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Background
Herpes infections are ubiquitous. Most adults have been exposed to herpes virus and manifest one of the signs of infection in the form of cold sores. There are two types of herpes simplex virus (HSV) infections, type 1 and type 2. In general, HSV-1 infections are associated with orolabial infection although cases of genital infection are increasing. HSV-2 infections are associated with genital infection and rarely orolabial infection.
The challenge for clinicians has to been to identify patients who are infected with HSV-2. The problem is the majority of infected and seropositive patients are usually asymptomatic or are culture negative. About 25% of adults in the United States are seropositive for HSV-2 but only 10-25% have a known history of recognized genital lesions. A recent study found reactivation of genital HSV-2 infection in asymptomatic seropositive patients is frequent.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION HIV-1 infection HSV-2 seropositivity markedly elevated in patients at high risk for acquiring HIV-1 LEUKEMIA, CHRONIC LYMPHOCYTIC
- 'Specific' cutaneous infiltrate of B-cell chronic lymphocytic leukemia at the site of a florid herpes simplex infection.
Ziemer M, Bornkessel A, Hahnfeld S, Weyers W.
Department of Dermatology, Friedrich-Schiller-University of Jena, Jena, Germany.
J Cutan Pathol. 2005 Sep;32(8):581-4. Abstract quote
Background: Specific cutaneous infiltrates in patients with leukemia generally carry a grim prognosis. However, non-neoplastic skin diseases may be associated with recruitment of normal and neoplastic leukocytes circulating in the peripheral blood. In those instances, neoplastic cells may be detected in skin lesions without an adverse effect on prognosis.
Methods: In a patient with B-cell chronic lymphocytic leukemia, a specific infiltrate developed at the site of a florid herpes simplex infection. Clinically, the lesion presented itself as an ulcerated tumor.
Results: Histopathologically, the lesion was characterized by a dense, diffuse infiltrate of small hyperchromatic lymphocytes throughout the entire dermis. Lymphocytes showed an aberrant CD20(+)/CD43(+)/CD5(+) phenotype of neoplastic B cells, and monoclonal rearrangement of immunoglobulin gamma genes could be demonstrated by polymerase chain reaction. Although criteria for leukemia cutis were fulfilled, the patient did well.
Conclusions: The cutaneous infiltrate of neoplastic cells seemed to be part of a physiologic response to the antigenic stimulus, rather than indicating an exacerbation of leukemia.MYCOSIS FUNGOIDES An unusual and fatal case of disseminated cutaneous herpes simplex. Infection in a patient with cutaneous T cell lymphoma (mycosis fungoides).
Goldgeier MH, Cohen SR, Braverman IM, Stenn KS.
J Am Acad Dermatol 1981 Feb;4(2):176-80 Abstract quote
A patient with plaque stage mycosis fungoides (MF) developed an atypical disseminated cutaneous herpes simplex virus (HSV) infection manifested by polycyclic cutaneous ulcers.
Although Tzanck preparations and serial antibody titers to herpes virus were negative, the diagnosis was readily established by viral culture and histologic examination of the skin lesions. Following adenine arabinoside therapy, the viral cultures of the ulcers became negative and the spread of virus-induced ulcerations ceased.
In an immunocompromised host with rapidly advancing, sharply punched-out polycyclic cutaneous ulcerations, herpes simplex infection should be considered even though the classical vesicular lesions are absent.
SEBORRHEIC KERATOSIS
Herpesvirus infection of seborrheic keratoses.Googe PB, King R.
Knoxville Dermatopathology Laboratory, Knoxville, Tennessee 37319, USA.
Am J Dermatopathol 2001 Apr;23(2):146-8 Abstract quote We present three examples of patients with seborrheic keratoses complicated by necrotizing herpesvirus infection. Two patients had localized cutaneous herpetic infections, and the third patient had a generalized cutaneous herpesvirus infection. Two of the lesions were thought to be squamous cell carcinoma. The third was clinically identified as inflamed seborrheic keratosis. Herpesvirus infection was not clinically suspected in two of the patients.
