J Cutan Pathol 2015: 42: 739–745 doi: 10.1111/cup.12531 John Wiley & Sons. Printed in Singapore
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Herpes zoster granulomatous dermatitis: histopathologic findings in a case series Several types of cutaneous reactions have been reported to arise at the site of herpes zoster (HZ) infection weeks to years after the acute disease. Among these, granulomatous reactions are the most frequently reported. In this study, we describe the spectrum of histopathologic findings of HZ granulomatous reactions observed in 26 patients with cutaneous lesions confined to the area of previous HZ eruption and compare them with biopsy specimens taken from 25 patients with acute HZ. All patients with persistent reactions from whom history was available presented within 12 weeks of the onset of the acute eruption. The most frequent findings were interstitial granulomatous dermatitis with lymphocytes, histiocytes and multinucleated giant cells displaying elastophagocytosis and a perineural, perivascular and perieccrine mononuclear inflammatory infiltrate rich in lymphocytes and plasma cells. Less common features included intra-arrector and peri-arrector pili granulomas, follicular dilatation and hyperkeratosis, and vasculitis. Specimens from patients with acute HZ were found to have small numbers of perineural plasma cells and most had subtle granulomatous inflammation, in patterns similar to the group with late granulomatous reactions. Our findings suggest that granulomatous reactions to varicella zoster virus represent a persistent evolving inflammatory reaction after acute infection. Keywords: granuloma, inflammation, zoster Ferenczi K, Rosenberg AS, McCalmont TH, Kwon EJ, Elenitsas R, Somach SC. Herpes zoster granulomatous dermatitis: histopathologic findings in a case series. J Cutan Pathol 2015; 42: 739–745. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
A variety of benign and malignant cutaneous reactions have been reported to develop at the site of resolved herpes zoster (HZ) weeks to years after the acute infection. These cutaneous reactions include granuloma annulare,1,2 granulomatous vasculitis,3,4 sarcoidal and tuberculoid non-specific granulomatous granuloma,5,6 dermatitis,7 lichenoid graft-versus-host disease,8
Katalin Ferenczi1 , Arlene S. Rosenberg1 , Timothy H. McCalmont2 , Eun Ji Kwon1 , Rosalie Elenitsas3 and Stephen C. Somach1 1
Departments of Dermatology and Pathology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA, 2 Department of Dermatology, University of California San Francisco, San Francisco, CA, USA, and 3 Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
Stephen C. Somach, MD Departments of Dermatology and Pathology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA Tel: +216 778 3376 Fax: +216 778 3137 e-mail: [email protected] Accepted for publication May 8, 2015
granulomatous folliculitis, lichen sclerosus, Rosai–Dorfman-like reaction,9 eosinophilic dermatosis,10 reactive perforating collagenosis11 and morphea.12 The spectrum of skin disease occurring in sites of healed varicella zoster virus (VZV) infection also includes atypical lymphoid proliferation,13 lymphoplasmacytoid lymphoma,14 T-cell lymphoma,15 leukemia
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Ferenczi et al. cutis,16,17 Kaposi sarcoma,18 pseudolymphoma,19 Candida infection and dermatophytosis.20 Among the diverse manifestations of cutaneous eruptions arising at the site of previous HZ, granulomatous reactions are the most frequently reported. Patients present with erythematous to violaceous papules and plaques in a zosteriform distribution, sometimes in association with post-herpetic neuralgia. In this study, we describe the spectrum of histopathologic findings in HZ granulomatous dermatitis observed in 26 patients with cutaneous lesions confined to the area of previous HZ eruption, and compare those to 25 specimens taken from patients with acute HZ. Methods A retrospective retrieval was performed using a database search to identify HZ granulomatous reaction specimens in the dermatopathology laboratories