The herpes family of viruses accounts for a significant proportion of human cutaneous disease. Although most episodes of viral infection can be diagnosed clinically, a small subset of these outbreaks will require biopsy for histologic interpretation and diagnosis. Most herpesviruses cause characteristic architectural and cytologic changes in the context of active infection, whereas the effects of some will not manifest until the future as malignant disease. Other infections may go unnoticed secondary to a lack of specific histologic findings. Because herpesviruses cause such a wide spectrum of cutaneous conditions, it is prudent that pathologists be aware of the varied clinical and histopathologic presentations so that these infections will not persist undiagnosed. Additionally, methods of virus detection will briefly be reviewed.

Herpesviridae, the herpes family of viruses that infects humans, consists of 8 separate species: herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus, human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8). All have double-stranded linear DNA enclosed within an icosahedral capsid, protein tegument, and lipid envelope. To multiply, these viruses rely on the host cell nucleus for DNA replication and transcription via RNA with subsequent synthesis of their gene products. It is for this reason that characteristic cytologic inclusions, when present, are located within the nucleus. Although the acute clinical presentation is often secondary to active virus replication and host immune response, resolution of symptoms does not herald clearance of the virus. Rather, infection persists for the life of the host, and the tissue type and site of latency differ depending on the species. Select herpesviruses have also been associated with neoplastic transformation, and their presence can be viewed as oncogenic.

Herpes infections will inevitably be encountered, whether in anatomic or clinical pathology. Thus, a high index of suspicion must exist, and correlation between clinical, histologic, and laboratory findings is often necessary to synthesize a complete understanding of the disease process.

HSV-1 and HSV-2

Although separate species, these viruses cause similar histologic and clinical findings, and speciation relies on laboratory investigation. Classic HSV-1 and HSV-2 clinical findings are described as painful grouped vesicles on an erythematous base, usually with admixed ulcerated and crusted lesions. A systemic prodrome of fever and malaise often coincides with the primary outbreak. Hypersensitivity to HSV is also one cause of the targetoid lesions of erythema multiforme.1 Abnormal presentations are not uncommon, particularly in the genital area and in the immunocompromised host, including verrucous papules, solitary ulcerations, and urinary retention.1 Herpes simplex virus 2 has been recently linked with the recurrence of atypical genital symptoms such as vulvar burning and itching, skin fissures, erythema, and repeat menstrual cycles with white vaginal discharge, often mistaken by the patient for a yeast infection2 (also C.C., T. Kuehl, MD, and P. Sulak, MD, unpublished data, 2010).

Historically, herpes labialis and herpes genitalis have been associated with HSV-1 and HSV-2, respectively. Recent investigation has shown that HSV-1 is now the most frequent cause of herpes genitalis in some populations.3 Furthermore, not all patients show symptoms of infection. For example, a landmark article by Wald et al4 demonstrated that 83% of HSV-2–seropositive patients are asymptomatic and will intermittently shed contagion regardless of symptomatology.

The histologic findings of HSV, when present, are pathognomonic. Affected cells are often multinucleate, and they can have either ground-glass, steel-gray nuclear inclusions with marginated chromatin or eosinophilic nuclear Cowdry A inclusions (Figure 1, B). Additionally, there is typically a vesicle (early) or ulceration (late) with surrounding pale and/or ballooning keratinocytes, acantholysis, and necrosis (Figure 1, A). Such changes are nearly always identified in the epidermis and often involve the hair follicles and sebaceous glands as well. Recurrent folliculitis can be due to selective, solitary involvement of a hair follicle by HSV (Figure 2, A through C). Less commonly, the sweat glands, acrosyringia, and nerves also show evidence of herpes infection.5 

Figure 1.

A, An intraepidermal vesicle is present with underlying superficial and deep perivascular and periadnexal lymphocytic inflammation. B, Closer inspection of the vesicle contents shows numerous multinucleated cells with ground-glass nuclear inclusions and marginated chromatin (hematoxylin-eosin, original magnifications ×20 [A] and ×400 [B]).

Figure 1.