The histologic changes were similar in all cases. Epidermal proliferation was accompanied by hyperkeratosis and pseudo horn cyst formation. Extensive keratinocyte necrosis was present along with balloon degeneration of keratinocytes, herpetic viral inclusions, and multinucleated giant cells. Viral lesions of molluscum contagiosum and human papillomavirus have been observed in benign skin proliferations.
Nevertheless, we were unable to find descriptions of herpesvirus involvement in seborrheic keratosis in a Medline search. Necrotic seborrheic keratoses should be carefully examined for the possibility of herpesvirus infection, a condition that may be improved by prompt medical intervention as demonstrated in one of our cases.
URETHRITIS Urethritis: An underestimated clinical variant of genital herpes in men?
Stephan Lautenschlager, MD
Alfred Eichmann, MD
Zurich, SwitzerlandJ Am Acad Dermatol 2002;46:307-8 Abstract quote
Two men had a first clinical episode of genital herpes presenting as nongonococcal urethritis in the absence of any penile lesions. Data on the etiologic function of herpes simplex in patients with nongonococcal urethritis are scarce and conflicting.
Considering our cases, the large amount of nongonococcal urethritis of unknown origin, and the high frequency of unrecognized genital herpes, herpes simplex virus may be a significant etiologic agent of nongonococcal urethritis and warrants necessary laboratory investigations in patients with clear mucoid urethral discharge.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL
Department of Oral Medicine, New Jersey Dental School, Newark, New Jersey 07103, USA.
Eight of the more than 80 known herpesviruses are human pathogens. Human herpes simplex virus (HSV) is a contagious infection with a large reservoir in the general population. It has a potential for significant complications in the immunocompromised host. In addition, psychological distress caused by the negative stigma associated with genital herpes and visible facial lesions in those experiencing frequent outbreaks renders it a challenging clinical dilemma.
This article reviews the epidemiology, pathogenesis, and diagnostic features of HSV infections, providing the clinician with an up-to-date understanding of the available management strategies for mucocutaneous HSV-induced disease.ECZEMA HERPETICUM
Predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases.Wollenberg A, Zoch C, Wetzel S, Plewig G, Przybilla B.
Department of Dermatology and Allergy, Ludwig Maximilian University, Munich, Germany.
J Am Acad Dermatol. 2003 Aug;49(2):198-205. Abstract quote BACKGROUND: Eczema herpeticum (EH) is a widespread herpes simplex virus infection of inflamed skin, most often occurring in patients with atopic dermatitis (AD). A monomorphic eruption of dome-shaped blisters and pustules in the eczematous lesions along with severe systemic illness lead to the clinical diagnosis, but atypical variants with disseminated slits may also occur. Topical use of corticosteroids is alleged to be a pathogenetic factor for EH, but predisposing factors for EH are largely unknown.Objective and methods We sought to characterize the clinical features and predisposing factors for EH. A retrospective analysis of 100 patients with EH seen from 1980 through 1996 and of 105 control patients with AD was performed.
RESULTS: Fever and lymphopenia were associated with EH, whereas an increased erythrocyte sedimentation rate was frequently seen in patients with EH and control patients who were impetiginized. In 100 patients with EH, primary herpes simplex virus infection was likely in 20 patients, and a secondary herpes simplex virus infection was suggestive in 26 patients. In all, 13 patients had a second EH, whereas 3 patients had a third EH. Patients with EH had a significantly earlier onset of AD and a significantly higher total serum IgE level than the control patients. More than 75% of the patients with EH had not received corticosteroid treatment in the 4 weeks before onset of EH.
CONCLUSIONS: The characteristics of patients with EH are those associated with severe manifestations of AD. The majority of EH occurs in patients with untreated AD, arguing against a role for topical corticosteroids in the development of EH.
EYE
Congenital diffuse necrotizing herpetic retinitis.Mansour AM, Nichols MM.
Department of Ophthalmology, University of Texas Medical Branch, Galveston 77550.
Graefes Arch Clin Exp Ophthalmol 1993 Feb;231(2):95-8 Abstract quote Neonatal Herpes simplex infections are usually contracted from the birth canal, and the systemic lesions develop several days to weeks after delivery.