at Cleveland Skin Pathology Laboratory, MetroHealth Medical Center (Cleveland, Ohio) and University of California, San Francisco (San Francisco, CA). All specimens for which an HZ granulomatous reaction was suggested by the pathologist were reviewed and only those in which clinical history substantiated previous HZ infection at the site were included in the study. Approximately one fourth of the specimens were collected prospectively. Additional cases (one each) were contributed by the Hospital of the University of Pennsylvania (Philadelphia, PA), Roger Williams Medical Center (Rhode Island, RI) and Chonbuk National University Hospital (Korea). Twenty-six formalin-fixed, paraffin-embedded skin biopsy specimens from patients with an eruption at the site of prior HZ and 25 specimens from patients with acute HZ were included. For the patients with granulomatous reactions, clinical information, including age, gender and the time elapsed between the onset of HZ and presentation, was reviewed. Patients ranged from 5 to 85 years, consisting of 8 men and 18 women. Anatomic sites included head and neck (11), trunk (9) and extremities (6). The time interval from the onset of HZ to presentation was available in 58% of the patients, ranging from 5 weeks to 3 months. In one patient, the lesions were reported to be present years after the initial HZ; however, the patient had a history of several dermatologic problems, and no accurate documentation of the acute infection was available. The clinical features of the 26 patients with persistent HZ reactions were
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variable and included a combination of clinical diagnoses and morphologic descriptions. The following are the reported morphologic descriptions with the cumulative number of occurrences with additional descriptors in parentheses: papules, n = 14 (erythematous-5, pruritic-2, hyperesthetic-2, edematous-1, hyperpigmented-1, eroded-1); plaques, n = 5 (painful-1, eroded-1); hyperpigmentation, n = 2; nodules, n = 1 and erythematous and hypopigmented patch, n = 1. Clinical diagnoses most often stated persistent reaction to VZV, followed by scar, n = 4; arthropod bite reaction, n = 4; squamous cell carcinoma/basal cell carcinoma, n = 3; eczema/contact dermatitis, n = 3; sarcoidosis, n = 2; granuloma annulare, n = 2; granuloma, n = 2; lichen planus, n = 2; factitial, n = 1; lymphoma, n = 1; xanthoma, n = 1; vitiligo, n = 1 and drug reaction, n = 1. No patient presented with vesicles, and no patient reported new eruptions in areas that had been completely healed after an acute HZ infection. Analysis of the histopathologic features was performed. Polymerase chain reaction (PCR) for detection of herpes viral genome was performed from the paraffin block in five cases. Results The histopathologic features of 26 biopsy specimens taken from patients who presented with cutaneous lesions at the site of previous involvement by HZ are summarized in Table 1. Findings included the presence or absence of scarring/fibrosis, inflammatory constituents, perineural, perifollicular and/or perieccrine inflammation, elastophagocytosis, dermal mucin, vasculitis and band-like inflammation at the dermal–epidermal junction. Granulomatous inflammation was seen in all cases but varied in pattern, with epithelioid granulomas, multinucleated giant cells, loosely aggregated epithelioid histiocytes and single interstitial histiocytes all being observed (Fig. 1). The presence of a perineural infiltrate composed of lymphocytes and plasma cells was a distinctive and prominent finding observed in 23/25 cases (92%) in which nerves were identified (Fig. 2A). In some cases, the inflammation surrounding the nerves appeared to be secondary to the perivascular inflammatory infiltrate around the neurovascular bundle. However, in other biopsy specimens, the perineural infiltrate was striking and did not appear to be the consequence of extension of the inflammation from a perivascular location. In
Herpes zoster granulomatous dermatitis Table 1. Summary of histopathologic findings in zoster-associated granulomatous dermatitis Biopsy interval after appearance of lesions (Number of patients/26 total)
