CME ARTICLE
Histological Spectrum of Cutaneous Herpes Infections Brian Hoyt, BS* and Jag Bhawan, MD†
Abstract: Herpes simplex virus and varicella zoster virus are doublestranded DNA viruses that commonly infect humans, resulting in cutaneous manifestations. Diagnosis is generally made based on clinical findings; however, when the presentation is atypical, biopsy can aid in making a correct diagnosis. The classic histopathological findings of herpetic infection are well established (acantholysis, ballooning degeneration, intranuclear inclusions, multinucleation, necrosis, and formation of vesicles or ulcers). Herpes infection can also cause histopathological changes in many dermal structures. Furthermore, herpes can masquerade as a variety of hematologic malignancies or benign cutaneous conditions. The histopathological spectrum of herpes infections is reviewed and discussed. Key Words: cutaneous, herpes, histology, simplex, zoster (Am J Dermatopathol 2014;36:609–619)
LEARNING OBJECTIVES After completing this CME activity, physicians should be better able to: • Identify and describe the broad spectrum of histopathological presentations of cutaneous herpes infections. • Maintain a high index of suspicion for herpes infections when viewing challenging histopathological cases.
INTRODUCTION Herpes simplex and varicella zoster are ubiquitous members of the herpesviridae family. These infections result in characteristic skin findings that are typically diagnosed clinically (Fig. 1). When the clinical presentation is unclear, biopsy can aid in making an accurate diagnosis. Histopathological diagnosis is usually straightforward; however, herpes can mimic a variety of benign and malignant cutaneous conditions. The cutaneous lesions of herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) are classically described as painful, grouped vesicles on an erythematous base. Lesions are prone to recurrence, often with a prodrome of burning, itching, or pain.1 Varicella zoster virus (VZV) has 2 distinct clinical From *Medical Student, The University of Texas Medical School at Houston, Houston, TX; and †Professor of Dermatology and Pathology, Head Dermatopathology Section, Vice Chairman, Department of Dermatology, Boston University School of Medicine, Boston, MA. All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Reprints: Jag Bhawan, MD, Section of Dermatopathology, Department of Dermatology, Boston University School of Medicine, 609 Albany St, J-308, Boston, MA 02118 (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
presentations. In children, the viral eruption usually presents with generalized vesicles on an erythematous base at various stages of evolution (chicken pox); whereas in adults, painful grouped vesicles typically arise in a dermatomal distribution (herpes zoster, shingles).1 In most instances, the clinical presentation of HSV and VZV is distinctive, rendering skin biopsy unnecessary. However, in some patients, particularly those with internal malignancies or who are immunocompromised, the clinical presentation can be atypical or misleading. In these situations, additional studies are often required. These include Tzank smear, viral culture, histological examination of slides stained with hematoxylin and eosin, immunohistochemistry, immunofluorescence, in situ hybridization, and polymerase chain reaction (PCR).1 This article will help readers understand and recognize the spectrum of histopathological presentations for cutaneous herpes infections and to be vigilant when reviewing such cases.
MATERIALS AND METHODS We herein review the histological spectrum of cutaneous herpes infections (including herpes simplex and varicella zoster). Hereafter, herpes will be used to refer to both HSV and VZV. We performed an extensive review of the literature available on PubMed using the following search terms: histology OR histopathology OR pathology OR pathologic AND herpes AND cutaneous. We also searched “atypical herpes histology.” We limited our review to the histopathology of active herpes infection, excluding instances of skin conditions appearing at the site of previously healed herpes infections.
RESULTS Histological Spectrum of Herpes Infection Herpes simplex and varicella zoster have a similar histopathological presentation.1 Low-power examination often reveals shallow vesicles (Fig. 2) or ulcers with ballooning keratinocytes, acantholysis, and necrosis.1 Cytopathic changes include enlarged and pale keratinocytes with steel-gray nuclei, marginated chromatin, multinucleated cells, nuclear molding, and eosinophilic intranuclear (Cowdry A) inclusions (Fig. 3).1,2 Herpetic changes are most commonly noted in the epidermis; however, dermal—including adnexal—structures are also frequently involved (Table 1). When evaluating dermal structures for evidence of herpes infection, the hair follicles and sebaceous glands (Fig. 4) are most frequently affected.1,3 Leinweber et al3 reviewed the histology of 65 cases of herpes infection diagnosed based on the presence of typical epithelial findings. On reviewing these www.amjdermatopathology.com |
609
Hoyt and Bhawan
Am J Dermatopathol Volume 36, Number 8, August 2014
FIGURE 1. Clinical photographs of herpes simplex showing grouped vesicles/pustules on the erythematous base (A) and in dermatomal distribution in herpes zoster (B). Reproduced with permission from Dermatopathology Interactive Atlas 2001, www.dermpathatlas.com. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
cases, they found herpetic changes in the hair follicles in 34/44 cases (77%) and sebaceous glands in 24/36 cases (67%).3 Histopathological features of herpes folliculitis include dense, deep perifollicular infiltrate, with lymphocytes scattered within the perifollicular sheath and follicular epithelium. Extravasation of erythrocytes and keratinocyte necrosis can also be seen.4 Classic herpetic changes in the overlying epidermis may be lacking,2,4 or the epidermis may be necrotic with inflammatory crust (Fig. 5). In such cases, the diagnosis can be difficult and one should look for multinucleate giant cells in perifollicular location. In a review of 21 patients with herpes folliculitis, cytopathic changes of the follicular keratinocytes—including necrosis, ballooning degeneration, and steel-gray nuclei—were seen in just over half of the cases. Herpetic infection was suspected on the basis of the perifollicular lymphocytic infiltrate with or without keratinocyte necrosis. The diagnosis in all 21 cases was confirmed by PCR of formalin-fixed paraffin-embedded tissue samples.4 Sebaceous glands may also demonstrate a lymphocytic infiltrate along with typical herpetic changes: ballooning of epithelial cells, necrosis, multinucleation, nuclear molding, and epithelial acanthosis.4,5 Herpes syringitis, herpetic infection of the eccrine glands or ducts, is a rare finding in cutaneous herpes.3,6–8 Epithelial cells of the eccrine glands and ducts (Fig. 6) reveal typical herpetic changes: multinucleation, ballooning degeneration, nuclear molding, and margination of chromatin.8 Muñoz et al6 reported an unusual association between herpes syringitis and eccrine squamous syringometaplasia in 3 patients with AIDS. Although herpes syringitis is more commonly associated with
immunosuppression; it can be seen in patients who are immunocompetent.3 In rare cases, involvement of the eccrine glands can assist in making proper diagnosis.8 It is believed that herpes remains latent in the sensory ganglia, and when it is reactivated, the virus migrates to the skin through peripheral nerves. Hence, it is not surprising that involvement of dermal nerves is commonly seen in herpes infections.9 Indeed, Worrell and Cockerell reviewed 54 cases of cutaneous herpes diagnosed by clinical features coupled with characteristic herpetic changes on biopsy. The peripheral nerves could be evaluated in 48 of the cases, and all of them demonstrated perineural inflammation. This inflammation consisted of a dense mixed infiltrate of lymphocytes and neutrophils in a diffuse interstitial pattern. In addition, intraneural infiltrate with Schwann cell hypertrophy, nuclear eosinophilia, and pyknosis was found in over half (26/48 patients, 54%) of the cases, and neuronal necrosis was present in 21/48 (44%) of cases.10 The neurons themselves were less frequently involved; only 4 cases (8%) showed cytopathic effects of herpes within the nerve cells.10 These cytopathic changes were similar to those seen in infected keratinocytes, including hyperchromatic nuclei, swelling, and degeneration; multinucleation of neurons was not seen.10 Leinweber et al3 also reported cytopathic changes to dermal neurons in only 9 of 61 cases (15%) with cutaneous herpes. The differential diagnosis for perineural inflammation (Fig. 7) is limited; thus, identifying this feature can be a significant clue in diagnosing a subtle herpes infection.5,9 Leukocytoclastic vasculitis is another common histological finding in cutaneous herpes infections (Fig. 8). In their
FIGURE 2. Intraepidermal and subepidermal blister with reticular degeneration (left inset), multinucleate giant cells (right inset) with many acantholytic cells and minimal inflammatory infiltrate. Hematoxylin and eosin, ·18; inset ·180.
