skin lesions cause few symptoms and may need no treatment. A topical steroid is generally sufficient for symptomatic areas. Systemic steroids are useful if there is significant malaise or swelling of the hands (as often occurs in EM due to orf virus), but should be used with caution in patients with underlying infective causes of EM. Mouth and eye care is important where these are involved, and oral steroids are usually administered in such cases.

PRACTICE POINTS

•	Annular erythemas are not common but should be considered if annular scaling lesions migrate and have negative mycology results or do not respond to antifungal agents.
•	Mixed clinical morphology of a rash does not mean it is erythema multiforme (EM); this is a specific clinicopathologic diagnosis.
•	Recurrent EM is almost always due to herpes simplex infection, even though this may be clinically occult.
•	In patients with predominantly mucosal EM, mycoplasma infection may be the trigger.

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White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.