We present the clinicopathologic findings in a newborn with a prenatal diagnosis of hydrocephalus who died at 1 day of age. Severe liquefaction necrosis and foci of calcification were present in the brain, adrenal glands, and retina. Cowdry type A intranuclear inclusions were present in the adrenal glands and retina. There was no clinical evidence of genital herpes in either parent.
This is the first documented case of in utero transmission of Herpes simplex infection, confirmed by the polymerase chain reaction, and causing fulminant necrotizing retinitis and encephalitis.
GLOSSITIS Herpes simplex virus glossitis Cutis 1987;40:406-409
N Engl J Med 1993;329:1859-1860May present with a geometric glossitis with a linear, cross-hatched, or branched fissuring of the tounge
Patients with Hodgkin's disease and herpes infection may present with nodules on the dorsal aspect of the tounge
KAPOSIFORM VARICELLIFORM ERUPTION
- Psoriasis herpeticum: three cases of Kaposi's varicelliform eruption in psoriasis.
Santmyire-Rosenberger BR, Nigra TP.
Department of Dermatology, Washington Hospital Center, Washington, DC 20010, USA.
J Am Acad Dermatol. 2005 Jul;53(1):52-6. Abstract quote
BACKGROUND: Kaposi's varicelliform eruption (KVE), first described in 1887 by Moritz Kaposi, refers to a disseminated cutaneous infection with herpesvirus type 1 or 2, vaccinia virus, or coxsackievirus A16 in a patient with another underlying dermatosis. When herpesvirus type 1 or 2 is the pathogenic virus, the term "eczema herpeticum" is used, independent of the underlying dermatologic diagnosis that preceded the eruption. KVE is most often seen in patients with underlying atopic dermatitis, but has also been seen in association with other papulosquamous and acantholytic disorders. However, eczema herpeticum rarely occurs in patients with psoriasis.
OBSERVATIONS: We present the clinical and laboratory findings of three patients in whom KVE developed during inpatient hospitalization for a psoriatic flare. These patients each had comorbidities that may have increased susceptibility to KVE.
CONCLUSIONS: KVE may rarely occur in patients with psoriasis. Erythroderma, systemic sepsis, therapy with immunosuppressant drugs, such as methotrexate and systemic steroids, and therapy with systemic retinoids may possibly increase susceptibility to KVE.TONSILS
Herpes simplex infection causing acute necrotizing tonsillitis.Wat PJ, Strickler JG, Myers JL, Nordstrom MR.
Division of Anatomic Pathology, Mayo Clinic, Rochester, MN 55905.
Mayo Clin Proc 1994 Mar;69(3):269-71 Abstract quote OBJECTIVE: To describe the clinical and pathologic features of acute herpetic tonsillitis and to compare the histologic findings with those of herpetic lymphadenitis.
DESIGN: We present a case report of a 22-year-old woman with bilateral cervical adenopathy, acute tonsillitis, and suspected peritonsillar abscess.
MATERIAL AND METHODS: Histologic examination of the excised tonsils demonstrated discrete necrotic areas that contained cells with intranuclear viral inclusions.
RESULTS: The diagnosis of herpetic tonsillitis was confirmed by demonstrating herpes simplex virus (HSV)-infected cells on paraffin section immunostains and by positive HSV cultures of the tonsillar tissue.
CONCLUSION: HSV infection is an uncommon cause of acute tonsillitis; the histologic findings are similar to those seen in herpes simplex lymphadenitis.
WHITLOW
PCR-based diagnosis of a case of herpetic whitlow in an AIDS patient.Nogueira ML, Oliveira AF, Araujo JG, Gallo MA, Fonseca JG, Bonjardim CA, Ferreira PC, Kroon EG.
Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil.
Rev Inst Med Trop Sao Paulo 1998 Sep-Oct;40(5):317-9 Abstract quote Herpetic infections are common complications in AIDS patients. The clinical features could be uncommon and antiviral chemotherapy is imperative.