610
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
Herpes Histology
FIGURE 4. Herpetic folliculitis showing characteristic cytopathologic changes. Hematoxylin and eosin, ·90. FIGURE 3. Intraepidermal and subepidermal blister with marked mixed inflammatory infiltrate, with many multinucleate giant cells and intranuclear inclusion characteristic of herpes infection (inset). Hematoxylin and eosin, ·18; inset ·90.
review of 54 cases, Worrell and Cockerell10 reported a leukocytoclastic vasculitis in 67% of patients. Vessel walls were found to contain fibrin deposits, suggesting that immune complexes may mediate this vasculitis.10 Interestingly, immunohistochemistry was performed in 2 cases, and did not identify herpes viral antigen in the endothelial cells.10 However, Cohen et al reported 2 cases of leukocytoclastic vasculitis in which viral inclusions were found in endothelial cells, adjacent pericytes, and dermal fibroblasts.11 Much less commonly, the perivascular infiltrate is predominantly mononuclear, consistent with a lymphocytic vasculitis (Fig. 9). One patient with a 10-year history of mycosis fungoides developed chronic, painless erythematous nodules on his face in the distribution of the third trigeminal nerve. These coalesced into confluent necrotic plaques with superficial ulceration. Histological examination revealed an obliterative lymphocytic vasculitis with a lymphohistiocytic infiltrate. Cowdry A bodies were seen in some endothelial cells; however, the epidermal changes were nondiagnostic. Diagnosis was confirmed by identifying viral particles in the endothelial cells using electron microscopy.12 Another patient who was undergoing chemotherapy for mediastinal large B-cell lymphoma developed red, painless nodules in his right axilla and on his right hand. Biopsy revealed superficial and deep perivascular lymphocytic infiltrate, without any changes to the overlying epidermis, leading to a preliminary diagnosis of lymphocytic vasculitis.
Immunohistochemistry subsequently revealed the presence of varicella zoster antigen in the endothelial cells and dermal dendrocytes.13
Herpes Mimicking Cutaneous Hematologic Malignancies Herpes infections can trigger a dense lymphocytic infiltrate (Fig. 10) that resembles cutaneous lymphoma (Table 2). The diagnostic challenge of this pseudolymphomatous response can be increased by the presence of marked lymphocytic atypia, monoclonal cell proliferations, and an absence of epidermal changes.3 In their retrospective review, Leinweber et al examined the histopathological findings of 65 cases of classic herpes infections. 68% of cases (44 of 65) exhibited atypical lymphocytes. Significant atypia, classified as .5% of cells, was seen in 46% of cases (30 of 65).3 Similarly, Resnik et al14 reviewed 45 cases that exhibited characteristic epithelial changes of herpes infection and found lymphocyte atypia in 71% of cases (32 of 45).
TABLE 1. Histopathological Spectrum of Cutaneous Herpes Structure Involved Epidermis Hair follicle Sebaceous glands Nerves Blood vessels (lymphocytic, leukocytoclastic vasculitides) Eccrine glands/ducts
2014 Lippincott Williams & Wilkins
FIGURE 5. Epidermal necrosis with scale crust. Scattered multinucleate giant cells are seen in the perifollicular location (arrows). Follicles also show extensive necrotic changes. The inset shows the multinucleate giant cells clearly. Hematoxylin and eosin, ·90; inset ·180 www.amjdermatopathology.com |
611
Hoyt and Bhawan
FIGURE 6. Eccrine duct (arrow) connecting to the epidermis with cytopathic changes of herpes. Hematoxylin and eosin, ·90.
Herpes infections can induce a pseudolymphomatous response containing clusters of CD30-positive lymphocytes.3,14–17 Expression of CD30 is classically associated with cutaneous lymphoproliferative disorders, a spectrum of diseases ranging from lymphomatoid papulosis to anaplastic large-cell lymphoma. Clusters of CD30-positive lymphocytes have also been described in other lymphomas and sarcomas.15 Furthermore, CD30-positive pseudolymphoma can be associated with benign inflammatory, infectious, and environmental skin conditions.15,16
Am J Dermatopathol Volume 36, Number 8, August 2014
In their review, Leinweber et al used immunohistochemistry to further characterize 23 cases that exhibited dense lymphoid infiltrates and atypical lymphoid cells. The presence of CD30-positive cells was identified in 19 cases (83%). They reported 2 cases of herpes infection that exhibited dense clusters of CD30-positive lymphocytes, strongly resembling CD30-positive lymphoproliferative disorders.3 Werner et al15 report 7 cases of herpes infections that produced a strong CD30-positive response, and Cepeda et al16 report 2 men who developed herpes infections that were associated with a CD30-positive pseudolymphoma. Another patient presented with subcutaneous nodules on his head and neck. Biopsy was suggestive of anaplastic large-cell lymphoma; however, his clinical features evolved to crusted erythema resembling herpes zoster. Review of the histology identified herpetic changes.17 Interestingly, 1 patient developed a subcutaneous nodule at the site of a previous VZV vaccination. Subsequent biopsy revealed pseudolymphoma consisting of clusters of CD30-positive immunoblasts. Diagnosis was established by in situ hybridization, which identified VZV DNA in occasional deep fibroblasts.18 Herpes can also incite a CD56-positive rich infiltrate, mimicking CD56-positive NK-/T-cell lymphoma, a form of nonHodgkin lymphoma. CD56 is a marker for natural killer cells, and can also be seen in several non-neoplastic skin conditions, including arthropod bite, lichen planus, lupus erythematosus, contact dermatitis, and atopic dermatitis.19 However, in these benign skin conditions, the proportion of CD56-positive cells is typically quite low (0.1%–9%).19 Malignancy may be suspected in the presence of angioinvasion, angiodestruction, dense clusters of CD56-positive cells, or marked atypia.19 A 53-year-old man presented with a firm, painless ulcer of the upper lip. Histopathology showed an intense lymphocytic infiltrate with many atypical cells with large nuclei. The infiltrate consisted of 80%–90% CD56-positive cells with a high proliferation rate, raising the concern for NK-/T-cell lymphoma. Immunohistochemical staining was positive for HSV-2 in the dermis, and the lesions resolved spontaneously in just over 2 weeks.19 Taddesse-Heath et al describe a 25-year-old woman who presented with a fungating 5-cm cerebriform mass in the nasopharynx. Lymphoma was suspected clinically, and histological evaluation revealed tissue necrosis and a dense
FIGURE 7. Ulcer with multinucleate giant cells (circle and the upper inset). Note the perineural inflammation (arrows and the lower inset). Hematoxylin and eosin ·18; upper inset ·180, lower inset ·90.
612
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
FIGURE 8. Herpetic vesicle pustule with many giant cells (circles) and changes of leukocytoclastic vasculitis. The inset shows vasculitis in higher magnification. Hematoxylin and eosin, ·45; inset ·180.
lymphoid infiltrate with CD56-positivity and high proliferative rate, suggestive of NK-/T-cell lymphoma. However, there was a lack of cytologic atypia, in situ hybridization studies for EBV was negative, and other classic features of NK-/T-cell lymphoma were absent. Closer review revealed multinucleated giant cells with intranuclear inclusions localized to areas of necrosis. Immunohistochemistry for HSV was focally positive in the multinucleated giant cells. DNA was extracted from formalin-fixed paraffin-embedded tissue, and PCR amplification revealed the presence of HSV-2.20 A 48-year-old man with a remote history of gastric lymphoma and renal cell carcinoma presented with a 3-week history of a mildly pruritic skin eruption on his upper
Herpes Histology
FIGURE 10. Atypical lymphoid cells infiltrate associated with herpes folliculitis. Hematoxylin and eosin, ·90.