Perineural inflammation (25 cases with nerves) Lymphohistiocytic Lymphoplasmacytic without epithelioid histiocytes Lymphoplasmacytic with loosely arranged epithelioid histiocytes Lymphoplasmacytic with epithelioid granulomas Vasculitis/venulitis Peri and intra-arrector pili granulomas (24 cases with arrector pili) Perieccrine inflammation (18 cases with eccrine glands) Lymphohistiocytic Lymphoplasmacytic without epithelioid histiocytes Lymphoplasmacytic with loosely arranged epithelioid histiocytes Lymphoplasmacytic with epithelioid granulomas Elastophagocytosis Perifollicular inflammation (18 cases with follicles) Acute suppurative Lymphohistiocytic Lymphoplasmacytic and suppurative Lymphoplasmacytic with loosely arranged epithelioid histiocytes Lymphoplasmacytic with epithelioid granulomas Cystic follicular change Interstitial granulomatous inflammation With multinucleated giant cells Without multinucleated giant cells Scar/fibrosis Perivascular inflammation Lymphoplasmacytic Lymphoplasmacytic with loosely arranged epithelioid histiocytes Lymphoplasmacytic with epithelioid granulomas
contrast to perineural inflammation, a perieccrine lymphoplasmacytic infiltrate was seen in 15/18 (83%) of the cases in which eccrine glands were included (Fig. 1E) and was almost always noted in the vicinity of a blood vessel, suggesting that it is most probably a secondary phenomenon. Elastophagocytosis was found in 18/26 cases (69%; Fig. 1C). Perifollicular inflammation was also common, being seen in 16/18 cases (89%) in which a follicle was present (Fig. 2C). Scarring was present in 11/26 specimens (42%). Intra-arrector pili and/or peri-arrector pili granulomatous inflammation was noted in 12 specimens (12/24, 50%, Fig. 2B). Other features included follicular infundibular dilatation and hyperkeratosis (9/18, 50%), dermal mucin (9/26, 35%) and band-like inflammation at the dermal–epidermal junction (5/26, 19%). A dermal perivascular lymphoplasmacytic and sometimes granulomatous infiltrate were noted in all the specimens. Vasculitis, including lymphocytic, neutrophilic and focally granulomatous
Less than 6 weeks: 5/26 6–9 weeks: 7/26 9–12 weeks: 3/26 Unknown: 11/26 24/25 1/25 11/25 9/25 3/25 6/23 12/24 16/18 1/18 8/18 6/18 1/18 18/26 16/18 1/18 2/18 1/18 9/18 3/18 9/18 23/26 18/23 5/23 11/26 26/26 20/26 7/26
vasculitis, was observed in 6/26 specimens (23%; Fig. 2D). Two specimens showed viral cytopathic effects within follicular epithelium (Fig. 3). PCR for the presence of VZV DNA was performed in five cases. VZV DNA was showed in only one specimen. No evidence of foreign body was noted by polariscopic examination in any of the specimens. Twenty-five specimens submitted with the clinical diagnosis of HZ showing herpes virus cytopathic effects were also evaluated. Of these specimens, 22/25 (88%) had perineural lymphocytic inflammation and 20/25 (80%) had plasma cells, which were usually inconspicuous. Interstitial histiocytes in an interstitial granulomatous dermatitis-like pattern were seen in 10/25 (40%). Early coalescing epithelioid granulomas, usually in a perivascular pattern, were seen in 16/25 (64%) specimens. Intra or peri-arrector pili histiocytes were seen in 6/25 (24%) specimens.
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Ferenczi et al.
Fig. 1. Spectrum of granulomatous inflammation in post-zoster granulomatous dermatitis. A) Epithelioid granulomas admixed with multinucleated giant cells. B) Interstitial granulomatous dermatitis composed of mononuclear histiocytes, with collagen degeneration and mucin deposition. C) Multinucleated giant cells with elastophagocytosis. D) Perineural inflammation with small epithelioid granulomas. E) Perieccrine inflammation with small epithelioid granulomas.
Fig. 2. Distinctive histopathologic features of post-zoster granulomatous dermatitis. A) Perineural lymphoplasmacytic inflammation. B) Granulomatous inflammation within arrector pili muscle. C) Follicular dilatation with hyperkeratosis and perifollicular inflammation. D) Vasculitis.