A, An intraepidermal vesicle is present with underlying superficial and deep perivascular and periadnexal lymphocytic inflammation. B, Closer inspection of the vesicle contents shows numerous multinucleated cells with ground-glass nuclear inclusions and marginated chromatin (hematoxylin-eosin, original magnifications ×20 [A] and ×400 [B]).

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Figure 2.

A, A hair follicle is extensively involved with a lymphohistiocytic inflammatory infiltrate. B, A few cells are present with nuclear changes. Some have ground-glass inclusions (arrows) and others have Cowdry A inclusions (arrowheads). C, Immunostaining for herpes simplex virus highlights brown nuclear inclusions with blue halos in both the single and multinucleated cells (hematoxylin-eosin, original magnifications ×100 [A] and ×400 [B]; herpes simplex virus 1, original magnification ×400 [C]).

Figure 2.

A, A hair follicle is extensively involved with a lymphohistiocytic inflammatory infiltrate. B, A few cells are present with nuclear changes. Some have ground-glass inclusions (arrows) and others have Cowdry A inclusions (arrowheads). C, Immunostaining for herpes simplex virus highlights brown nuclear inclusions with blue halos in both the single and multinucleated cells (hematoxylin-eosin, original magnifications ×100 [A] and ×400 [B]; herpes simplex virus 1, original magnification ×400 [C]).

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T lymphocytes infiltrate active lesions, sometimes so floridly as to attain pseudolymphoma status, after which symptoms resolve.5 CD8-positive T cells interact directly with HSV-infected keratinocytes by forming junctions and immunologic synapses leading to keratinocyte death. Once clinical resolution is achieved, HSV-specific T cells remain at the dermal-epidermal junction in immediate proximity to terminal sensory nerve endings. Both HSV-1 and HSV-2 become latent in dorsal root ganglia. When HSV DNA reemerges in the extraneural tissue, the quantity of existing HSV-specific CD8-positive T cells is increased, leading to more rapid clearance of HSV and remission of clinical symptoms, if any.6 

Varicella Zoster Virus

Varicella zoster virus affects humans in a bimodal distribution, occurring in children (chicken pox) and adults (herpes zoster, or shingles). The virus penetrates the respiratory mucosa and rapidly disseminates throughout the body, causing a generalized eruption of vesicles on erythematous bases. Infiltration of the vesicles with inflammatory cells leads to pustule formation, which is followed by ulceration and encrustation. Multiple crops of vesicles appear throughout the course of disease, leading to lesions in various stages of evolution. Fever and lymphadenopathy frequently accompany these cutaneous signs. Varicella zoster virus becomes latent in the spinal cord ganglia when the host immune response is sufficient.

About half of affected individuals will develop VZV reactivation by 80 years,7 especially in immunocompromised individuals, with extracutaneous symptoms causing significant morbidity.8 Herpes zoster is heralded by a sensation of tingling and burning in a unilateral dermatomal distribution accompanied by fever, chills, headache, stomachache, and/or malaise. A maculopapular rash follows 48 to 72 hours later, with subsequent vesicles and ulcer formation similar to those of primary VZV.9 Generalized herpes zoster does occur in a minority of patients, and this is accompanied by visceral involvement in 50% of cases.10 Dermatomes from T3 to L3 are most frequently affected. Not uncommonly, patients may present with the prodrome and lack the vesicles and ulcers. The pain and cutaneous signs generally resolve 7 to 10 days after the initial symptoms; however, postherpetic neuralgia is a common complication. Special names have been given to characteristic dermatomal outbreaks, including Ramsay-Hunt syndrome (geniculate ganglion of the facial nerve, possibly even including the auditory nerve) and herpes zoster ophthalmicus (ophthalmic ganglion of the trigeminal nerve).9 Histologically, VZV is identical to HSV-1 and HSV-2 (Figure 3, A and B).5 

Figure 3.

A, Varicella produces similar vesicles to herpes simplex. When cells containing the characteristic nuclear changes are absent, diagnosis may depend on a positive polymerase chain reaction. B, Like its histologic counterparts, varicella may present as folliculitis. C, Varicella may have the same ground-glass inclusions with marginated chromatin (arrows) (hematoxylin-eosin, original magnifications ×100 [A], ×200 [B], and ×400 [C]).