abdomen. Physical examination revealed a 8- · 6-cm faintly erythematous nonscaly plaque with 4 indurated papules localized within the plaque. Biopsy revealed interface dermatitis with abundant CD3-positive lymphocytes coupled with scattered CD56-positive and CD20-positive cells. Preliminary suspicion was angiocentric (NK-/T-cell) lymphoma; however, deeper sections revealed multinucleated follicular keratinocytes, consistent with herpes folliculitis. The lesions resolved spontaneously.2 Marked plasma cell infiltrate mimicking plasmacytoma has been described in patients with cutaneous herpes infections. Plasmacytic infiltrate (Fig. 11) associated with cutaneous herpes is most commonly seen in patients with HIV/AIDS.21 Mosunjac et al reported a 41-year-old man with AIDS who presented with a large scrotal mass with superficial ulceration. Plasmacytoma or plasmacytoid lymphoma was suspected when intraoperative frozen section showed numerous plasma cells. However, flow cytometry failed to show a monoclonal proliferation. Subsequent PCR using formalin-fixed paraffin-embedded tissue demonstrated the presence of HSV-2 DNA.21 Plasma cell atypia due to herpes infection has only been reported on one occasion. Boyd et al reported the case of a 35-year-old woman with pemphigus vulgaris treated with prednisone and methotrexate who presented with a perineal ulcer. Histological examination revealed atypical plasma cells, suggestive of a cutaneous plasmacytoma with atypia. However, immunoperoxidase staining for HSV was positive
TABLE 2. Herpes Mimicking Hematologic Malignancies Hematologic Malignancy Mimicked by Herpes Infection
FIGURE 9. Intraepidermal vesicle with acantholytic cells, marked papillary dermal edema, perivascular lymphocytic cells with damage and infiltration of vessel walls by lymphocytes. Hematoxylin and eosin, ·45; inset ·180. 2014 Lippincott Williams & Wilkins
Lymphomatoid papulosis/aLTCL NK-/T-cell lymphoma Plasmacytoma B-cell lymphoma T-cell lymphoma, unclassified Leukemia cutis aLTCL, Anaplastic large cell lymphoma.
www.amjdermatopathology.com |
613
Hoyt and Bhawan
Am J Dermatopathol Volume 36, Number 8, August 2014
TABLE 3. Herpes Mimicking Inflammatory Skin Conditions Inflammatory Condition Mimicked by Herpes Arthropod bite Benign lymphocytic infiltrate Dermatitis artefacta Erythema multiforme Linear IgA dermatosis Lupus Rosacea
Herpes Mimicking Inflammatory Skin Conditions FIGURE 11. Predominantly plasmacytic infiltrate in a case of herpes. Note the multinucleate giant cells in the box. Hematoxylin and eosin, ·90.
in an aggregate of keratinocytes adjacent to the epidermal ulceration. The lesion resolved with oral valacyclovir.22 Herpes can also masquerade as cutaneous B-cell lymphoma. A 45-year-old Japanese woman presented with recurrent nodules on her right palm. Two previous skin biopsies were suggestive of cutaneous B-cell lymphoma. Examination of her right palm revealed 2 adjacent hard red nodules with a few small vesicles on the surface. A repeat biopsy with immunohistochemical staining demonstrated an impressive inflammatory infiltrate composed of numerous large atypical B cells with intermingled CD30-positive cells and small T cells without clonal rearrangement. The patient had recently developed a vesiculopustular lesion on the left hand. This was biopsied and histopathological examination demonstrated epidermal changes consistent with herpes. This prompted immunohistochemical staining of the specimen from the right hand. The presence of HSV antigen was identified in the epidermal cells from the vesicular epidermis.23 In addition to the lymphoproliferative and NK-/T-cell pseudolymphomatous presentations, herpes can also present as a nonspecific cutaneous T-cell lymphoma.3,24 A 42-yearold man with HIV presented with an enlarging, ulcerated, friable tumor on the glans and shaft of his penis. The initial biopsy lacked epidermis, but demonstrated a florid lymphocytic dermal infiltrate that primarily consisted of CD4-positive cells. A T-cell receptor clone was identified using PCR/ single-strand conformational polymorphism, raising the suspicion for a neoplastic process. However, a repeat biopsy demonstrated characteristic features of herpes infection. Immunohistochemistry confirmed the presence of HSV-2 in affected keratinocytes.24 Herpes simplex mimicking leukemia cutis has only been described in 1 patient. Hassel et al described a 55-year-old man with a 5-year history of chronic lymphocytic leukemia who presented with a penile ulcer. The initial biopsy showed an atypical lymphocytic infiltrate, and a diagnosis of leukemia cutis was made. However, subsequent studies (Tzank preparation and viral culture) found the lesion to be herpetic. The patient improved significantly when treated with oral and topical acyclovir.25
614
| www.amjdermatopathology.com
Cutaneous herpes infections can also mimic a variety of nonmalignant inflammatory conditions (Table 3). A 43-year-old woman presented with unilateral “painful, red indurated lumps” on her forehead and scalp. Biopsy of a lesion showed superficial and deep perivascular and periadnexal infiltrate without any herpetic changes in the epidermis. This was initially interpreted as cutaneous lupus erythematosus. However, the degree of perineural involvement prompted further sectioning, which revealed herpetic folliculitis.5 Early herpes infections can also mimic discoid lupus erythematosus.13 Leinweber et al describe 2 cases of cutaneous herpes in which the inflammatory infiltrate contained large numbers of eosinophils (Fig. 12). In this context, herpes can resemble a pseudolymphomatous arthropod bite reaction.3 Linear IgA dermatosis is the name given to a group of autoimmune vesiculobullous diseases characterized by linear deposition of IgA along the basement membrane zone of the epidermis. Linear IgA deposition has been reported in a single case of a 78-year-old man with disseminated VZV. In this patient, Tzanck smear demonstrated multinucleated giant cells, and punch biopsy showed findings consistent with herpes infection (including intraepidermal bullae, multinucleated giant cells, focal epidermal necrosis, hemorrhage, and perivascular
FIGURE 12. Herpetic vesicle with multinucleate giant cells in the box, with many eosinophils (arrows). Hematoxylin and eosin, ·90. 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
FIGURE 13. Scattered necrotic keratinocytes mimicking erythema multiforme in a case of herpes. Hematoxylin and eosin, ·45; inset ·80.
and diffuse lymphocytic and neutrophilic inflammation). Direct immunofluorescence revealed intense linear deposition of IgA at the basement membrane. Indirect immunofluorescence failed to reveal circulating IgG or IgA anti–basement membrane zone antibodies. Viral culture was positive for VZV, and the patient was treated with acyclovir with complete resolution of skin lesions.26 In this context, linear deposition of IgA may reflect a nonspecific finding as various immune deposits can be seen in several infectious or inflammatory conditions, genodermatoses, or other skin conditions.27 When herpes induces a nonspecific lymphocytic infiltrate without characteristic herpetic changes, it can be interpreted as rosacea,14 benign lymphocytic infiltrate,28 or erythema multiforme (Fig. 13).28 One patient presented with recurrent ulcerated and excoriated skin lesions on her face; she was diagnosed with dermatitis artefacta as her initial biopsy results simply showed “chronic inflammation.” Repeat biopsy showed an ulcer with abnormal keratinocytes at the periphery. Some of the keratinocytes exhibited intranuclear inclusions, and multinucleated keratinocytes were also seen. The nuclei of these abnormal keratinocytes stained positively for herpes virus antigens on immunohistochemistry. The patient was treated with oral acyclovir and experienced moderate clinical improvement.29
DISCUSSION Typically when herpes infections mimic other diseases, evidence of herpetic infection can be seen on reviewing the
FIGURE 14. Immunostaining with herpes virus antibody highlights the infected keratinocytes, ·90. 2014 Lippincott Williams & Wilkins
Herpes Histology
original slides.17 Additionally, deeper sections may reveal herpetic changes in the dermal structures that were not present in the original sections.2,5,14 However, in some patients, herpetic changes are not evident clinically or histologically. This can be frustrating for both practitioners and patients as the diagnosis remains elusive. In such circumstances, in situ hybridization, immunohistochemistry (Fig. 14), or PCR can aid in making a correct diagnosis.1 We identified 6 cases in which the diagnosis of herpes was made solely by these adjunctive studies (without any specific histopathological findings by the routine hematoxylin and eosin staining). Three patients are reported with pseudolymphomatous herpes infections that lacked specific herpetic changes. In each of these cases, the correct diagnosis was made by immunohistochemistry.19,22,23 Leukocytoclastic vasculitis is another histopathological presentation of herpes that has been reported without any diagnostic herpetic changes (3 patients). In these patients, the correct diagnosis was obtained by PCR3,30 or immunohistochemistry.13
CONCLUSIONS The spectrum of histological presentations in cutaneous herpes infection extends beyond the classic epidermal findings. Involvement of dermal and adnexal structures may provide clues to a lurking herpetic infection, particularly when epidermal changes are lacking. Herpes infection can incite a pseudolymphomatous response that mimics a variety of hematologic malignancies. Furthermore, herpes can masquerade as one of the several inflammatory cutaneous conditions. Many adjunctive studies exist to aid clinicians in identifying herpetic infection when the clinical and histological presentation is unclear. REFERENCES 1. Chisholm C, Lopez L. Cutaneous infections caused by Herpesviridae: a review. Arch Pathol Lab Med. 2011;135:1357–1362. 2. Bae-Harboe YS, Bhawan J, Demierre MF, et al. Herpes folliculitis masquerading as cutaneous lymphoma. Am J Dermatopathol. 2013;35: 663–665. 3. Leinweber B, Kerl H, Cerroni L. Histopathologic features of cutaneous herpes virus infections (herpes simplex, herpes varicella/zoster): a broad spectrum of presentations with common pseudolymphomatous aspects. Am J Surg Pathol. 2006;30:50–58. 4. Böer A, Herder N, Winter K, et al. Herpes folliculitis: clinical, histopathological, and molecular pathologic observations. Br J Dermatol. 2006; 154:743–746. 5. Walsh N, Boutilier R, Glasgow D, et al. Exclusive involvement of folliculosebaceous units by herpes: a reflection of early herpes zoster. Am J Dermatopathol. 2005;27:189–194. 6. Muñoz E, Valks R, Fernández-Herrera J, et al. Herpetic syringitis associated with eccrine squamous syringometaplasia in HIV-positive patients. J Cutan Pathol. 1997;24:425–428. 7. Rinder HM, Murphy GF. Eccrine duct involvement by herpes zoster. Arch Dermatol. 1984;120:261–262. 8. Sedrak MP, Marek M, Matherene R, et al. Syringitis: a clue to herpes infection. Dermatol Online J. 2012;18:6. 9. Abbas O, Bhawan J. Cutaneous perineural inflammation: a review. J Cutan Pathol. 2010;37:1200–1211. 10. Worrell JT, Cockerell CJ. Histopathology of peripheral nerves in cutaneous herpesvirus infection. Am J Dermatopathol. 1997;19:133–137. 11. Cohen C, Trapuckd S. Leukocytoclastic vasculitis associated with cutaneous infection by herpesvirus. Am J Dermatopathol. 1984;6:561–565.