A rapid diagnosis could prevent incorrect approaches and treatment. The polymerase chain reaction is a rapid, specific and sensible method for DNA amplification and diagnosis of infectious diseases, especially viral diseases. This approach has some advantages compared with conventional diagnostic procedures.
Recently we have reported a new PCR protocol to rapid diagnosis of herpetic infections with suppression of the DNA extraction step. In this paper we present a case of herpetic whitlow with rapid diagnosis by HSV-1 specific polymerase chain reaction using the referred protocol.
HISTOPATHOLOGY CHARACTERIZATION GENERAL
- Histopathologic features of cutaneous herpes virus infections (herpes simplex, herpes varicella/zoster): a broad spectrum of presentations with common pseudolymphomatous aspects.
Leinweber B, Kerl H, Cerroni L.
From the Department of Dermatology, Medical University of Graz, Graz, Austria.
Am J Surg Pathol. 2006 Jan;30(1):50-8. Abstract quote
Cutaneous eruptions caused by herpes simplex 1/2 (HSV-1/2) and herpes varicella/zoster (VZV) represent common dermatoses. In some cases, they present with atypical clinical and/or histopathologic features, including presence of dense lymphoid infiltrates with atypical lymphocytes simulating cutaneous lymphomas.
In this study, we reviewed the biopsy specimens of 65 patients (33 males, 32 females; mean age, 61.2 years; median age, 62 years; age range, 19-96 years) with cutaneous eruptions caused by HSV-1/2 or VZV.
Histologic examination revealed several atypical findings, including presence of dense lymphoid infiltrates, angiotropism, and atypical lymphocytes simulating malignant lymphoma. Immunohistochemistry performed in 22 cases showed a predominant T-cell infiltrate, in the majority of cases with variable numbers of CD30+ and CD56+ cells. Two cases with a pseudolymphomatous appearance and small clusters of CD30+ cells revealed a monoclonal population of T lymphocytes by PCR analysis, underlying the difficulties in classifying some of these cases correctly.
Our study indicates that cutaneous herpes infections can exhibit several atypical histopathologic, immunohistochemical, and molecular features, and that in given cases accurate clinicopathologic correlation and short-term follow-up controls are necessary for differentiation from cutaneous lymphomas.
VARIANTS FOLLICULITIS
- Exclusive Involvement of Folliculosebaceous Units by Herpes: A Reflection of Early Herpes Zoster.
Walsh N, Boutilier R, Glasgow D, Shaffelburg M.
From the *Departments of Pathology, Capital District Health Authority and Dalhousie University, Halifax; daggerColchester Regional Hospital, Truro; double daggerCape Breton Regional Hospital, Sydney; and section signDepartment of Dermatology, Valley Regional Hospital, Kentville, Nova Scotia, Canada.
Am J Dermatopathol. 2005 Jun;27(3):189-194. Abstract quote
The histopathological changes of herpes simplex, herpes zoster, and varicella are considered to be indistinguishable from one another. Evaluation of the clinical setting, with adjunctive studies if necessary, generally clarifies the specific diagnosis. Vesicular lesions in all three conditions can involve epidermal and adnexal epithelium with characteristic cytopathic features.
We describe three patients with non-vesicular eruptions on the head and neck whose biopsies revealed exclusive folliculosebaceous involvement by herpes. All three patients developed typical herpes zoster within days of the biopsy. There is compelling scientific evidence in the literature indicating that, in herpes zoster, the virus is transported from dorsal root or trigeminal ganglia via myelinated nerves to the skin. These terminate at the isthmus of hair follicles and primary infection of follicular and sebaceous epithelium occurs. Spread of infection to the epidermis follows. In contrast, data pertaining to recurrent herpes simplex indicates that axonal transport of the virus from sensory ganglia to the skin is directed primarily to the epidermis, via terminal non-myelinated nerve twigs.
The clinical evolution of our three cases and scientific data in the literature indicate that exclusive folliculosebaceous involvement by herpes, in the setting of a non-vesicular eruption, represents early herpes zoster.INCOGNITO
- Herpes incognito most commonly is herpes zoster and its histopathologic pattern is distinctive!