Figure 3.

A, Varicella produces similar vesicles to herpes simplex. When cells containing the characteristic nuclear changes are absent, diagnosis may depend on a positive polymerase chain reaction. B, Like its histologic counterparts, varicella may present as folliculitis. C, Varicella may have the same ground-glass inclusions with marginated chromatin (arrows) (hematoxylin-eosin, original magnifications ×100 [A], ×200 [B], and ×400 [C]).

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Epstein-Barr Virus

Epstein-Barr virus causes infectious mononucleosis and is associated with several benign and malignant conditions, including Burkitt lymphoma, nasopharyngeal carcinoma, posttransplant lymphoproliferative disorders, Kikuchi histiocytic necrotizing lymphadenitis, hydroa vacciniforme, Gianotti-Crosti syndrome, and oral hairy leukoplakia. Infectious mononucleosis presents with fever, pharyngitis, lymphadenopathy, and malaise. Hepatosplenomegaly may also be present. This infection is self-limited, and most individuals are affected by young adulthood. Epstein-Barr virus becomes latent in B lymphocytes.11 

Skin manifestations are uncommon and, when present, are usually found in immunocompromised individuals.12 A maculopapular or morbilliform eruption may be seen concurrently with acute EBV symptoms, but histopathology is nonspecific. Gianotti-Crosti syndrome, also called papular acrodermatitis of childhood, is a childhood exanthem that typically occurs following upper respiratory infection or infectious mononucleosis. It consists of pink-red papules or papulovesicles on the extensor surface of the extremities, cheeks, and buttocks. These papules are often pruritic and may coalesce into confluent patches.12 Microscopically, Gianotti-Crosti syndrome can exhibit spongiotic, lichenoid, or lymphocytic vasculitis patterns. Basal layer vacuolar change, red blood cell extravasation, and papillary dermal edema may be present as well (Figure 4, A and B).13 

Figure 4.

A, Slight psoriasiform hyperplasia is present with superficial and middermal, predominantly perivascular lymphocytic infiltrate. B, Vacuolar degeneration is present at the dermal-epidermal junction, and extravasated red blood cells are seen in the interstitial areas (hematoxylin-eosin, original magnifications ×100 [A] and ×400 [B]).

Figure 4.

A, Slight psoriasiform hyperplasia is present with superficial and middermal, predominantly perivascular lymphocytic infiltrate. B, Vacuolar degeneration is present at the dermal-epidermal junction, and extravasated red blood cells are seen in the interstitial areas (hematoxylin-eosin, original magnifications ×100 [A] and ×400 [B]).

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Oral hairy leukoplakia is most often seen in human immunodeficiency virus–infected patients and in patients with other immunosuppressive conditions. “Hairy” irregular projections, composed of keratin and sometimes surrounded by parakeratosis, protrude from white plaques found on the lateral aspects of the tongue. The squamous mucosa contains ballooning, pale cells that may contain typical nuclear changes, which include Cowdry A inclusions, ground-glass nuclei with marginated chromatin, and nuclear beading.

Cytomegalovirus

Cytomegalovirus is acquired by late childhood in the majority of individuals. The initial infection is nonspecific and rarely causes the patient to seek medical attention.14 Once the primary infection is cleared, the virus becomes latent in peripheral blood leukocytes. Reactivation occurs in immunosuppressed patients and is accompanied by fever, malaise, leukopenia, and the very uncommon appearance of a macular rash. Other infrequent acute cutaneous manifestations include ulcers, petechiae, purpuric eruptions, necrotic papules, vesicobullous eruptions, vasculitis, and sclerodermoid reactions.11,15 

Cytomegalovirus infects blood vessel endothelium when reactivated in cutaneous tissue. The biopsy will show nonspecific inflammation, dilated vessels, and possible overlying ulceration. Cytomegalovirus infection is identifiable on hematoxylin-eosin staining if cytomegalic endothelial cells are present that contain characteristic large, eosinophilic, intranuclear inclusions surrounded by a halo (owl's eye nucleus; Figure 5, A through D). Often these inclusions are not visible, and immunohistochemical stains or in situ hybridization must be used for accurate diagnosis.11 Three distinct patterns of vascular injury have been identified in skin biopsies: leukocytoclastic vasculitis, necrotizing lymphocytic vasculitis, and pauci-inflammatory endothelial cell injury with luminal thrombosis and vascular dropout. Although the leukocytoclastic vasculitis and necrotizing lymphocytic vasculitis patterns present with palpable purpura, the pauci-inflammatory variant is more likely to present with acute ischemic organ injury and/or progressive cutaneous sclerosis.15 

Figure 5.