Discussion Herpes viruses target cutaneous nerve endings and establish a life-long latency in the sensory ganglia following primary infection. Cutaneous HZ represents reactivation of a latent infection, presumably as a result of viral migration
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along peripheral nerves from the dorsal ganglia to the skin. After primary VZV infection and possibly following HZ, maintenance of viral latency and control of viral reactivation is influenced by both cellular and humoral arms of the immune system. The virus is known to stimulate
Herpes zoster granulomatous dermatitis
Fig. 3. Early post-zoster granulomatous dermatitis in the presence of persistent viral cytopathic effect. A) Scanning magnification shows superficial and deep inflammation. B) A central follicle shows viral cytopathic effect. C) Poorly formed perineural and perivascular epithelioid granulomas.
a dramatic increase in VZV-specific T-cells that recognize VZV glycoproteins (including gE, gB) and prevent disseminated infection. An increase in VZV IgG antibodies via induction of humoral-mediated immunity is also known to occur as a means of neutralizing the virus in case of reactivation (for review, see Ref. 21). The pathogenesis of granulomatous reactions occurring at the site of prior HZ lesions is not fully understood. Cell-mediated immune responses mediated by T lymphocytes reacting to local antigenic stimulus, especially VZV-specific T-cells which produce IFN-γ and TNF-α may be involved in their pathogenesis (for review, see Ref. 22). A delayed hypersensitivity reaction induced by the virus or tissue antigens altered by the virus has been suggested.22 It has been hypothesized that HZ granulomas may represent a reaction to minute amounts of persistent viral proteins in the absence of the viral genome.23 VZV DNA has been detected in HZ granulomas by PCR. Early lesions, particularly those developing less than one month after VZV infection, were found to contain viral DNA, but no DNA was found in late lesions.7 Nikkels et al. reported a high frequency of VZV major envelope glycoproteins gE and gB in monocytes-macrophages in granulomatous reactions that developed earlier rather than later after the previous VZV infection. This finding suggests that the development of granulomatous reactions in sites of resolved HZ may be as a result of persistence of viral envelope glycoproteins rather than complete viral particles.23
Granulomatous reactions arising in sites of previous HZ fall into a wide array of histopathologic patterns, including granulomatous vasculitis, sarcoidal and tuberculoid granulomas, granulomatous folliculitis, non-specific granulomatous dermatitis and granulomatous dermatitis mimicking granuloma annulare. While the histopathologic features of these granulomatous reactions are not detailed in some reports, a review of the first case report of granuloma annulare occurring in a site of HZ has photomicrographs showing features of interstitial granulomatous dermatitis with peri-adnexal inflammation, very similar to what we observed in our cases, but not typical of granuloma annulare, favoring an HZ granulomatous reaction.1 We observed all the reported patterns of granulomatous inflammation in our cases, suggesting that most of these reported cases represent persistent granulomatous reactions to the virus rather than unrelated granulomatous dermatitis occurring in HZ scars. Malignancy arising at the healed site of HZ was described by Wyburn-Mason in 1955, who postulated that disruption of innervation of affected tissues might predispose to the development of malignancy at the site.24 The description of this phenomenon was expanded upon by Wolf, who suggested that dermatoses occurring in the site of healed HZ virus infection represent an isotopic response, which is defined as ‘the occurrence of a new skin disorder at the site of another, unrelated and already healed skin disease’.25 This is to be distinguished from the isomorphic response of Koebner, in which
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Ferenczi et al. lesions of an existing skin disease (such as lichen planus or psoriasis) occur at a site of prior injury. While cutaneous neoplasms and secondary cutaneous involvement of hematopoietic malignancies may represent an isotopic response, our data strongly favor post-zoster granulomatous dermatitis as a persistent inflammatory reaction to viral proteins rather than an isotopic response. Several findings support this. All cases with a documented timeframe occurred 1–3 months after the onset of acute infection, with most cases reported as papules developing in resolving HZ lesions rather than in completely healed sites. In two of our cases, viral cytopathic changes were still present within follicular epithelium. Finally, the presence of persistent viral proteins in granulomatous lesions favors an etiologic role of these proteins in the