INFLAMMATORY DISORDERS OF THE SKIN AND SUBCUTIS:
A PRACTICAL AND ANALYTICAL APPROACH



CASE #2: PITYRIASIS ROSEA

Cynthia M. Magro, M.D., A.Neil Crowson, M.D., and Martin C. Mihm Jr., M.D.

Introduction/Clinical Features Pityriasis rosea (PR) is an idiopathic self-limited dermatosis which characteristically manifests salmon-colored macules, papules and papulovesicles sometimes associated with purpura. The characteristic "herald" patch occurs in the central back and extends in a symmetrical fashion to the proximal extremities, often following lines of cleavage and showing peripheral "cigarette paper-like" scales. Histopathology The histopathology of PR comprises a superficial perivascular lymphocytic infiltrate which shows exocytosis predominantly localized to suprapapillary plates, a slightly acanthotic epidermis, and mounds of parakeratin overlying the areas of epidermal damage. Pityriasis Rosea Pityriasis Rosea Spongiosis may be significant and plasma may be seen in the scale. Eosinophils may be present in some cases, but this is an unusual finding and might point more towards one of the differential diagnoses of PR, namely, the pityriasiform drug reaction. Colloid bodies may be scattered throughout the full-thickness of the epidermis; dyskeratosis may be pronounced in the basal layers as lesions involute. A characteristic finding as is the presence of superficial dermal and intra-epidermal hemorrhage. Multinucleated keratinocytes may be seen and may be indicative of humanherpes type VII cytopathic changes. Pathogenesis A viral based etiology has long been suspected in light of case clustering, occurrence in family members, and an antecedant upper respiratory tract illness. Recently an infectious based etiology was suggested by studies on peripheral blood mononuclear cells from PR patients showed ballooning cells and syncytia after 7 days in culture whereas peripheral blood mononuclear cells from controls and recovered PR patients did not. This cytopathic effect was also documented in a PR patient who relapsed. In serum supernatant, herpesvirus virions were detected by EM; PCR identified human herpesvirus-7 DNA in peripheral blood mononuclear cells, plasma and skin from all of a group of patients with active PR. However, case control studies show no increased incidence of antibodies to HHV 6 or 7 in patients with PR; the issue remains in doubt. Antibodies to parvovirus B19 have been also been described in patients with PR. Differential Diagnosis Among the differential diagnoses of PR under the microscope is that of a viral exanthem, for example, that seen in Giannoti-Crosti syndrome. The fact that PR has features reminiscent of that encountered in viral exanthems such as Giannoti-Crosti syndrome is not surprising given its probable pathogenesis. Both entities share lymphocytic exocytosis, spongiosis, and hemorrhage. In our experience, the most helpful discriminating features are the absence of acanthosis, the presence of a cell-poor vacuolar interface dermatitis, the more frequent identification of vesicles within the epidermis, and the lack of alterations of stratum corneum, all of which point towards an acute viral exanthem. In addition a concomitant interstitial granulomatous dermatitis may be seen within the superficial dermis in patients with acute viral exanthema. With respect to pityriasiform drug eruptions, tissue eosinophilia is an important clue. It should be emphasized that any elderly patient who manifests a PR-like eruption may have as the etiologic basis a drug reaction. Other differential diagnostic considerations include the so-called auto-eczematization or id reaction. A sudden generalized or localized vesicular dermatitis developing in association with a defined local dermatitis or cutaneous infection is known as an id reaction. If the patient has a remote cutaneous fungal infection, such as tinea pedis, the appellation dermatophytid is used. In some cases the underlying localized dermatitis leading to generalized auto-eczematization is stasis dermatitis. The histopathology is that of an acute spongiotic dermatitis virtually indistinguishable from the allergic contact dermatitis. The pathogenetic basis is an abnormal immune response to autologous skin antigens whereby activated T-lymphocytes appear to be the mediators of the response. References Cavani A, Mei D, Guerra E, Corinti S, Giani M, Pirrotta L, Puddu P, Girolomoni G. J Invest Dermatol 1998;111:621-8 Chuh AA, Peiris JS. Lack of evidence of active human herpesvirus 7 (HHV-7) infection in three cases of pityriasis rosea in children. Pediatr Dermaol 2001;18:381-3. Chuh AA, Chiu SS, Peiris JS. Human herpesvirus 6 and 7 DNA in peripheral blood leukocytes and plasma in patients with pityriasis rosea by polymerase chain reaction: a prospective case control study. Acta Derm Venereol 2001;81:289-09 Clark SH Jr, Mihm MC Jr. Reed RJ, Ainsworth AM. The lymphocytic infiltrates of the skin. Hum Pathol. 