A, A diffuse dermal inflammatory infiltrate involves the deeper reticular dermis. The overlying epidermis is intact and the cleft is an artifact. B, The deeper dermis shows a lymphohistiocytic inflammatory infiltrate with scattered eosinophils. One dermal blood vessel shows a markedly enlarged endothelial cell with large nucleus and intranuclear inclusion. C, Another markedly enlarged endothelial cell with intranuclear inclusion and halo formation. D, Immunohistochemistry for cytomegalovirus antigen shows an enlarged endothelial cell with large nucleus and intranuclear inclusion with positive immunostaining (hematoxylin-eosin, original magnifications ×100 [A], ×400 [B], and ×1000 [C]; cytomegalovirus immunostain, original magnification ×1000 [D]). Reproduced with permission from the International Journal of Dermatology,15 John Wiley and Sons, publisher.

Figure 5.

A, A diffuse dermal inflammatory infiltrate involves the deeper reticular dermis. The overlying epidermis is intact and the cleft is an artifact. B, The deeper dermis shows a lymphohistiocytic inflammatory infiltrate with scattered eosinophils. One dermal blood vessel shows a markedly enlarged endothelial cell with large nucleus and intranuclear inclusion. C, Another markedly enlarged endothelial cell with intranuclear inclusion and halo formation. D, Immunohistochemistry for cytomegalovirus antigen shows an enlarged endothelial cell with large nucleus and intranuclear inclusion with positive immunostaining (hematoxylin-eosin, original magnifications ×100 [A], ×400 [B], and ×1000 [C]; cytomegalovirus immunostain, original magnification ×1000 [D]). Reproduced with permission from the International Journal of Dermatology,15 John Wiley and Sons, publisher.

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HHV-6 and HHV-7

Human herpesvirus 6 and HHV-7 are members of the roseola virus genus.16 Clinically, they cause exanthem subitum (roseola infantum), and biopsy is extremely uncommon given the characteristic clinical syndrome. Affected children have a prodrome of high fever for 3 to 5 days, immediately followed by the appearance of diffuse erythematous macules and papules that blanch with pressure and have white halos surrounding each lesion. The rash lasts for 1 to 2 days before resolution.11 These viruses remain latent in mononuclear cells.16,17 Human herpesvirus 6 has been implicated in acute graft versus host disease with simultaneous skin rash. Virus has been detected in skin tissue as well as in peripheral blood during or within 10 days of the cutaneous rash and acute graft versus host disease symptoms.17 Human herpesvirus 6 has also been associated with, among other diseases, infectious mononucleosis, Rosai-Dorfman disease, and various malignancies.18 Human herpesvirus 7 has been linked to pityriasis rosea.16 The histopathologic findings for HHV-6 and HHV-7 cutaneous infections are nonspecific and related to the disease process, not the virus.

HHV-8 (Kaposi Sarcoma–Associated Herpesvirus)

Human herpesvirus 8 is likely a relatively ubiquitous virus. The route of transmission is uncertain. Many children exhibit seropositivity, indicating an innocuous form of transmission. However, sexual transmission is also likely given that seropositive rates are higher among homosexual males and patients attending sexually transmitted disease centers.18 In addition, transmission from latent infections in organ grafts may be possible.19 The primary infection has been recently elucidated in a pediatric case series. Human herpesvirus 8 was detected in 6 children with fever of unknown origin, 5 of whom had concurrent erythematous macules that blanched with pressure. The rash began on the face and spread to the trunk, arms, and legs. With progression, the macules evolved into papules. Resolution occurred 3 to 8 days after the lesions appeared.18 