www.amjdermatopathology.com |
615
Hoyt and Bhawan
12. Erhard H, Rünger TM, Kreienkamp M, et al. Atypical varicella-zoster virus infection in an immunocompromised patient: result of a virusinduced vasculitis. J Am Acad Dermatol. 1995;32:908–911. 13. Uhoda I, Piérard-Franchimont C, Piérard GE. Varicella-zoster virus vasculitis: a case of recurrent varicella without epidermal involvement. Dermatology. 2000;200:173–175. 14. Resnik KS, DiLeonardo M. Herpes incognito. Am J Dermatopathol. 2000;22:144–150. 15. Werner B, Massone C, Kerl H, et al. Large CD30-positive cells in benign, atypical lymphoid infiltrates of the skin. J Cutan Pathol. 2008; 35:1100–1107. 16. Cepeda LT, Pieretti M, Chapman SF, et al. CD30-positive atypical lymphoid cells in common non-neoplastic cutaneous infiltrates rich in neutrophils and eosinophils. Am J Surg Pathol. 2003;27: 912–918. 17. Shiohara J, Koga H, Uhara H, et al. Herpes zoster histopathologically mimicking CD30-positive anaplastic large cell lymphoma. J Eur Acad Dermatol Venereol. 2009;23:618–619. 18. Porto DA, Comfere NI, Myers LM, et al. Pseudolymphomatous reaction to varicella zoster virus vaccination: role of viral in situ hybridization. J Cutan Pathol. 2010;37:1098–1102. 19. Fernandez-Flores A, Rodriguez-Prado N. An ulcerated lesion due to HSV-2 infection with a CD56+ cell predominant inflammatory infiltrate. Acta Dermatovenerol Alp Panonica Adriat. 2011;20:201–205. 20. Taddesse-Heath L, Feldman JI, Fahle GA, et al. Florid CD4+, CD56+ T-cell infiltrate associated with Herpes simplex infection simulating nasal NK-/T-cell lymphoma. Mod Pathol. 2003;16:166–172.
616
| www.amjdermatopathology.com
Am J Dermatopathol Volume 36, Number 8, August 2014
21. Mosunjac M, Park J, Wang W, et al. Genital and perianal herpes simplex simulating neoplasia in patients with AIDS. AIDS Patient Care STDS. 2009;23:153–158. 22. Boyd AS, Zwerner JP, Miller JL. Herpes simplex virus-induced plasmacytic atypia. J Cutan Pathol. 2012;39:270–273. 23. Fukamachi S, Kimura T, Kobayashi M, et al. Palmar pseudolymphoma associated with herpes simplex infection. J Cutan Pathol. 2010;37:808–811. 24. Wain EM, Antony F, Appleton MA, et al. Genital herpes masquerading as a cutaneous T-cell lymphoma: a report of two cases. J Cutan Pathol. 2008;35:770–773. 25. Hassel MH, Lesher JL Jr. Herpes simplex mimicking leukemia cutis. J Am Acad Dermatol. 1989;21:367–371. 26. Blickenstaff RD, Perry HO, Peters MS. Linear IgA deposition associated with cutaneous varicella-zoster infection: a case report. J Cutan Pathol. 1988;15:49–52. 27. Miller DD, Bhawan J. Bullous tinea pedis with direct immunofluorescence positivity: when is a positive result not autoimmune bullous disease? Am J Dermatopathol. 2013;35:587–594. 28. Austin C, Egbert B, Miller AC, et al. Herpesvirus infection of the skin: new histopathologic clues to the diagnosis. American Society of Dermatopathology Abstracts, Annual Meeting, November 29 and 30, 1984. Arch Dermatol. 1984;120:1608. 29. Tucker WF, Harrington CI, Underwood JC. Recurrent herpes simplex infection masquerading as dermatitis artefacta. Arch Dermatol. 1987;123:435–436. 30. Baek YS, Shin WU, Song HJ, et al. Plantar leukocytoclastic vasculitis with detection of herpes simplex virus type 2 by PCR assay. Int J Dermatol. 2013; 52:1434–1435.
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
Herpes Histology
CME EXAM INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITS™ The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers. An annual total of 12 AMA PRA Category 1 Credits is available through the twelve 2014 issues of The American Journal of Dermatopathology. This activity is available for credit through December 31, 2014. Accreditation Statement Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation Statement Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one (1) AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete the quiz, answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money order for the $15 processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001 Market Street, 3rd Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit, and must be postmarked by the expiration date. Answer sheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation.
CME EXAMINATION AUGUST 2014 Please mark your answers on the ANSWER SHEET. After completing this CME activity, physicians should be better able to identify and describe the broad spectrum of histopathological presentations of cutaneous herpes infections, and maintain a high index of suspicion for herpes infections when viewing challenging histopathological cases. CME Questions 1. Which inclusion bodies are found in histopathological sections of herpes simplex virus (HSV) and varicella zoster virus (VZV)? a. Verocay bodies b. Cowdry A bodies c. Cowdry B bodies d. Henderson–Patterson bodies e. Guarnieri bodies 2. Which of the following histologic findings are NOT associated with HSV or VZV infection? a. Nuclear moulding b. Multinucleated keratinocytes c. Ballooning degeneration d. Koilocyte formation e. Steel-gray nuclei 3. Which of the following histologic findings may suggest the presence of herpes folliculitis? a. Eosinophils around hair follicle b. “Swarm of bees” lymphocytic inflammation c. Trichomalacia d. Follicular plugging e. Necrosis of hair follicles 2014 Lippincott Williams & Wilkins
www.amjdermatopathology.com |
617
Hoyt and Bhawan
Am J Dermatopathol Volume 36, Number 8, August 2014
4. Herpes mimicking an NK-/T-cell lymphoma would likely stain heavily for which surface marker? a. CD 56 b. CD 45 c. CD 68 d. CD 117 e. CD 20 5. Cutaneous herpes infection (HSV and VZV) can result in a histopathological presentation that mimics each of the following EXCEPT: a. Anaplastic large cell lymphoma b. Plasmacytoma c. Smallpox d. Linear IgA dermatitis e. Erythema multiforme 6. Which of the following statements is false? a. Herpes infection occasionally incites a monoclonal lymphocytic infiltrate. b. NK-/T-cell lymphoma has a reported association with EBV. c. A plasmocytic response to herpes (HSV/VZV) infection is more likely in patients who are immunosuppressed. d. Herpes infection can result in multinucleation of neurons. e. Lymphocytic atypia can be noted in greater than 50 percent of cases of cutaneous herpes infections.