1974; 5:25-43. Cohen LM, Skopicki DK, Harrist TJ, Clark Jr WH. Noninfectious vesiculobullous and vesiculopustular diseases. In : Elder D, Elenitsas R, Jaworsky C, Johnson B, Ed's. Crowson AN, Magro CM. Drug eruptions. In : Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co,1998:257-270. Drago F, Ranieri E, Malaguti F, Battifoglio ML, Losi E, Rebora A. Human herpesvirus 7 in patients with pityriasis rosea. Electron microscopy investigations and polymerase chain reaction in mononuclear cells, plasma and skin. Dermatology 1997;195:374-8. Dvorak AM, Mihm MC Jr, Dvorak HF. Morphology of delayed-type hypersensitivity reactions in man. II. Ultrastructural alterations affecting the microvasculature and the tissue mast cells. Lab Invest. 1976;34:179-191. Dvorak HF, Mihm MC Jr, Dvorak AM, Johnson RA, Manseau EJ, Morgan E, Colvin RB. Morphology of delayed type hypersensitivity reactions in man. I. Quantitive description of the inflammatory response. Lab Invest. 1974;31:111-130. Dvorak HF, Mihm MC Jr. Basophilic leukocytes in allergic contact dermatitis. J Exp Med 1972;135:235-254. Farber-Marcus BS, Bergman R, Porath B et al. Serum antibodies to parvovirus B19 in patients with pityriasis rosea. Dermatology 1997;194:371. Kwan TH. Spongiotic dermatitis. In: Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co, 1998:17-32. Muhlbauer JE, Bhan AK, Harrist TJ, Moscicki RA, Rand R, Caughman W, Loss R, Mihm MC Jr. Immunopathology of pityriasis lichenoides acuta. J Am Acad Dermatol. 1984;10Pt I: 783-795. Rowe A, Bunker CB. Interleukin-4 and the interleukin-4 receptor in allergic contact dermatitis. Contact Dermatitis 1998;38:36-9 Toussaint S, Kamino H. Noninfectious erythematous, papular, and squamous diseases. In: Elder D, Elenitsas R, Jaworsky C, Johnson B, Ed's. Lever's Histopathology of the skin, 8th Ed'n, Philadelphia: Lippincott-Raven, 1997:151-184. Weedon D. The spongiotic reaction pattern. In : Skin Pathology. Edinburgh : Churchill Livingstone. 1997:83-107. OTHER SPONGIOTIC/ECZEMATOUS TISSUE REACTIONS (see Table 1): PHOTO-ALLERGIC REACTIONS Introduction/Pathogenesis Photo-allergic dermatitis may be due to the topical application or oral ingestion of an allergen resulting in either a photo-contact dermatitis or photo-drug reaction. The absorption of light energy appears to alter the photo-sensitizing chemical to produce a hapten which attaches to an endogenous protein carrier producing a hypersensitivity response. Clinical Features The lesions are characterized by pruritic erythematous papules and plaques in a photo distribution ie, the face, dorsal aspects of the arms, and the neck. Such reactions occur within twenty-four to forty-eight hours after sun exposure. Among the topical allergens are fragrances such as musk and sun-screens containing benzophenones. Plants have also been implicated. Systemically administered drugs which may induce photo-allergy include quinine, quinidine, chlorpromazine and tetracycline. Histopathology The eczematous component encompasses changes which are virtually identical to those described for acute allergic contact dermatitis including marked spongiosis with exocytosis of lymphocytes and eosinophils and Langerhans'cell- and eosinophil-containing intraepidermal vesicles. Features favoring photoallergy are a deeper extent of the dermal-based inflammatory cell infiltrate and striking vascular changes, namely endothelial cell swelling, mural edema, and variable fibrin deposition. Both the intensity of the perivascular lymphocytic infiltrate and the injurious vascular alterations decreases in intensity as the base of the biopsy is approached. Certain drugs, specifically the thiazides and anti-histamines, may evoke a lichenoid photodermatitis whose histomorphology does not resemble the prototypic photo-allergic dermatitis; this will be considered in greater detail in the section of interface dermatitis. THE DIFFERENTIAL DIAGNOSIS OF PSORIASIFORM TISSUE REACTIONS: NUMMULAR ECZEMA Introduction/Pathogenesis Hypersensitivity reactions of diverse type may form annular lesions to which the term "nummular eczem" is applied. The