inflammatory process. In addition to the defining feature of a granulomatous dermatitis, we report the frequent occurrence of an inflammatory infiltrate composed of lymphocytes and plasma cells in a prominent perineural distribution. A similar infiltrate was seen around the vessels and eccrine coils in most cases. The perineural inflammation was observed in a large majority of cases of zoster-associated granuloma. The presence of perineural inflammatory changes in HZ granulomatous reactions was originally described by Araki et al. who reported granulomas in close association with peripheral nerves.26 More recently, Kapoor et al. have reported the presence of a lymphohistiocytic infiltrate with a perineurovascular and follicular pattern in five patients with post-herpetic granuloma annulare.27 The presence of inflammation composed of lymphocytes and plasma cells in a perineural distribution in delayed HZ reactions when viral particles are not typically showed could be as a result of residual viral proteins. In contrast, in acute HZ, a dense perineural inflammatory infiltrate is invariably described and is probably related to a cell-mediated immune reaction to reactivated VZV replicating in the skin.28 A distinctive finding in 50% of cases was the presence of intra-arrector pili granulomas. While secondary involvement of the muscle because of its proximity to the follicle or blood vessels is a possibility, VZV is known to directly infect skeletal muscle, particularly in HZ ophthalmicus, in which it may cause orbital myositis.29 Similar involvement of smooth muscle in skin could also occur, accounting for granulomas in arrector pili, and possibly vasculitis of larger cutaneous vessels containing smooth muscle.
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Another distinctive finding in our data is the presence of follicular infundibular dilatation and hyperkeratosis, which was seen in 50% of cases. This was frequently accompanied by prominent follicular inflammation. The follicular inflammation probably represents a persistent inflammatory reaction to follicular VZV infection, and the dilatation and hyperkeratosis may be a manifestation of the damage to the infected follicle.30 Granulomatous vasculitis has been reported to occur in sites of HZ.31 This finding was present in one of our cases, and an additional five cases showed foci of lymphocytic and neutrophilic vasculitis involving smaller vessels. The specimens in which vasculitis was observed tended to occur in patients presenting within a shorter interval from onset of HZ infection. Trends in the patterns of inflammation based upon the duration of lesions were noted. In early lesions (those present less than 6 weeks), an interstitial granulomatous dermatitis pattern with loosely aggregated epithelioid histiocytes predominated, and vasculitis was more likely to be present. These early findings appeared to represent a continuum of features seen with acute HZ. Later lesions were more probably to have well-formed epithelioid granulomas and multinucleated giant cells, probably representing evolution of the granulomatous reaction. This study of the histopathologic features of ‘post-zoster’ granulomatous dermatitis was undertaken with the notion that this inflammatory process represents an unusual immunologic reaction which becomes activated in response to persistent viral antigens. In our series, there were no instances of lesions developing in areas of completely healed HZ infection. Two of the patients in the series presented with lesions showing acute viral cytopathic effect in specimens also showing granulomatous reactions and perineural plasma cells. These findings lead us to conclude that the ‘post-zoster’ granulomatous dermatitis occurs in a continuum with the acute inflammatory response to the virus. To evaluate this premise further, we reviewed 25 biopsy specimens which were submitted with the clinical impression of HZ, confirmed by the identification of herpetic viral cytopathic effect. We found that 80% of specimens showing acute HZ have subtle perineural lymphoplasmacytic inflammation and over half to have a granulomatous component to the inflammation. Given the striking overlapping histopathologic features
Herpes zoster granulomatous dermatitis with our study specimens, these findings support the concept of a persistent inflammatory response to the virus, which tends to come to attention in patients with a greater than average duration of skin lesions. Based on the findings, we favor the diagnostic term ‘herpes zoster granulomatous dermatitis’, as in our experience, the commonly-used term ‘post-zoster
granulomatous dermatitis’ does not reflect the true nature of the pathologic process. Acknowledgements The authors acknowledge Dr Caroline S. Wilkel from Roger Williams Medical Center and Dr Chull-Wan Ihm at Chonbuk National University Hospital for their contribution of post-zoster granuloma cases.