618
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
2014 Lippincott Williams & Wilkins
Herpes Histology
www.amjdermatopathology.com |
619
Histological Spectrum of Cutaneous Herpes Infections Brian Hoyt, BS* and Jag Bhawan, MD†
Abstract: Herpes simplex virus and varicella zoster virus are doublestranded DNA viruses that commonly infect humans, resulting in cutaneous manifestations. Diagnosis is generally made based on clinical findings; however, when the presentation is atypical, biopsy can aid in making a correct diagnosis. The classic histopathological findings of herpetic infection are well established (acantholysis, ballooning degeneration, intranuclear inclusions, multinucleation, necrosis, and formation of vesicles or ulcers). Herpes infection can also cause histopathological changes in many dermal structures. Furthermore, herpes can masquerade as a variety of hematologic malignancies or benign cutaneous conditions. The histopathological spectrum of herpes infections is reviewed and discussed. Key Words: cutaneous, herpes, histology, simplex, zoster (Am J Dermatopathol 2014;36:609–619)
LEARNING OBJECTIVES After completing this CME activity, physicians should be better able to: • Identify and describe the broad spectrum of histopathological presentations of cutaneous herpes infections. • Maintain a high index of suspicion for herpes infections when viewing challenging histopathological cases.
INTRODUCTION Herpes simplex and varicella zoster are ubiquitous members of the herpesviridae family. These infections result in characteristic skin findings that are typically diagnosed clinically (Fig. 1). When the clinical presentation is unclear, biopsy can aid in making an accurate diagnosis. Histopathological diagnosis is usually straightforward; however, herpes can mimic a variety of benign and malignant cutaneous conditions. The cutaneous lesions of herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) are classically described as painful, grouped vesicles on an erythematous base. Lesions are prone to recurrence, often with a prodrome of burning, itching, or pain.1 Varicella zoster virus (VZV) has 2 distinct clinical From *Medical Student, The University of Texas Medical School at Houston, Houston, TX; and †Professor of Dermatology and Pathology, Head Dermatopathology Section, Vice Chairman, Department of Dermatology, Boston University School of Medicine, Boston, MA. All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Reprints: Jag Bhawan, MD, Section of Dermatopathology, Department of Dermatology, Boston University School of Medicine, 609 Albany St, J-308, Boston, MA 02118 (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
presentations. In children, the viral eruption usually presents with generalized vesicles on an erythematous base at various stages of evolution (chicken pox); whereas in adults, painful grouped vesicles typically arise in a dermatomal distribution (herpes zoster, shingles).1 In most instances, the clinical presentation of HSV and VZV is distinctive, rendering skin biopsy unnecessary. However, in some patients, particularly those with internal malignancies or who are immunocompromised, the clinical presentation can be atypical or misleading. In these situations, additional studies are often required. These include Tzank smear, viral culture, histological examination of slides stained with hematoxylin and eosin, immunohistochemistry, immunofluorescence, in situ hybridization, and polymerase chain reaction (PCR).1 This article will help readers understand and recognize the spectrum of histopathological presentations for cutaneous herpes infections and to be vigilant when reviewing such cases.
MATERIALS AND METHODS We herein review the histological spectrum of cutaneous herpes infections (including herpes simplex and varicella zoster). Hereafter, herpes will be used to refer to both HSV and VZV. We performed an extensive review of the literature available on PubMed using the following search terms: histology OR histopathology OR pathology OR pathologic AND herpes AND cutaneous. We also searched “atypical herpes histology.” We limited our review to the histopathology of active herpes infection, excluding instances of skin conditions appearing at the site of previously healed herpes infections.
RESULTS Histological Spectrum of Herpes Infection Herpes simplex and varicella zoster have a similar histopathological presentation.1 Low-power examination often reveals shallow vesicles (Fig. 2) or ulcers with ballooning keratinocytes, acantholysis, and necrosis.1 Cytopathic changes include enlarged and pale keratinocytes with steel-gray nuclei, marginated chromatin, multinucleated cells, nuclear molding, and eosinophilic intranuclear (Cowdry A) inclusions (Fig. 3).1,2 Herpetic changes are most commonly noted in the epidermis; however, dermal—including adnexal—structures are also frequently involved (Table 1). When evaluating dermal structures for evidence of herpes infection, the hair follicles and sebaceous glands (Fig. 4) are most frequently affected.1,3 Leinweber et al3 reviewed the histology of 65 cases of herpes infection diagnosed based on the presence of typical epithelial findings. On reviewing these www.amjdermatopathology.com |
609
Hoyt and Bhawan
Am J Dermatopathol Volume 36, Number 8, August 2014
FIGURE 1. Clinical photographs of herpes simplex showing grouped vesicles/pustules on the erythematous base (A) and in dermatomal distribution in herpes zoster (B). Reproduced with permission from Dermatopathology Interactive Atlas 2001, www.dermpathatlas.com. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
cases, they found herpetic changes in the hair follicles in 34/44 cases (77%) and sebaceous glands in 24/36 cases (67%).3 Histopathological features of herpes folliculitis include dense, deep perifollicular infiltrate, with lymphocytes scattered within the perifollicular sheath and follicular epithelium. Extravasation of erythrocytes and keratinocyte necrosis can also be seen.4 Classic herpetic changes in the overlying epidermis may be lacking,2,4 or the epidermis may be necrotic with inflammatory crust (Fig. 5). In such cases, the diagnosis can be difficult and one should look for multinucleate giant cells in perifollicular location. In a review of 21 patients with herpes folliculitis, cytopathic changes of the follicular keratinocytes—including necrosis, ballooning degeneration, and steel-gray nuclei—were seen in just over half of the cases. Herpetic infection was suspected on the basis of the perifollicular lymphocytic infiltrate with or without keratinocyte necrosis. The diagnosis in all 21 cases was confirmed by PCR of formalin-fixed paraffin-embedded tissue samples.4 Sebaceous glands may also demonstrate a lymphocytic infiltrate along with typical herpetic changes: ballooning of epithelial cells, necrosis, multinucleation, nuclear molding, and epithelial acanthosis.4,5 Herpes syringitis, herpetic infection of the eccrine glands or ducts, is a rare finding in cutaneous herpes.3,6–8 Epithelial cells of the eccrine glands and ducts (Fig. 6) reveal typical herpetic changes: multinucleation, ballooning degeneration, nuclear molding, and margination of chromatin.8 Muñoz et al6 reported an unusual association between herpes syringitis and eccrine squamous syringometaplasia in 3 patients with AIDS. Although herpes syringitis is more commonly associated with
immunosuppression; it can be seen in patients who are immunocompetent.3 In rare cases, involvement of the eccrine glands can assist in making proper diagnosis.8 It is believed that herpes remains latent in the sensory ganglia, and when it is reactivated, the virus migrates to the skin through peripheral nerves. Hence, it is not surprising that involvement of dermal nerves is commonly seen in herpes infections.9 Indeed, Worrell and Cockerell reviewed 54 cases of cutaneous herpes diagnosed by clinical features coupled with characteristic herpetic changes on biopsy. The peripheral nerves could be evaluated in 48 of the cases, and all of them demonstrated perineural inflammation. This inflammation consisted of a dense mixed infiltrate of lymphocytes and neutrophils in a diffuse interstitial pattern. In addition, intraneural infiltrate with Schwann cell hypertrophy, nuclear eosinophilia, and pyknosis was found in over half (26/48 patients, 54%) of the cases, and neuronal necrosis was present in 21/48 (44%) of cases.10 The neurons themselves were less frequently involved; only 4 cases (8%) showed cytopathic effects of herpes within the nerve cells.10 These cytopathic changes were similar to those seen in infected keratinocytes, including hyperchromatic nuclei, swelling, and degeneration; multinucleation of neurons was not seen.10 Leinweber et al3 also reported cytopathic changes to dermal neurons in only 9 of 61 cases (15%) with cutaneous herpes. The differential diagnosis for perineural inflammation (Fig. 7) is limited; thus, identifying this feature can be a significant clue in diagnosing a subtle herpes infection.5,9 Leukocytoclastic vasculitis is another common histological finding in cutaneous herpes infections (Fig. 8). In their
FIGURE 2. Intraepidermal and subepidermal blister with reticular degeneration (left inset), multinucleate giant cells (right inset) with many acantholytic cells and minimal inflammatory infiltrate. Hematoxylin and eosin, ·18; inset ·180.