etiology is unknown for many such cases, but does not appear to relate to the atopic diathesis. Possible associations include stasis dermatitis and drug therapy. Clinical Nummular eczema is characterized clinically by papules and papulovesicular lesions which coalesce to produce one or more coin-shaped plaques which may have a weeping surface. There is a predilection to involve the dorsum of the hands, the extensor aspects of the forearms, the lower parts of the legs, and the posterior aspect of the trunk. The course is one of chronicity with remissions and exacerbations. Histopathology The histology is that of an eczematous dermatitis, the precise features of which depend on the age of lesion biopsied. Lesions of early onset can look like an acute allergic contact dermatitis with marked spongiosis and vesiculation. However, eosinophilic spongiosis as noted in the prototypic allergic contact dermatitis is not common. Lesions are more often biopsied in a chronic or subacute phase and have more florid epidermal hyperplasia and less spongiosis, typically without vesiculation. The superficial dermal-based infiltrate can be quite heavy and comprises a mixed population of lymphocytes, histiocytes, neutrophils and eosinophils. As the lesions are pruritic there may be changes indicative of external trauma, as manifested by an impetignized scale crust namely neutrophil imbued parakeratosis with admixed bacteria, wedge-shaped areas of eosinophilic epidermal necrosis, subepidermal fibrin deposition and hemorrhage. Old lesions have a morphology defined by lichen simplex chronicus, the hallmarks of which are marked epidermal hyperplasia with hyperkeratosis, a variable dermal-based infiltrate and the absence of intraepidermal inflammatory cells. Differential diagnosis The differential diagnosis of nummular eczema includes atopic eczema and seborrheic dermatitis. Regarding atopic eczema, the patients may have other features of the atopic diathesis, such as asthma, allergic rhinitis; in addition the rash is characteristically accentuated on the extensor surfaces of the arms and legs. Over time, a lichenified dermatitis with a predilection for the flexural surfaces of the arms and legs develop. In later life, the only manifestation of the atopic diathesis may be a hand and foot dermatitis. The etiology is still unclear, however, IgE-mediated late-phase responses and a TH2/TH1 imbalance appear to be operative. The histology resembles the chronic phase of nummular eczema by virtue of moderate to marked epidermal hyperplasia with hyperkeratosis and slight spongiosis with some exocytosis of lymphocytes. The dermis shows variable fibroplasia and a superficial perivascular lymphocytic and eosinophilic infiltrate. Seborrheic dermatitis is distinctive clinically manifesting as erythematous or greasy yellow scaling papules and plaques involving the scalp, ears, eyebrows, eyelid margins and nasal labial folds (the so-called "seborrheic" areas). Males are more commonly affected. Some cases are associated with AIDS. The histopathology resembles a subacute or chronic spongiotic dermatitis. Eosinophilic spongiosis is absent. There are usually no eosinophils within the superficial dermis. The spongiotic and parakeratotic changes can manifest peri-follicular accentuation. In patients with AIDS, focal dyskeratosis and dermal-based plasmacellular infiltrates are diagnostic clues. The neutrophil imbued parakeratosis in concert with granular cell layer diminution may mimic psoriasis, but the areas of neutrophil-rich parakeratosis have a propensity to involve the follicular ostia and peri-follicular epidermis, a localization not observed in psoriasis. In addition, psoriasis rarely has a concomitant spongiotic eczematous component, and the characteristic hallmarks of the psoriatic diathesis, suprapapillary plate attenuation and dermal papillae capillary ectasia, are not observed in seborrheic dermatitis. References Cohen LM, Skopicki DK, Harrist TJ, Clark Jr WH. Noninfectious vesiculobullous andvsiculopustular diseases. In : Elder D, Elenitsas R, Jaworsky C, Johnson B, Ed's. Lever's Histopathology of the skin, 8th Ed'n, Philadelphia: Lippincott-Raven, 1997:209-252 Kwan TH. Spongiotic dermatitis. In: Barnhill R, Crowson AN, Busam K, Granter S ed's. Textbook of Dermatopathology. New York : McGraw-Hill Co, 1998:17-32. Mihm MC, Jr, Soter NA, Dvorak HF, Austen KF. The structures of normal skin and the morphology of atopic eczema. J Invest Dermatol 1976;67:305-12. Soter NA, Mihm MC Jr. Morphology of atopic eczema. Acta Derm Venereol (Stockh) Suppl 1980;92:11-15. Weedon D. The spongiotic reaction pattern. In : Skin Pathology. Edinburgh : Churchill Livingstone. 