References 1. Guill MA, Goette DK. Granuloma annulare at sites of healing herpes zoster. Arch Dermatol 1978; 114: 1383. 2. Packer RH, Fields JP, King LE Jr. Granuloma annulare in herpes zoster scars. Cutis 1984; 34: 177. 3. Langenberg A, Yen TS, LeBoit PE. Granulomatous vasculitis occurring after cutaneous herpes zoster despite absence of viral genome. J Am Acad Dermatol 1991; 24: 429. 4. Baalbaki SA, Malak JA, al-Lhars MA, Natarajan S. Granulomatous vasculitis in herpes zoster scars. Int J Dermatol 1994; 33: 268. 5. Bisaccia E, Scarborough DA, Carr RD. Cutaneous sarcoid granuloma formation in herpes zoster scars. Arch Dermatol 1983; 119: 788. 6. Fischer G, Jaworski R. Granuloma formation in herpes zoster scars. J Am Acad Dermatol 1987; 16: 1261. 7. Serfling U, Penneys NS, Zhu WY, Sisto M, Leonardi C. Varicella-zoster virus DNA in granulomatous skin lesions following herpes zoster. A study by the polymerase chain reaction. J Cutan Pathol 1993; 20: 28. 8. Sanli H, Anadolu R, Arat M. Dermatomal lichenoid graft-versus-host disease within herpes zoster scars. Int J Dermatol 2003; 42: 562. 9. Requena L, Kutzner H, Escalonilla P, Ortiz S, Schaller J, Rohwedder A. Cutaneous reactions at sites of herpes zoster scars: an expanded spectrum. Br J Dermatol 1998; 138: 161. 10. Mitsuhashi Y, Kondo S. Post-zoster eosinophilic dermatosis. Br J Dermatol 1997; 136: 465. 11. Lee HN, Lee DW, Lee JY, Cho BK. Two cases of reactive perforating collagenosis
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arising at the site of healed herpes zoster. Int J Dermatol 2001; 40: 191. Noh TW, Park SH, Kang YS, Lee UH, Park HS, Jang SJ. Morphea developing at the site of healed herpes zoster. Ann Dermatol 2011; 23: 242. Talpur R, Duvic M. Atypical lymphoid infiltration occurring at the site of a healed varicella zoster infection. Clin Lymphoma 2003; 3: 253. Aloi FG, Appino A, Puiatti P. Lymphoplasmocytoid lymphoma arising in herpes zoster scars. J Am Acad Dermatol 1990; 22: 130. Paydas S, Sahin B, Yavuz S, Tuncer I, Gonlusen G. Lymphomatous skin infiltration at the site of previous varicella zoster virus infection in a patient with T cell lymphoma. Leuk Lymphoma 2000; 37: 229. Elgoweini M, Blessing K, Jackson R, Duthie F, Burden AD. Coexistent granulomatous vasculitis and leukaemia cutis in a patient with resolving herpes zoster. Clin Exp Dermatol 2011; 36: 749. Bahadoran P, Lacour JP, Ortonne JP. Leukaemia cutis at the site of prior herpes zoster. Br J Dermatol 1997; 136: 465. Niedt GW, Prioleau PG. Kaposi’s sarcoma occurring in a dermatome previously involved by herpes zoster. J Am Acad Dermatol 1988; 18(2 Pt 2): 448. Sanchez JL, Mendez JA, Palacio R. Cutaneous pseudolymphoma at the site of resolving herpes zoster. Arch Dermatol 1981; 117: 377. Huang CW, Tu ME, Wu YH, Lin YC. Isotopic response of fungal granuloma following facial herpes zoster infections – report of three cases. Int J Dermatol 2007; 46: 1141. Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996; 9: 361.