610
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
Herpes Histology
FIGURE 4. Herpetic folliculitis showing characteristic cytopathologic changes. Hematoxylin and eosin, ·90. FIGURE 3. Intraepidermal and subepidermal blister with marked mixed inflammatory infiltrate, with many multinucleate giant cells and intranuclear inclusion characteristic of herpes infection (inset). Hematoxylin and eosin, ·18; inset ·90.
review of 54 cases, Worrell and Cockerell10 reported a leukocytoclastic vasculitis in 67% of patients. Vessel walls were found to contain fibrin deposits, suggesting that immune complexes may mediate this vasculitis.10 Interestingly, immunohistochemistry was performed in 2 cases, and did not identify herpes viral antigen in the endothelial cells.10 However, Cohen et al reported 2 cases of leukocytoclastic vasculitis in which viral inclusions were found in endothelial cells, adjacent pericytes, and dermal fibroblasts.11 Much less commonly, the perivascular infiltrate is predominantly mononuclear, consistent with a lymphocytic vasculitis (Fig. 9). One patient with a 10-year history of mycosis fungoides developed chronic, painless erythematous nodules on his face in the distribution of the third trigeminal nerve. These coalesced into confluent necrotic plaques with superficial ulceration. Histological examination revealed an obliterative lymphocytic vasculitis with a lymphohistiocytic infiltrate. Cowdry A bodies were seen in some endothelial cells; however, the epidermal changes were nondiagnostic. Diagnosis was confirmed by identifying viral particles in the endothelial cells using electron microscopy.12 Another patient who was undergoing chemotherapy for mediastinal large B-cell lymphoma developed red, painless nodules in his right axilla and on his right hand. Biopsy revealed superficial and deep perivascular lymphocytic infiltrate, without any changes to the overlying epidermis, leading to a preliminary diagnosis of lymphocytic vasculitis.
Immunohistochemistry subsequently revealed the presence of varicella zoster antigen in the endothelial cells and dermal dendrocytes.13
Herpes Mimicking Cutaneous Hematologic Malignancies Herpes infections can trigger a dense lymphocytic infiltrate (Fig. 10) that resembles cutaneous lymphoma (Table 2). The diagnostic challenge of this pseudolymphomatous response can be increased by the presence of marked lymphocytic atypia, monoclonal cell proliferations, and an absence of epidermal changes.3 In their retrospective review, Leinweber et al examined the histopathological findings of 65 cases of classic herpes infections. 68% of cases (44 of 65) exhibited atypical lymphocytes. Significant atypia, classified as .5% of cells, was seen in 46% of cases (30 of 65).3 Similarly, Resnik et al14 reviewed 45 cases that exhibited characteristic epithelial changes of herpes infection and found lymphocyte atypia in 71% of cases (32 of 45).
TABLE 1. Histopathological Spectrum of Cutaneous Herpes Structure Involved Epidermis Hair follicle Sebaceous glands Nerves Blood vessels (lymphocytic, leukocytoclastic vasculitides) Eccrine glands/ducts
2014 Lippincott Williams & Wilkins
FIGURE 5. Epidermal necrosis with scale crust. Scattered multinucleate giant cells are seen in the perifollicular location (arrows). Follicles also show extensive necrotic changes. The inset shows the multinucleate giant cells clearly. Hematoxylin and eosin, ·90; inset ·180 www.amjdermatopathology.com |
611
Hoyt and Bhawan
FIGURE 6. Eccrine duct (arrow) connecting to the epidermis with cytopathic changes of herpes. Hematoxylin and eosin, ·90.
Herpes infections can induce a pseudolymphomatous response containing clusters of CD30-positive lymphocytes.3,14–17 Expression of CD30 is classically associated with cutaneous lymphoproliferative disorders, a spectrum of diseases ranging from lymphomatoid papulosis to anaplastic large-cell lymphoma. Clusters of CD30-positive lymphocytes have also been described in other lymphomas and sarcomas.15 Furthermore, CD30-positive pseudolymphoma can be associated with benign inflammatory, infectious, and environmental skin conditions.15,16
Am J Dermatopathol Volume 36, Number 8, August 2014
In their review, Leinweber et al used immunohistochemistry to further characterize 23 cases that exhibited dense lymphoid infiltrates and atypical lymphoid cells. The presence of CD30-positive cells was identified in 19 cases (83%). They reported 2 cases of herpes infection that exhibited dense clusters of CD30-positive lymphocytes, strongly resembling CD30-positive lymphoproliferative disorders.3 Werner et al15 report 7 cases of herpes infections that produced a strong CD30-positive response, and Cepeda et al16 report 2 men who developed herpes infections that were associated with a CD30-positive pseudolymphoma. Another patient presented with subcutaneous nodules on his head and neck. Biopsy was suggestive of anaplastic large-cell lymphoma; however, his clinical features evolved to crusted erythema resembling herpes zoster. Review of the histology identified herpetic changes.17 Interestingly, 1 patient developed a subcutaneous nodule at the site of a previous VZV vaccination. Subsequent biopsy revealed pseudolymphoma consisting of clusters of CD30-positive immunoblasts. Diagnosis was established by in situ hybridization, which identified VZV DNA in occasional deep fibroblasts.18 Herpes can also incite a CD56-positive rich infiltrate, mimicking CD56-positive NK-/T-cell lymphoma, a form of nonHodgkin lymphoma. CD56 is a marker for natural killer cells, and can also be seen in several non-neoplastic skin conditions, including arthropod bite, lichen planus, lupus erythematosus, contact dermatitis, and atopic dermatitis.19 However, in these benign skin conditions, the proportion of CD56-positive cells is typically quite low (0.1%–9%).19 Malignancy may be suspected in the presence of angioinvasion, angiodestruction, dense clusters of CD56-positive cells, or marked atypia.19 A 53-year-old man presented with a firm, painless ulcer of the upper lip. Histopathology showed an intense lymphocytic infiltrate with many atypical cells with large nuclei. The infiltrate consisted of 80%–90% CD56-positive cells with a high proliferation rate, raising the concern for NK-/T-cell lymphoma. Immunohistochemical staining was positive for HSV-2 in the dermis, and the lesions resolved spontaneously in just over 2 weeks.19 Taddesse-Heath et al describe a 25-year-old woman who presented with a fungating 5-cm cerebriform mass in the nasopharynx. Lymphoma was suspected clinically, and histological evaluation revealed tissue necrosis and a dense
FIGURE 7. Ulcer with multinucleate giant cells (circle and the upper inset). Note the perineural inflammation (arrows and the lower inset). Hematoxylin and eosin ·18; upper inset ·180, lower inset ·90.
612
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
FIGURE 8. Herpetic vesicle pustule with many giant cells (circles) and changes of leukocytoclastic vasculitis. The inset shows vasculitis in higher magnification. Hematoxylin and eosin, ·45; inset ·180.
lymphoid infiltrate with CD56-positivity and high proliferative rate, suggestive of NK-/T-cell lymphoma. However, there was a lack of cytologic atypia, in situ hybridization studies for EBV was negative, and other classic features of NK-/T-cell lymphoma were absent. Closer review revealed multinucleated giant cells with intranuclear inclusions localized to areas of necrosis. Immunohistochemistry for HSV was focally positive in the multinucleated giant cells. DNA was extracted from formalin-fixed paraffin-embedded tissue, and PCR amplification revealed the presence of HSV-2.20 A 48-year-old man with a remote history of gastric lymphoma and renal cell carcinoma presented with a 3-week history of a mildly pruritic skin eruption on his upper
Herpes Histology
FIGURE 10. Atypical lymphoid cells infiltrate associated with herpes folliculitis. Hematoxylin and eosin, ·90.
