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26 April 2017 - Case of the Week #423

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Thanks to Dr. Cristina Aguilar, Guthrie Clinic, for contributing this case and Dr. Hillary Zalaznick, Myriad Genetics, Inc., Utah (USA) for writing the discussion. To contribute a Case of the Week, first make sure that we are currently accepting cases, then follow the guidelines on our main Case of the Week page.


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Case of the Week #423

Clinical history:
A 73 year old woman presented with a viral rash on her lower right leg. Punch biopsy was performed.

Micro images:

What is your diagnosis?

Herpes virus vesicular dermatitis.

Test question (answer at the end):
Which of the following is NOT a cytologic change seen in herpes virus-infected cells?

A. Multinucleation
B. Margination of chromatin
C. Prominent nucleoli
D. Nuclear molding


The biopsies show acantholytic epidermis with suprabasilar blisters. The blisters occur at different levels within the epithelium, and scattered keratinocytes show the classic cytologic features of a herpes virus infection: multinucleation, nuclear molding and margination of the chromatin (the "three M's"). Eosinophilic inclusions (Cowdry type A) are present in the nucleus, sometimes with a halo in between the inclusion and the chromatin (Wick: Silverberg's Principles and Practice of Surgical Pathology and Cytopathology, 5th ed, 2015).

Herpes simplex I (HSV1), herpes simplex II (HSV2), and varicella-zoster virus (VZV) all look similar histopathologically and cytopathologically. The clinical presentations are different, however; primary infections with VZV (chicken pox) typically occur in children as itchy, painful vesicles with clear fluid on an erythematous base, mostly on the face and trunk. Recurrence of VZV (herpes zoster, shingles) can occur in the elderly or immunocompromised, but lesions usually appear in a dermatomal distribution on the skin. Blisters from HSV1 and HSV2 appear on the lips and genitals, but can appear on other parts of the skin as in herpes gladiatorum, or on the cornea. Lesions on mucosal surfaces such as the esophagus are usually ulcerated, with infected cells found at the edges of the ulcer (Wick: Silverberg's Principles and Practice of Surgical Pathology and Cytopathology, 5th ed, 2015).

Herpes viruses can also infect organ systems, such as the lungs and liver, where they cause acute inflammation and necrosis. Cells with the characteristic viral cytopathic changes may be difficult to find, but immunohistochemical stains can aid the diagnosis and help differentiate HSV from VZV (Wick: Silverberg's Principles and Practice of Surgical Pathology and Cytopathology, 5th ed, 2015).

The differential diagnosis includes other intra-epithelial blistering disorders, such as pemphigus vulgaris (PV) or Hailey-Hailey disease. PV also shows acantholysis and suprabasilar blisters, but the basal layer of keratinocytes remains attached to the basement membrane, giving those cells a "tombstone" appearance. Direct immunofluorescence will show IgG deposits in a chicken wire pattern around the keratinocytes in the vast majority of patients with PV. The blisters in Hailey-Hailey disease (benign familial pemphigus) are suprabasilar as well, but the roof of the blister has a "dilapidated brick wall appearance." Neither of these conditions shows the viral cytologic changes characteristic of herpes viruses (Wick: Silverberg's Principles and Practice of Surgical Pathology and Cytopathology, 5th ed, 2015). Of note, multinucleated keratinocytes (also known as multinucleated epidermal giant cells) that are somewhat reminiscent of herpes virus-infected cells can be seen in non- infectious inflammatory dermatoses, but these multinucleated cells will lack the other viral cytologic changes seen with herpes virus infection (Am J Dermatopathol 2015;37:e143).

Test Question Answer:
Prominent nucleoli

Image 01 Image 02