Boer A, Herder N, Blodorn-Schlicht N, Falk T.
Dermatologikum Hamburg, Stephansplatz 5, 20354 Hamburg, Germany.
Am J Dermatopathol. 2006 Apr;28(2):181-6. Abstract quote
Infections of the skin by herpesviruses do not always present themselves in typical fashion. Conventional microscopy is used routinely to confirm infection by herpesviruses, but sometimes typical signs such as multinucleated epithelial cells or "ghosts" of them are not encountered in a specimen (so-called herpes incognito).
We studied 35 patients in whom infection with herpesviruses was differentially diagnosed clinically but in whom a biopsy specimen had been taken for confirmation. Only those patients in whom histopathologic findings had been interpreted as being "not diagnostic" of herpesvirus infection by 2 independent dermatopathologists were included. Clinical and histopathologic findings were correlated with results from polymerase chain reaction studies on formalin-fixed paraffin-embedded tissue. Polymerase chain reaction revealed herpesvirus-specific DNA in 12 of 35 specimens, 10 being varicella zoster virus (VZV) positive, 1 herpes simplex virus (HSV)-2 positive, and 1 HSV-1 positive. Ten of these 12 cases presented themselves in very similar fashion (8 VZV, 1 HSV-1, 1 HSV-2).
All lesions were macular or papular and typified mostly by dense perivascular and sparse interstitial superficial and deep infiltrates of lymphocytes, sometimes assuming a patchy lichenoid pattern. Infiltrates were prominent in and around adnexal structures, often peppering follicles, sebaceous glands, and eccrine glands. Lymphocytes were also found in the lower part of the epidermis accompanied by a combination of spongiosis and vacuolar alteration. The papillary dermis was often edematous; extravasated erythrocytes in variable numbers were a common finding. Lymphocytes sometimes had large and polygonal nuclei. Neutrophils and nuclear dust were present occasionally; eosinophils were rare.
We conclude that herpes incognito most commonly is herpes zoster and its histopathologic pattern is distinctive.
PERIPHERAL NERVES
Histopathology of peripheral nerves in cutaneous herpesvirus infection.Worrell JT, Cockerell CJ.
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, USA.
Am J Dermatopathol 1997 Apr;19(2):133-7 Abstract quote Cutaneous herpesvirus infection is a common viral disorder manifest by epidermal and/or mucosal vesicle formation. Though it is believed that the virus most likely resides in regional sensory ganglia following primary infection and that cutaneous involvement represents reactivation of a latent infection, the histopathology of cutaneous nerves in sites of disease has not been well characterized.
In order to assess and characterize the pathologic changes of these nerves, we retrospectively examined 54 cases of cutaneous and mucosal herpesvirus infection as defined by the presence of diagnostic multinucleate epithelial giant cells that demonstrated viral cytopathic effect. Dermal nerves were evaluable in 48 of 54 cases. All cases showed perineural inflammation that consisted of a dense mixed lymphocyte-polymorphonuclear cell infiltrate. Twenty-six cases exhibited intraneural infiltrations accompanied by Schwann cell hypertrophy with nuclear eosinophilia and pyknosis. Frank neuronal necrosis was present in 21 cases, with viral cytopathic effect evident within neurons of four cases. The degree of peri- and intraneural inflammation correlated with the severity of the inflammatory response within the dermis in most cases; however, in eight cases there was inflammatory involvement of neurovascular structures distant from and out of proportion to dermal and epidermal changes.
Immunoperoxidase staining using a polyvalent antibody to human herpesvirus was performed in two cases and demonstrated viral antigen within nerve twigs. This pattern of peripheral nerve twig inflammation, along with the occurrence of more distant neural involvement, may prove to have diagnostic implications and serve as a clue in the recognition of cutaneous herpesvirus infection, particularly in cases with subtle or absent epidermal alteration.
Furthermore, the presence of inflammation within and around nerves as well as degenerative changes suggest that nerve twigs are not passive conduits for viral spread but may be directly involved in infection.
