Dermatology: Practical and Conceptual Review | Dermatol Pract Concept 2014;4(4):3 21 DERMATOLOGY PRACTICAL & CONCEPTUAL www.derm101.com Epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection: multinucleated epithelial giant cells in the epidermis of lesional skin biopsies from patients with acantholytic dermatoses can histologically mimic a herpes virus infection Philip R. Cohen1, Taraneh Paravar1, Robert A. Lee1 1 Division of Dermatology, University of California San Diego, San Diego, California Keywords: acantholytic, cell, dermatoses, dermatosis, disease, epidermis, epithelial, giant, Grover, herpes, infection, multinucleated, pemphigus, transient, virus, vulgaris Citation: Cohen PR, Paravar T, Lee RA. Epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection: multinucleated epithelial giant cells in the epidermis of lesional skin biopsies from patients with acantholytic dermatoses can histologically mimic a herpes virus infection. Dermatol Pract Concept. 2014;4(4):3. http://dx.doi.org/10.5826/dpc.0404a03 Received: July 22, 2014; Accepted: July 24, 2014; Published: October 31, 2014 Copyright: ©2014 Cohen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The authors have no conflicts of interest to disclose. All authors have contributed significantly to this publication. Corresponding author: Philip R. Cohen, M.D., Division of Dermatology, University of California, San Diego, CA, USA. Email: mitehead@ gmail.com Background: Multinucleated giant cells in the epidermis can either be epithelial or histiocytic. Epithe- lial multinucleated giant cells are most often associated with herpes virus infections. Purpose: To review the histologic differential diagnosis of conditions with epithelial and histiocytic multinucleated giant cells—since multinucleated giant cells in the epidermis are not always pathog- nomonic of a cutaneous herpes virus infection—and to summarize dermatoses in which herpes virus infection has been observed to coexist. Methods: Two individuals with acantholytic dermatoses whose initial lesional skin biopsies showed multinucleated epithelial giant cells suggestive of a herpes virus infection are reported. Using the PubMed database, an extensive literature search was performed on multinucleated giant cell (and epidermis, epithelial, and histiocytic) and herpes virus infection. Relevant papers were reviewed to discover the skin conditions with either multinucleated giant cells in the epidermis or coincident cuta- neous herpes virus infection. Results: Initial skin biopsies from patients with either pemphigus vulgaris or transient acantholytic dermatosis mimicked herpes virus infection; however, laboratory studies and repeat biopsies estab- lished the correct diagnosis of their acantholytic dermatosis. Hence, epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection. Indeed, epithelial multinucleated giant cells in the epidermis can be observed not only in the presence of infection (herpes virus), but also acantholytic dermatoses and tumors (trichoepithelioma and pleomorphic basal cell carcinoma). Histiocytic multinucleated giant cells in the epidermis can be observed in patients with either giant cell lichenoid dermatitis or lichen nitidus of the palms. (continued next page) ABSTRACT 22 Review | Dermatol Pract Concept 2014;4(4):3 Introduction Herpes virus infection of the skin is characterized by the find- ing of multinucleated giant cells in the epidermis. We report two individuals with acantholytic dermatoses whose initial lesional skin biopsies showed multinucleated epithelial giant cells suggestive of a herpes virus infection; however, all viral studies were negative and subsequent biopsies of their lesions demonstrated pathognomonic features of either pemphigus vulgaris or transient acantholytic dermatosis. The histologic differential diagnosis of conditions with multinucleated giant cells in the epidermis is reviewed and dermatoses in which herpes virus infection has been observed to coexist are sum- marized. Case reports Case 1 A 24-year-old Caucasian woman presented with painful oral sores that persisted after a short tapering course of oral cor- ticosteroids (methylprednisolone dose pack) that was stopped after 5 days. Her past medical history was significant for type 1 diabetes mellitus and genital herpes simplex virus infection. She subsequently developed tender fluid-filled blisters of her axilla and groin and was empirically