Skin nontumor

• Comparable or equivalent histologic terms: cutaneous hypersensitivity reaction / response, dermal hypersensitivity response, urticarial hypersensitivity reaction
• For idiopathic pruritic skin conditions, some clinicians include dermal hypersensitivity reaction in their clinical differential diagnosis
• Similar or equivalent terms: itchy red bump disease, papular dermatitis, subacute prurigo and urticarial dermatitis
• Note: papular urticaria is a synonym for arthropod bite reactions; drug induced hypersensitivity syndrome (DIHS) is a specific type of drug reaction

• Idiopathic cases tend to involve the trunk, upper extremities or lower extremities, often symmetrically
• In cases with an identified disorder, involved sites should be compatible with the specific disorder (J Am Acad Dermatol 2002;47:898, Arch Dermatol 2006;142:29, J Am Acad Dermatol 2014;70:263)

• Histologic reaction pattern that must be confirmed microscopically but the final diagnosis requires clinical correlation
• Deeper tissue sections to rule out other diagnoses may be needed; e.g., folliculitis, spongiotic dermatitis, scabies may become apparent only in deeper sections
• Exceptionally, may be a paraneoplastic hypersensitivity reaction (J Am Acad Dermatol 2010;63:e13, Clin Exp Dermatol 2016;41:322)

• Idiopathic cases have chronic course with potentially unsatisfactory responses to treatment (see Treatment)
• No reported impact on life expectancy in idiopathic cases

• In cases with a clinically confirmed disorder, management is dictated by standard management for that disorder
• In idiopathic cases, treatment is symptomatic and management tends to be challenging and unsatisfactory
• Phototherapy, systemic steroids and immunosuppressants, such as methotrexate and mycophenolate mofetil have been reported (J Am Acad Dermatol 1998;38:929, J Dermatolog Treat 2015;26:431, Arch Dermatol 2006;142:1512, Ann Dermatol 2017;29:143)

Contributed by Maxwell A. Fung, M.D.

Contributed by Maxwell A. Fung, M.D.

• Differential diagnosis of dermal hypersensitivity reaction is broad; clinical correlation is required in all instances
• Drug eruption:
  • Subtle vacuolar interface changes or spongiosis are often present
• Arthropod bite reaction (papular urticaria):
  • Infiltrates tend to be deeper and denser with abundant eosinophils; may involve subcutis; may show centrally positioned intraepidermal vesicle or crusted erosion / ulcer (punctum)
  • Clinically, the lesions should be exclusively papules, erythematous and usually edematous / urticarial and tend to occur either as a single or localized cluster of papules on the extremities, ideally with a patient confirmed mosquito, flea, mite or other arthropod exposure
• Atopic dermatitis:
  • Biopsies of atopic dermatitis usually present as spongiotic dermatitis so more prominent spongiosis, such as spongiotic vesicles and confluent or diffuse parakeratosis, would support this possibility
  • Clinically, patients present with eczematous skin plaques or papules and a personal or history of atopy; diagnostic criteria (Hanifin-Rajka) for atopic dermatitis may be applied by the clinician
• Contact dermatitis:
  • Biopsies of contact dermatitis usually present as spongiotic dermatitis, so more prominent spongiosis, such as spongiotic vesicles and confluent or diffuse parakeratosis, would support this possibility
  • Clinically, allergens or irritants may be confirmed by clinical history or patch testing
• Spongiotic / eczematous dermatitis, NOS:
  • Dermal hypersensitivity reaction with more prominent spongiosis, such as spongiotic vesicles and confluent or diffuse parakeratosis, would support this possibility
  • Clinical correlation is required to confirm a specific type of spongiotic / eczematous dermatitis (e.g., atopic, contact, nummular)
• Urticaria:
  • Dermal hypersensitivity reaction with no epidermal changes at all; dermal edema and neutrophils typically present in addition to the lymphocytes and eosinophils
• Pruritic urticarial papules and plaques of pregnancy (PUPPP):
  • Dermal hypersensitivity reaction, sometimes with more prominent spongiosis and marked papillary dermal edema
• Associated with malignancy or other systemic conditions:
  • Dense, eosinophil predominant infiltrates have been reported; reported associations include Hodgkin lymphoma, large B cell lymphoma, leukemia, myelodysplastic syndrome, prostate cancer, colon cancer, vulvar cancer, breast cancer, autoimmune diseases, herpes virus and H. pylori infection (Clin Exp Dermatol 2016;41:322, J Am Acad Dermatol 2010;63:e13, J Cutan Pathol 2012;39:929, JAAD Case Rep 2020;6:156)
• Urticarial vasculitis:
  • In addition to clinical correlation, evidence of vasculitis from another biopsy or a positive direct immunofluorescence (DIF) result would typically be required
• Bullous pemphigoid:
  • Infiltrate of eosinophils centered upon the dermoepidermal junction and within the epidermis (eosinophilic spongiosis) would be typical of the urticarial or prebullous phase of pemphigoid
  • Positive DIF result from perilesional skin would be required
• Scabies:
  • Crust and prominent eosinophils are typical
  • Deeper sections, multiple biopsies or scabies prep may be required to identify diagnostic findings (mite, eggs, feces [scybala])
• Wells syndrome (eosinophilic cellulitis) and other eosinophil predominant infiltrates:
  • Dermal hypersensitivity reaction must contain eosinophils but the infiltrate is predominately lymphocytic (Dermatol Clin 2012;30:667)
  • Flame figures typify Wells syndrome but may be present occasionally in any eosinophil rich dermal infiltrate
• Viral exanthem:
  • Vacuolar interface dermatitis, often with extravasated erythrocytes and exocytosis of lymphocytes, often accompanies sparse dermal infiltrates
  • Eosinophils are not specifically characteristic of a viral exanthem but would not exclude this possibility

• Fung: Inflammatory Diseases of the Dermis and Epidermis, 2010, Billings: Inflammatory Dermatopathology: A Pathologist's Survival Guide, 2nd Edition, 2016, UpToDate: Uritcarial Dermatitis [Accessed 22 September 2021], Curr Allergy Asthma Rep 2015;15:62, Int J Dermatol 2019;58:e196, J Cutan Pathol 2021;48:592, Australas J Dermatol 2014;55:137, J Am Acad Dermatol 2010;62:541

Which of the following histologic findings is required for the diagnosis of dermal hypersensitivity reaction?

1. Eosinophils
2. Granulomas
3. Neutrophils
4. Plasma cells
5. Spongiosis

A. Eosinophils. Required histologic features of dermal hypersensitivity reaction include a perivascular and interstitial lymphocytic infiltrate with eosinophils. Neutrophils and spongiosis are variable but not required findings. Granulomas and plasma cells are not features of dermal hypersensitivity reaction.

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Reference: Dermal hypersensitivity reaction

A punch biopsy of a pruritic eruption of 5 years duration involving the trunk of a 64 year old man is reported as a dermal hypersensitivity reaction. The pathologist commented that deeper sections were negative. The microscopic description documents scant parakeratosis and spongiosis. Which of the following may be considered in the differential diagnosis?

1. Folliculitis
2. Sarcoid
3. Syphilis
4. Urticaria
5. Urticarial dermatitis

E. Urticarial dermatitis. The negative deeper sections are against folliculitis. Sarcoid would require granulomas which are not a feature of dermal hypersensitivity reaction. Syphilis typically shows a psoriasiform lichenoid pattern with plasma cells. The parakeratosis and spongiosis excludes urticaria.

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Reference: Dermal hypersensitivity reaction