1997:83-107. SUPERFICIAL ERYTHEMA ANNULARE CENTRIFUGUM Introduction/Clinical Erythema annulare centrifugum, one of the gyrate erythemas, comprises one or more annular fixed or migratory erythematous lesions, often with a "trailing" scale at the advancing edge, which tend to involve the trunk and proximal extremities. Lesions have been divided into superficial and deep types depending upon the presence or absence of the superficial scale. Onset is most often in early adulthood or middle age. The initial lesion is a pink infiltrative papule which slowly enlarges to form a ring as the center fades. Some lesions reach a diameter of 8.0 - 10.0 cm over several weeks while others manifest eccentric expansion to generate an irregular arciform pattern. They may last from days to months and can be associated with purpuric or pigmented residua. The differential diagnoses clinically include erythema gyratum repens, erythema chronicum migrans, annular erythema of infancy and erythema marginatum. Pathogenesis A variety of trigger factors are implicated (see Table); with respect to superficial EAC, roughly one-third of cases are associated with superficial fungal infections at remote sites, or are temporally associated with the ingestion of bread molds suggesting that these cases represent a form of fungal id reaction. Similar lesions may be seen in the neonatal period in which they be a sign of maternal lupus erythematosus; however the histology is one of lupus erythematosus defining the entity of neonatal lupus erythematosus. Histopathology The deep variant of EAC manifests tight "sleeve-like" cuffs of lymphocytes around superficial and deep blood vessels, unaccompanied by exocytosis, spongiosis or a parakeratotic scale crust, while the superficial variant of EAC characteristically has a similar, but more superficially disposed perivascular lymphocytic or lympho-eosinophilic infiltrate with pronounced exocytosis, mounds of parakeratin overlying the areas of epidermal damage, and frequent striking edema of the papillary dermis. The epidermis is classically not altered in thickness while, in the cases associated with remote fungal infection, neutrophils are often present in the scale crust as a component of the id reaction. Some vacuolar change along the dermal-epidermal junction may be seen. Endothelial swelling, sometimes accompanied by dermal hemorrhage, completes the picture. With respect to differential diagnosis, the histopathology of erythema gyratum repens closely simulates superficial EAC, although the clinical picture - a migrating eruption with a pattern mimicking marble or the cut surface of a tree trunk, should enable distinction. With respect to erythema marginatum, dyskeratotic cells in the epidermis and a superficial neutrophil rich urticarial tissue reaction are present. The most important distinguishing feature for erythema chronicum migrans is positive Borrelia serology; we rely heavily on serological studies, as opposed to silver stains, in any migratory erythema which develops in locations where Lyme disease is endemic. Features suggestive of erythema chronicum migrans include a lymphocytic and plasmacellular neuritis and plasma cells within the dermal infiltrate. Pauci-inflammatory vasculopathic changes accompanied by dermal mucin have been described as an additional morphologic reaction pattern seen in patients with erythema chronicum migrans. Such a morphology is found in the lateral erythematous border of a plaque of ECM. References Clark WH Jr, Mihm MC Jr, Reed RJ, Ainsworth A. The lymphocytic infiltrates of the skin. Human Pathol. 1974; 5: 25-43. Hood AF, Kwan TH, Mihm MC Jr, Horn TD. Primer of Dermatopathology. Second edition. Boston: Little, Brown & Co, 1993. TABLE 1 Spongiotic Dermatitis Allergic contact dermatitis Allergic eczematous drug reaction Photoallergic dermatitis of contact or drug based etiology Auto-eczematization/id reaction Incipient phase of nummular eczema Moderate spongiosis with vesiculation; no eosinophilic exocytosis Atopic eczema Subacute and chronic nummular eczema Seborrheic dermatitis Moderate spongiosis with parakeratosis, erythrocyte extravasation and variable keratinocyte necrosis Pityriasis rosea (PR) PR like drug eruption Superficial EAC Erythema Gyratum Repens Viral exanthem/Papular acrodermatitis of Childhood (Gianotti-Crosti Syndrome)