treated with oral vala- cyclovir 1000 mg twice daily without improvement. Examination of the oral cavity showed ulcers on the hard palate, the buccal mucosa and the mucosa of the gingiva and labia. Pustules, vesicles, and bullae were observed within the right axillae (Figure 1) and the labia majora. A lesional skin biopsy from the right axilla was performed; specimens for bacterial culture, direct fluorescent antibody studies and viral cultures were also obtained. Microscopic examination showed epidermal necrosis and ulceration surmounted by basophilic debris; rare cocci-shaped bacteria were seen within the inflammatory scale crust. Focal reticular degeneration, intraepidermal neutrophilic pustules forming a suprabasilar cleft, and numerous multinucleated Conclusions: Epithelial and histiocytic multinucleated giant cell can occur in the epidermis. Kerati- nocyte-derived multinucleated giant cells are most commonly associated with herpes virus infection; yet, they can also be observed in patients with skin tumors or acantholytic dermatoses. Cutaneous herpes simplex virus infection can coexist in association with other conditions such as acantholytic dermatoses, benign skin tumors, bullous disorders, hematologic malignancies, inflammatory derma- toses, and physical therapies. However, when a herpes virus infection is suspected based upon the discovery of epithelial multinucleated giant cells in the epidermis, but either the clinic presentation or lack of response to viral therapy or absence of confirmatory laboratory studies does not support the diagnosis of a viral infection, the possibility of a primary acantholytic dermatosis should be consid- ered and additional lesional skin biopsies performed. Also, because hematoxylin and eosin staining is not the golden standard for confirmation of autoimmune bullous dermatoses, skin biopsies for direct immunofluorescence should be performed when a primary bullous dermatosis is suspected since the histopathology observed on hematoxylin and eosin stained sections can be misleading. ABSTRACT (continued) Figure 1. The right axilla of a woman with pemphigus vulgaris shows pustules and vesicles on a faint erythematous base. (Copy- right: ©2014 Cohen et al.) keratinocyte giant cells demonstrating nuclear molding were noted. There was a perivascular infiltrate in the upper dermis consisting of neutrophils and eosinophils (Figure 2). The pathology was consistent with a herpes virus infec- tion. The patient was hospitalized and treated for dissemi- nated herpes virus infection with intravenous acyclovir at a dose of 10 mg per kilogram every 8 hours. The bacterial culture grew methicillin-resistant Staphylococcus aureus and intravenous vancomycin was added. She continued to develop similar-appearing new lesions not only in her mouth, axilla and groin, but also on her arms and abdomen; in addition, earlier pustules and vesicles had enlarged and/or ruptured (Figure 3). The direct fluorescence antibody studies and the viral cultures were negative for both herpes simplex virus and varicella-zoster virus. Repeat skin biopsies were performed for routine staining and direct immunofluorescence. Microscopic examination showed an intraepidermal blis- ter containing acantholytic keratinocytes, numerous eosino- phils, and occasional neutrophils; the adjacent epithelium showed spongiosis with eosinophils. Perivascular inflamma- tion, consisting of prominent eosinophils and occasional lym- Review | Dermatol Pract Concept 2014;4(4):3 23 phocytes, was present in the upper dermis (Figure 4). Direct immunofluorescence showed positive intercellular staining in the epidermis for IgG and C3. Subsequently, enzyme-linked immunosorbent assay (ELISA) testing demonstrated that the serum IgG titers were elevated for both desmoglein 1 and desmoglein 3. Figure 2. (A) Distant, (B) close and (C) closer views of the initial biopsy specimen that showed features consistent with a herpes virus infection. (A) Basophilic debris is seen within the inflammatory scale crust overlying necrosis and ulceration of the epidermis. (B) There is a suprabasilar cleft showing an intraepidermal neutrophilic pustule; multinucleated keratinocyte giant cells are noted in the pustule. (C) Nuclear molding can also be noted within several of the multinucle- ated keratinocyte giant cells (hematoxylin and eosin; a= x4, b=20, c=x40). (Copyright: ©2014 Cohen et al.) A B C Figure 3. Enlargement and/or