Human herpesvirus 8 is the causative organism of Kaposi sarcoma, which, in the United States, occurs most frequently in association with immunosuppression, primarily human immunodeficiency virus infection. In at-risk patients, purple macules or plaques mimicking purpura, hematomas, or small angiomas appear spontaneously on any portion of the body. Some lesions may behave indolently, whereas others may grow rapidly with subsequent ulceration.11 Human herpesvirus 8 has tropism for endothelial cells, similar to cytomegalovirus, and its affinity for endothelium has led some authors to propose these cells as the site of latency.20 

Kaposi sarcoma is categorized into patch, plaque, and nodular phases (Figure 6, A through C). Early lesions are characterized by a proliferation of small vessels surrounding more ectatic vessels, which may be mistaken for other angiomatous tumors. No unique cytologic inclusions pathognomonic of HHV-8 infection have been identified with hematoxylin-eosin staining, and immunohistochemical stains are used to confirm the diagnosis. As the lesions progress, the vascular proliferation forms slitlike vascular spaces with associated extravasated red blood cells, hemosiderin-laden macrophages, lymphoplasmacytic infiltrate, distinct cytoplasmic borders, and hyaline globules.21 

Figure 6.

A, The nodular phase consists of hypercellular lesions that protrude from the skin surface. B, This nodule consists of a markedly dense spindled-cell proliferation and red blood cell extravasion. C, Immunostaining for human herpesvirus 8 (HHV-8) confirms the diagnosis of Kaposi sarcoma (hematoxylin-eosin, original magnifications ×20 [A] and ×400 [B]; HHV-8 immunostain, original magnification ×400 [C]).

Figure 6.

A, The nodular phase consists of hypercellular lesions that protrude from the skin surface. B, This nodule consists of a markedly dense spindled-cell proliferation and red blood cell extravasion. C, Immunostaining for human herpesvirus 8 (HHV-8) confirms the diagnosis of Kaposi sarcoma (hematoxylin-eosin, original magnifications ×20 [A] and ×400 [B]; HHV-8 immunostain, original magnification ×400 [C]).

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Histopathologic examination of hematoxylin-eosin–stained slides, even when coupled with the clinical history, occasionally will not be sufficient for diagnosis, and additional detection methods may be necessary. Viral culture is still viewed as the gold standard, but it is time consuming and has a lower sensitivity compared with other modalities. Tzanck smears for HSV and VZV are easily and rapidly prepared in the clinical setting and, when positive, allow for quick, inexpensive diagnosis.22 Heterophile (monospot) testing is a practical clinical option for EBV infection.20 In situ hybridization for HSV-1, HSV-2, cytomegalovirus, and EBV11,12,23 and immunohistochemistry for HSV-1, HSV-2, VZV, EBV, cytomegalovirus, and HHV-8 are common methods, but each can have background staining that hinders evaluation.

Immunofluorescence is also available except for HHV-6 and HHV-7, and is more sensitive than viral culture.24 Polymerase chain reaction methods are becoming increasingly popular because of rapid turnaround time, increased sensitivity and specificity, and ability to detect and quantify viral particles. However, these methods are more expensive and availability may be limited.8,20,23,25,26 Serology is sensitive, but not specific with immunoglobulin (Ig) G antibodies to a virus, only indicating a history of infection. Detection of IgM antibodies is mandatory to determine if the infection was recent.27 Enzyme-linked immunosorbent assays are also effective, primarily in the detection of EBV and HHV-8.20,28 

Herpesviruses are ubiquitous in nature and affect virtually every individual. Accurate diagnosis may be rendered in a significant proportion of patients based solely on clinical presentation. However, pathologists will likely be consulted when the presentation is atypical or ambiguous. Treatment generally relies on symptom palliation, antiviral medications, and/or treating the underlying illness. Without updated awareness of clinical, histologic, and laboratory presentations, these infections can remain undiagnosed and untreated. Because herpesviruses are never permanently cleared from the body, undetected disease may either persist or reactivate, inevitably causing worsened morbidity and, occasionally, increased mortality.

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Author notes

From the Department of Pathology, Scott & White Memorial Hospital, Temple, Texas.

The authors have no relevant financial interest in the products or companies described in this article.