abdomen. Physical examination revealed a 8- · 6-cm faintly erythematous nonscaly plaque with 4 indurated papules localized within the plaque. Biopsy revealed interface dermatitis with abundant CD3-positive lymphocytes coupled with scattered CD56-positive and CD20-positive cells. Preliminary suspicion was angiocentric (NK-/T-cell) lymphoma; however, deeper sections revealed multinucleated follicular keratinocytes, consistent with herpes folliculitis. The lesions resolved spontaneously.2 Marked plasma cell infiltrate mimicking plasmacytoma has been described in patients with cutaneous herpes infections. Plasmacytic infiltrate (Fig. 11) associated with cutaneous herpes is most commonly seen in patients with HIV/AIDS.21 Mosunjac et al reported a 41-year-old man with AIDS who presented with a large scrotal mass with superficial ulceration. Plasmacytoma or plasmacytoid lymphoma was suspected when intraoperative frozen section showed numerous plasma cells. However, flow cytometry failed to show a monoclonal proliferation. Subsequent PCR using formalin-fixed paraffin-embedded tissue demonstrated the presence of HSV-2 DNA.21 Plasma cell atypia due to herpes infection has only been reported on one occasion. Boyd et al reported the case of a 35-year-old woman with pemphigus vulgaris treated with prednisone and methotrexate who presented with a perineal ulcer. Histological examination revealed atypical plasma cells, suggestive of a cutaneous plasmacytoma with atypia. However, immunoperoxidase staining for HSV was positive
TABLE 2. Herpes Mimicking Hematologic Malignancies Hematologic Malignancy Mimicked by Herpes Infection
FIGURE 9. Intraepidermal vesicle with acantholytic cells, marked papillary dermal edema, perivascular lymphocytic cells with damage and infiltration of vessel walls by lymphocytes. Hematoxylin and eosin, ·45; inset ·180. 2014 Lippincott Williams & Wilkins
Lymphomatoid papulosis/aLTCL NK-/T-cell lymphoma Plasmacytoma B-cell lymphoma T-cell lymphoma, unclassified Leukemia cutis aLTCL, Anaplastic large cell lymphoma.
www.amjdermatopathology.com |
613
Hoyt and Bhawan
Am J Dermatopathol Volume 36, Number 8, August 2014
TABLE 3. Herpes Mimicking Inflammatory Skin Conditions Inflammatory Condition Mimicked by Herpes Arthropod bite Benign lymphocytic infiltrate Dermatitis artefacta Erythema multiforme Linear IgA dermatosis Lupus Rosacea
Herpes Mimicking Inflammatory Skin Conditions FIGURE 11. Predominantly plasmacytic infiltrate in a case of herpes. Note the multinucleate giant cells in the box. Hematoxylin and eosin, ·90.
in an aggregate of keratinocytes adjacent to the epidermal ulceration. The lesion resolved with oral valacyclovir.22 Herpes can also masquerade as cutaneous B-cell lymphoma. A 45-year-old Japanese woman presented with recurrent nodules on her right palm. Two previous skin biopsies were suggestive of cutaneous B-cell lymphoma. Examination of her right palm revealed 2 adjacent hard red nodules with a few small vesicles on the surface. A repeat biopsy with immunohistochemical staining demonstrated an impressive inflammatory infiltrate composed of numerous large atypical B cells with intermingled CD30-positive cells and small T cells without clonal rearrangement. The patient had recently developed a vesiculopustular lesion on the left hand. This was biopsied and histopathological examination demonstrated epidermal changes consistent with herpes. This prompted immunohistochemical staining of the specimen from the right hand. The presence of HSV antigen was identified in the epidermal cells from the vesicular epidermis.23 In addition to the lymphoproliferative and NK-/T-cell pseudolymphomatous presentations, herpes can also present as a nonspecific cutaneous T-cell lymphoma.3,24 A 42-yearold man with HIV presented with an enlarging, ulcerated, friable tumor on the glans and shaft of his penis. The initial biopsy lacked epidermis, but demonstrated a florid lymphocytic dermal infiltrate that primarily consisted of CD4-positive cells. A T-cell receptor clone was identified using PCR/ single-strand conformational polymorphism, raising the suspicion for a neoplastic process. However, a repeat biopsy demonstrated characteristic features of herpes infection. Immunohistochemistry confirmed the presence of HSV-2 in affected keratinocytes.24 Herpes simplex mimicking leukemia cutis has only been described in 1 patient. Hassel et al described a 55-year-old man with a 5-year history of chronic lymphocytic leukemia who presented with a penile ulcer. The initial biopsy showed an atypical lymphocytic infiltrate, and a diagnosis of leukemia cutis was made. However, subsequent studies (Tzank preparation and viral culture) found the lesion to be herpetic. The patient improved significantly when treated with oral and topical acyclovir.25
614
| www.amjdermatopathology.com
Cutaneous herpes infections can also mimic a variety of nonmalignant inflammatory conditions (Table 3). A 43-year-old woman presented with unilateral “painful, red indurated lumps” on her forehead and scalp. Biopsy of a lesion showed superficial and deep perivascular and periadnexal infiltrate without any herpetic changes in the epidermis. This was initially interpreted as cutaneous lupus erythematosus. However, the degree of perineural involvement prompted further sectioning, which revealed herpetic folliculitis.5 Early herpes infections can also mimic discoid lupus erythematosus.13 Leinweber et al describe 2 cases of cutaneous herpes in which the inflammatory infiltrate contained large numbers of eosinophils (Fig. 12). In this context, herpes can resemble a pseudolymphomatous arthropod bite reaction.3 Linear IgA dermatosis is the name given to a group of autoimmune vesiculobullous diseases characterized by linear deposition of IgA along the basement membrane zone of the epidermis. Linear IgA deposition has been reported in a single case of a 78-year-old man with disseminated VZV. In this patient, Tzanck smear demonstrated multinucleated giant cells, and punch biopsy showed findings consistent with herpes infection (including intraepidermal bullae, multinucleated giant cells, focal epidermal necrosis, hemorrhage, and perivascular
FIGURE 12. Herpetic vesicle with multinucleate giant cells in the box, with many eosinophils (arrows). Hematoxylin and eosin, ·90. 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
FIGURE 13. Scattered necrotic keratinocytes mimicking erythema multiforme in a case of herpes. Hematoxylin and eosin, ·45; inset ·80.
and diffuse lymphocytic and neutrophilic inflammation). Direct immunofluorescence revealed intense linear deposition of IgA at the basement membrane. Indirect immunofluorescence failed to reveal circulating IgG or IgA anti–basement membrane zone antibodies. Viral culture was positive for VZV, and the patient was treated with acyclovir with complete resolution of skin lesions.26 In this context, linear deposition of IgA may reflect a nonspecific finding as various immune deposits can be seen in several infectious or inflammatory conditions, genodermatoses, or other skin conditions.27 When herpes induces a nonspecific lymphocytic infiltrate without characteristic herpetic changes, it can be interpreted as rosacea,14 benign lymphocytic infiltrate,28 or erythema multiforme (Fig. 13).28 One patient presented with recurrent ulcerated and excoriated skin lesions on her face; she was diagnosed with dermatitis artefacta as her initial biopsy results simply showed “chronic inflammation.” Repeat biopsy showed an ulcer with abnormal keratinocytes at the periphery. Some of the keratinocytes exhibited intranuclear inclusions, and multinucleated keratinocytes were also seen. The nuclei of these abnormal keratinocytes stained positively for herpes virus antigens on immunohistochemistry. The patient was treated with oral acyclovir and experienced moderate clinical improvement.29
DISCUSSION Typically when herpes infections mimic other diseases, evidence of herpetic infection can be seen on reviewing the
FIGURE 14. Immunostaining with herpes virus antibody highlights the infected keratinocytes, ·90. 2014 Lippincott Williams & Wilkins
Herpes Histology
original slides.17 Additionally, deeper sections may reveal herpetic changes in the dermal structures that were not present in the original sections.2,5,14 However, in some patients, herpetic changes are not evident clinically or histologically. This can be frustrating for both practitioners and patients as the diagnosis remains elusive. In such circumstances, in situ hybridization, immunohistochemistry (Fig. 14), or PCR can aid in making a correct diagnosis.1 We identified 6 cases in which the diagnosis of herpes was made solely by these adjunctive studies (without any specific histopathological findings by the routine hematoxylin and eosin staining). Three patients are reported with pseudolymphomatous herpes infections that lacked specific herpetic changes. In each of these cases, the correct diagnosis was made by immunohistochemistry.19,22,23 Leukocytoclastic vasculitis is another histopathological presentation of herpes that has been reported without any diagnostic herpetic changes (3 patients). In these patients, the correct diagnosis was obtained by PCR3,30 or immunohistochemistry.13
CONCLUSIONS The spectrum of histological presentations in cutaneous herpes infection extends beyond the classic epidermal findings. Involvement of dermal and adnexal structures may provide clues to a lurking herpetic infection, particularly when epidermal changes are lacking. Herpes infection can incite a pseudolymphomatous response that mimics a variety of hematologic malignancies. Furthermore, herpes can masquerade as one of the several inflammatory cutaneous conditions. Many adjunctive studies exist to aid clinicians in identifying herpetic infection when the clinical and histological presentation is unclear. REFERENCES 1. Chisholm C, Lopez L. Cutaneous infections caused by Herpesviridae: a review. Arch Pathol Lab Med. 2011;135:1357–1362. 2. Bae-Harboe YS, Bhawan J, Demierre MF, et al. Herpes folliculitis masquerading as cutaneous lymphoma. Am J Dermatopathol. 2013;35: 663–665. 3. Leinweber B, Kerl H, Cerroni L. Histopathologic features of cutaneous herpes virus infections (herpes simplex, herpes varicella/zoster): a broad spectrum of presentations with common pseudolymphomatous aspects. Am J Surg Pathol. 2006;30:50–58. 4. Böer A, Herder N, Winter K, et al. Herpes folliculitis: clinical, histopathological, and molecular pathologic observations. Br J Dermatol. 2006; 154:743–746. 5. Walsh N, Boutilier R, Glasgow D, et al. Exclusive involvement of folliculosebaceous units by herpes: a reflection of early herpes zoster. Am J Dermatopathol. 2005;27:189–194. 6. Muñoz E, Valks R, Fernández-Herrera J, et al. Herpetic syringitis associated with eccrine squamous syringometaplasia in HIV-positive patients. J Cutan Pathol. 1997;24:425–428. 7. Rinder HM, Murphy GF. Eccrine duct involvement by herpes zoster. Arch Dermatol. 1984;120:261–262. 8. Sedrak MP, Marek M, Matherene R, et al. Syringitis: a clue to herpes infection. Dermatol Online J. 2012;18:6. 9. Abbas O, Bhawan J. Cutaneous perineural inflammation: a review. J Cutan Pathol. 2010;37:1200–1211. 10. Worrell JT, Cockerell CJ. Histopathology of peripheral nerves in cutaneous herpesvirus infection. Am J Dermatopathol. 1997;19:133–137. 11. Cohen C, Trapuckd S. Leukocytoclastic vasculitis associated with cutaneous infection by herpesvirus. Am J Dermatopathol. 1984;6:561–565.