rupture of pustules and vesicles in the right axilla of the women with pemphigus vulgaris. (Copyright: ©2014 Cohen et al.) Figure 4. (A) Distant and (B) closer views of the repeat biopsy specimen that establish the diagnosis of pemphigus vulgaris. Acantholytic kera- tinocytes, numerous eosinophils, and occasional neutrophils are present in an intraepidermal blister; eosinophilic spongiosis is present in the adjacent epithelium. Prominent eosinophils and occasional lymphocytes compose the perivascular infiltrate in the upper dermis (hematoxylin and eosin; a= x20, b=x40). (Copyright: ©2014 Cohen et al.) A B 24 Review | Dermatol Pract Concept 2014;4(4):3 Figure 5. (A) Distant, (B) close and (C) closer view of the left upper chest of a woman with transient acantholytic dermatosis presenting as pruritic erythematous papules. (Copyright: ©2014 Cohen et al.) A B C Figure 6. (A) Distant, (B) close and (C) closer views of the initial biopsy specimen that showed features consistent with a herpes virus infection. (A) An intraepidermal vesicle with suprabasilar epidermal acantholysis and cleft formation is noted. (B and C) Closer views show neutrophils and eosinophils in both the intraepidermal vesicle and the dermis; in the blister cavity, multinucleated keratinocyte gi- ant cells with nuclear molding are also noted (hematoxylin and eo- sin; a= x4, b=x20, c=x40). (Copyright: ©2014 Cohen et al.) A B C Correlation of the clinical findings, laboratory studies, and repeat skin biopsies established a diagnosis of pemphigus vulgaris. Initial management included 60 mg daily of oral prednisone. She also received intravenous rituximab, 2 doses of 1000 mg each separated by 2 weeks, prior to tapering her daily prednisone over the next 6 months. Her skin lesions resolved without recurrence. Case 2 A healthy 40-year-old Caucasian woman presented with a recurrent itchy rash on her chest and abdomen of more than one-year duration. Her past medical history was negative for herpes virus infection. Cutaneous examination revealed discrete pruritic ery- thematous and crusted papules on her chest and abdomen (Figure 5). A lesional biopsy was performed. Empiric topical treatment was initiated with triamcinolone 0.1% ointment. Review | Dermatol Pract Concept 2014;4(4):3 25 Microscopic examination showed suprabasilar epider- mal acantholysis and cleft formation with neutrophils and eosinophils in both the intraepidermal vesicle and the dermis. Multinucleated keratinocyte giant cells with nuclear molding were also seen in the blister cavity (Figure 6). The pathologic findings were interpreted as a herpes virus infection. The clinical features and improvement with topical corti- costeroid therapy did not correlate with the observed patho- logic findings. Direct fluorescence antibody studies and viral cultures did not demonstrate herpes virus infection. A repeat skin biopsy was performed of a new lesion on her upper chest. The second biopsy specimen showed acanthosis with focal acantholysis and dyskeratosis; viral cytopathic changes were absent. Lymphocytic inflammation was present in the upper dermis (Figure 7). Correlation of the clinical presentation, labo- ratory studies, and pathologic changes established the diagno- sis of transient acantholytic dyskeratosis (Grover’s disease). Discussion Multinucleated giant cells can be observed in the epidermis (Table 1) [1-10]. The etiology of the giant cells can either be epithelial or histiocytic. Histiocytic epidermal multinucleated giant cells have been noted in giant cell lichenoid dermatitis [7,8] and lichen nitidus of the palms [9,10]. TABLE 1. Conditions with multinucleated giant cells in the epidermis Epithelial cell origin Acantholytic dermatosis Pemphigus vulgaris [current report] Transient acantholytic dermatosis [current report] Infection Herpes virus infection [1-3] Tumors Benign Trichoepithelioma [4] Malignant Pleomorphic basal cell carcinoma [5,6] Histiocytic cell origin Giant cell lichenoid dermatitis [7,8] Lichen nitidus of the palms [9,10] Figure 7. (A) Distant, (B) close and (C) closer views of the repeat bi- opsy specimen that establish the diagnosis of transient acantholytic dermatosis. Acanthosis, with focal acantholysis and dyskeratosis, is noted in the epidermis and lymphocytic inflammation is present in the upper dermis; viral cytopathic changes are absent (hematoxylin and eosin; a= x4, b=x20, c=x40). (Copyright: ©2014 Cohen et al.) A B