SYRINGITIS
- Nodular Herpes Zoster with Herpetic Syringitis and No Epidermal Involvement in a Patient With Burkitt Lymphoma.
Alonso-Perez A, Fraga J, Delgado Y, Aragues M, Nam-Cha S, Garcia-Diez A.
*Department of Dermatology, Hospital Universitario de la Princesa, Madrid, Spain daggerDepartment of Pathology, Hospital Universitario de la Princesa, Madrid, Spain.
Am J Dermatopathol. 2006 Jun;28(3):194-196. Abstract quote
Herpes zoster (HZ) occurs with an increased incidence in immunosuppressed patients, in whom it frequently displays atypical clinical presentations. Herpetic syringitis, the involvement of the eccrine epithelium by herpes virus infection, is an infrequently described histologic pattern that has been rarely and almost exclusively reported in HIV-infected patients.
We report the case of a woman with Burkitt lymphoma who developed 2 nodular, asymptomatic lesions while receiving treatment with chemotherapy and radiotherapy for her hematological disease. Histology showed viropathic changes in the epithelium of eccrine glands not in the epidermis. PCR was positive for varicella-zoster virus (VZV). Nodular herpes zoster seems to be an exceptional clinical presentation.
We report another such case which is, as far as we know, the first report of herpetic syringitis with no concomitant epidermal involvement.
Subtle clues to the diagnosis of the herpesvirus by light microscopy. Herpetic syringitis.Sangueza OP, Gordon MD, White CR Jr.
Department of Pathology, Oregon Health Sciences University, Portland 97201, U.S.A.
Am J Dermatopathol 1995 Apr;17(2):163-8 Abstract quote Among the numerous infections to which AIDS patients are susceptible, those caused by herpesvirus (simplex and varicella/zoster) are among the most common. Because herpetic infections may be the first manifestations of AIDS and often are associated with poor prognosis, rapid and accurate diagnosis of them is imperative.
Herpesvirus infection may be diagnosed histopathologically by the presence of ballooned, acantholytic, and multinucleated keratinocytes; intranuclear eosinophilic viral inclusions; steel gray color of affected keratinocytic cytoplasm and nuclei, chromatin margination, and necrotic acantholytic keratinocytes in older lesions. These changes are often limited to the epidermis, but there may frequently be involvement of epithelia of follicles (herpetic folliculitis) and sebaceous glands as well. Similar changes, although seldom noted, may be present in eccrine ducts and glands (herpetic syringitis).
Recognition of subtle histologic clues concerning the secretory and ductal components of sweat glands in an unusual case of herpes infection facilitated rapid diagnosis in an AIDS patient, allowing appropriate treatment.
Herpetic syringitis associated with eccrine squamous syringometaplasia in HIV-positive patients.Munoz E, Valks R, Fernandez-Herrera J, Fraga J.
Department of Pathology, Hospital Universitario de la Princesa, Madrid, Spain.
J Cutan Pathol 1997 Aug;24(7):425-8 Abstract quote Herpetic syringitis has been described as a rare manifestation of herpes virus infection in patients with an immunodeficiency, usually secondary to human immunodeficiency virus (HIV) infection. Eccrine squamous syringometaplasia (ESS) is an infrequent alteration of the eccrine duct epithelium reported in association with several conditions, including chronic ulcers, inflammatory processes, and patients receiving chemotherapy. The association of herpetic syringitis with ESS has not been reported before.
We identified 3 cases of herpetic syringitis associated with ESS in patients with the acquired immunodeficiency syndrome. In 2 of 3 cases the signs of herpetic syringitis were limited to the metaplastic duct epithelium, but in 1 case there were also herpetic alterations without ESS.
The histological features of herpetic infection in HIV-positive patients may be atypical and lack the typical epidermal alterations, observing only an extensive epidermal necrosis. In those cases, the alterations of the eccrine ducts may be a diagnostic clue in the diagnosis of herpetic infection. ESS of the ductal epithelium is probably secondary to the herpetic infection, although it might also stimulate the extension of the herpetic infection. Further studies are needed to elucidate the association of ESS and herpes virus infection.
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