www.amjdermatopathology.com |
615
Hoyt and Bhawan
12. Erhard H, Rünger TM, Kreienkamp M, et al. Atypical varicella-zoster virus infection in an immunocompromised patient: result of a virusinduced vasculitis. J Am Acad Dermatol. 1995;32:908–911. 13. Uhoda I, Piérard-Franchimont C, Piérard GE. Varicella-zoster virus vasculitis: a case of recurrent varicella without epidermal involvement. Dermatology. 2000;200:173–175. 14. Resnik KS, DiLeonardo M. Herpes incognito. Am J Dermatopathol. 2000;22:144–150. 15. Werner B, Massone C, Kerl H, et al. Large CD30-positive cells in benign, atypical lymphoid infiltrates of the skin. J Cutan Pathol. 2008; 35:1100–1107. 16. Cepeda LT, Pieretti M, Chapman SF, et al. CD30-positive atypical lymphoid cells in common non-neoplastic cutaneous infiltrates rich in neutrophils and eosinophils. Am J Surg Pathol. 2003;27: 912–918. 17. Shiohara J, Koga H, Uhara H, et al. Herpes zoster histopathologically mimicking CD30-positive anaplastic large cell lymphoma. J Eur Acad Dermatol Venereol. 2009;23:618–619. 18. Porto DA, Comfere NI, Myers LM, et al. Pseudolymphomatous reaction to varicella zoster virus vaccination: role of viral in situ hybridization. J Cutan Pathol. 2010;37:1098–1102. 19. Fernandez-Flores A, Rodriguez-Prado N. An ulcerated lesion due to HSV-2 infection with a CD56+ cell predominant inflammatory infiltrate. Acta Dermatovenerol Alp Panonica Adriat. 2011;20:201–205. 20. Taddesse-Heath L, Feldman JI, Fahle GA, et al. Florid CD4+, CD56+ T-cell infiltrate associated with Herpes simplex infection simulating nasal NK-/T-cell lymphoma. Mod Pathol. 2003;16:166–172.
616
| www.amjdermatopathology.com
Am J Dermatopathol Volume 36, Number 8, August 2014
21. Mosunjac M, Park J, Wang W, et al. Genital and perianal herpes simplex simulating neoplasia in patients with AIDS. AIDS Patient Care STDS. 2009;23:153–158. 22. Boyd AS, Zwerner JP, Miller JL. Herpes simplex virus-induced plasmacytic atypia. J Cutan Pathol. 2012;39:270–273. 23. Fukamachi S, Kimura T, Kobayashi M, et al. Palmar pseudolymphoma associated with herpes simplex infection. J Cutan Pathol. 2010;37:808–811. 24. Wain EM, Antony F, Appleton MA, et al. Genital herpes masquerading as a cutaneous T-cell lymphoma: a report of two cases. J Cutan Pathol. 2008;35:770–773. 25. Hassel MH, Lesher JL Jr. Herpes simplex mimicking leukemia cutis. J Am Acad Dermatol. 1989;21:367–371. 26. Blickenstaff RD, Perry HO, Peters MS. Linear IgA deposition associated with cutaneous varicella-zoster infection: a case report. J Cutan Pathol. 1988;15:49–52. 27. Miller DD, Bhawan J. Bullous tinea pedis with direct immunofluorescence positivity: when is a positive result not autoimmune bullous disease? Am J Dermatopathol. 2013;35:587–594. 28. Austin C, Egbert B, Miller AC, et al. Herpesvirus infection of the skin: new histopathologic clues to the diagnosis. American Society of Dermatopathology Abstracts, Annual Meeting, November 29 and 30, 1984. Arch Dermatol. 1984;120:1608. 29. Tucker WF, Harrington CI, Underwood JC. Recurrent herpes simplex infection masquerading as dermatitis artefacta. Arch Dermatol. 1987;123:435–436. 30. Baek YS, Shin WU, Song HJ, et al. Plantar leukocytoclastic vasculitis with detection of herpes simplex virus type 2 by PCR assay. Int J Dermatol. 2013; 52:1434–1435.
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
Herpes Histology
CME EXAM INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITS™ The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers. An annual total of 12 AMA PRA Category 1 Credits is available through the twelve 2014 issues of The American Journal of Dermatopathology. This activity is available for credit through December 31, 2014. Accreditation Statement Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation Statement Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one (1) AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete the quiz, answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money order for the $15 processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001 Market Street, 3rd Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit, and must be postmarked by the expiration date. Answer sheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation.
CME EXAMINATION AUGUST 2014 Please mark your answers on the ANSWER SHEET. After completing this CME activity, physicians should be better able to identify and describe the broad spectrum of histopathological presentations of cutaneous herpes infections, and maintain a high index of suspicion for herpes infections when viewing challenging histopathological cases. CME Questions 1. Which inclusion bodies are found in histopathological sections of herpes simplex virus (HSV) and varicella zoster virus (VZV)? a. Verocay bodies b. Cowdry A bodies c. Cowdry B bodies d. Henderson–Patterson bodies e. Guarnieri bodies 2. Which of the following histologic findings are NOT associated with HSV or VZV infection? a. Nuclear moulding b. Multinucleated keratinocytes c. Ballooning degeneration d. Koilocyte formation e. Steel-gray nuclei 3. Which of the following histologic findings may suggest the presence of herpes folliculitis? a. Eosinophils around hair follicle b. “Swarm of bees” lymphocytic inflammation c. Trichomalacia d. Follicular plugging e. Necrosis of hair follicles 2014 Lippincott Williams & Wilkins
www.amjdermatopathology.com |
617
Hoyt and Bhawan
Am J Dermatopathol Volume 36, Number 8, August 2014
4. Herpes mimicking an NK-/T-cell lymphoma would likely stain heavily for which surface marker? a. CD 56 b. CD 45 c. CD 68 d. CD 117 e. CD 20 5. Cutaneous herpes infection (HSV and VZV) can result in a histopathological presentation that mimics each of the following EXCEPT: a. Anaplastic large cell lymphoma b. Plasmacytoma c. Smallpox d. Linear IgA dermatitis e. Erythema multiforme 6. Which of the following statements is false? a. Herpes infection occasionally incites a monoclonal lymphocytic infiltrate. b. NK-/T-cell lymphoma has a reported association with EBV. c. A plasmocytic response to herpes (HSV/VZV) infection is more likely in patients who are immunosuppressed. d. Herpes infection can result in multinucleation of neurons. e. Lymphocytic atypia can be noted in greater than 50 percent of cases of cutaneous herpes infections.
618
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
2014 Lippincott Williams & Wilkins
Herpes Histology
www.amjdermatopathology.com |
619