C Epithelial multinucleated giant cells are most often asso- ciated with herpes virus infections [1-3]. However, they occasionally occur in either benign or malignant tumors of epidermal cell origin such as trichoepitheliomas or basal cell carcinomas, respectively [4-6]. We recently observed multi- nucleated giant cells of keratinocyte origin, which mimicked those noted in herpes virus infection, in the epidermis of patients with acantholytic dermatoses: pemphigus vulgaris [11-15] and transient acantholytic dermatosis [16-21]. Herpes virus infections of the skin usually present as erythematous-based vesicles. Microscopic examination of a 26 Review | Dermatol Pract Concept 2014;4(4):3 lesional biopsy often shows multinucleated ballooned kerati- nocyte giant cells in the epidermis containing steel-gray nuclei with accentuation of nucleoplasm at their periphery; acantho- lytic, sometime necrotic, keratinocytes within intraepidermal blisters can also be noted. The diagnosis of herpes virus infec- tion can be confirmed by direct fluorescent antibody testing or viral culture [1-3,22-25]. Herpes simplex virus infection can coexist in associa- tion with other skin conditions; this likely represents the coincident development of this viral infection in an immuno- compromised district—an area of skin that have been made vulnerable by a previous or concurrent cutaneous disorder [26]. In addition to acantholytic dermatoses and bullous dis- orders (Table 2) [27-33], herpes simplex virus can also occur in association with hematologic malignancies [27,34,35], inflammatory dermatoses [27,35], and physical therapies [27,35,36]. Rarely, herpes virus infection has been discovered in benign skin tumors, such as seborrheic keratoses [37]. Our patients had acantholytic dermatoses that were ini- tially interpreted to represent a herpes virus infection based on the presence of multinucleated epithelial giant cells in the epidermis of lesional skin biopsies. However, additional eval- uation (including direct fluorescent antibody studies and viral cultures) was negative for a viral infection. In addition, one patient failed to improve after oral or intravenous treatment with antiviral therapy. Subsequently, repeat biopsies for direct immunofluorescence and/or routine histology established the correct diagnosis for both patients. Conclusion Epithelial and histiocytic multinucleated giant cell can occa- sionally be found in the epidermis. Although keratinocyte- TABLE 2. Acantholytic or bullous dermatoses in which herpes simplex virus infection has been demonstrated to be present in the skin lesion [27-33] Bullous pemphigoid Epidermolysis bullosa Familial benign chronic pemphigus (Hailey-Hailey disease) Keratosis follicularis (Darier’s disease) Pemphigus foliaceus Pemphigus vulgaris Staphylococcus scalded skin syndrome Transient acantholytic dermatosis (Grover’s disease) derived multinucleated giant cells are most commonly caused by a herpes virus infection, they can also be observed in either benign or malignant skin tumors or in patients with acantho- lytic dermatoses. Indeed, our patients presented with vesicular skin lesions that showed epidermal multinucleated giant cells on their initial biopsy specimens and were initially inter- preted to represent a herpes virus infection. However, direct fluorescent antibody and culture studies did not confirm the diagnosis of a viral infection. Subsequently, repeat lesional skin biopsies revealed pathologic features that were able to establish the correct diagnosis of either pemphigus vulgaris or transient acantholytic dermatosis. Therefore, when a herpes virus infection is suspected based upon the discovery of epi- thelial multinucleated giant cells in the epidermis, but either the clinic presentation or lack of response to viral therapy or absence of confirmatory laboratory studies does not support the diagnosis of a viral infection, the possibility of a primary acantholytic dermatosis should be considered and additional lesional skin biopsies performed. Also, because hematoxylin and eosin staining is not the golden standard for confirmation of autoimmune bullous dermatoses, skin biopsies for direct immunofluorescence should be performed when a primary bullous dermatosis is suspected since the histopathology observed on hematoxylin and eosin stained sections can be misleading. References 1. Cohen PR. 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