22. Gibney MD, Nahass GT, Leonardi CL. Cutaneous reactions following herpes zoster infections: report of three cases and a review of the literature. Br J Dermatol 1996; 134: 504. 23. Nikkels AF, Snoeck R, Rentier B, Pierard GE. Chronic verrucous varicella zoster virus skin lesions: clinical, histological, molecular and therapeutic aspects. Clin Exp Dermatol 1999; 24: 346. 24. Wyburn-Mason R. Malignant change arising in tissues affected by herpes. Br Med J 1955; 2: 1106. 25. Wolf R, Brenner S, Ruocco V, Filioli FG. Isotopic response. Int J Dermatol 1995; 34: 341. 26. Araki E, Kambe N, Takahashi K, Miyachi Y, Utani A. Multiple dermatomal daughter lesions of postzoster granuloma. Br J Dermatol 2007; 156: 1369. 27. Kapoor R, Piris A, Saavedra AP, Duncan LM, Nazarian RM. Wolf isotopic response manifesting as postherpetic granuloma annulare: a case series. Arch Pathol Lab Med 2013; 137: 255. 28. Worrell JT, Cockerell CJ. Histopathology of peripheral nerves in cutaneous herpesvirus infection. Am J Dermatopathol 1997; 19: 133. 29. Volpe NJ, Shore JW. Orbital myositis associated with herpes zoster. Arch Ophthalmol 1991; 109: 471. 30. Nikkels AF, Pierard GE. Necrotizing varicella zoster virus folliculitis. Eur J Dermatol 2003; 13: 587. 31. Rodriguez-Pereira C, Suarez-Penaranda JM, del Rio E, Forteza-Vila J. Cutaneous granulomatous vasculitis after herpes zoster infection showing polyarteritis nodosa-like features. Clin Exp Dermatol 1997; 22: 274.
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© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Herpes zoster granulomatous dermatitis: histopathologic findings in a case series Several types of cutaneous reactions have been reported to arise at the site of herpes zoster (HZ) infection weeks to years after the acute disease. Among these, granulomatous reactions are the most frequently reported. In this study, we describe the spectrum of histopathologic findings of HZ granulomatous reactions observed in 26 patients with cutaneous lesions confined to the area of previous HZ eruption and compare them with biopsy specimens taken from 25 patients with acute HZ. All patients with persistent reactions from whom history was available presented within 12 weeks of the onset of the acute eruption. The most frequent findings were interstitial granulomatous dermatitis with lymphocytes, histiocytes and multinucleated giant cells displaying elastophagocytosis and a perineural, perivascular and perieccrine mononuclear inflammatory infiltrate rich in lymphocytes and plasma cells. Less common features included intra-arrector and peri-arrector pili granulomas, follicular dilatation and hyperkeratosis, and vasculitis. Specimens from patients with acute HZ were found to have small numbers of perineural plasma cells and most had subtle granulomatous inflammation, in patterns similar to the group with late granulomatous reactions. Our findings suggest that granulomatous reactions to varicella zoster virus represent a persistent evolving inflammatory reaction after acute infection. Keywords: granuloma, inflammation, zoster Ferenczi K, Rosenberg AS, McCalmont TH, Kwon EJ, Elenitsas R, Somach SC. Herpes zoster granulomatous dermatitis: histopathologic findings in a case series. J Cutan Pathol 2015; 42: 739–745. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
A variety of benign and malignant cutaneous reactions have been reported to develop at the site of resolved herpes zoster (HZ) weeks to years after the acute infection. These cutaneous reactions include granuloma annulare,1,2 granulomatous vasculitis,3,4 sarcoidal and tuberculoid non-specific granulomatous granuloma,5,6 dermatitis,7 lichenoid graft-versus-host disease,8
Katalin Ferenczi1 , Arlene S. Rosenberg1 , Timothy H. McCalmont2 , Eun Ji Kwon1 , Rosalie Elenitsas3 and Stephen C. Somach1 1
Departments of Dermatology and Pathology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA, 2 Department of Dermatology, University of California San Francisco, San Francisco, CA, USA, and 3 Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
Stephen C. Somach, MD Departments of Dermatology and Pathology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA Tel: +216 778 3376 Fax: +216 778 3137 e-mail: [email protected] Accepted for publication May 8, 2015
granulomatous folliculitis, lichen sclerosus, Rosai–Dorfman-like reaction,9 eosinophilic dermatosis,10 reactive perforating collagenosis11 and morphea.12 The spectrum of skin disease occurring in sites of healed varicella zoster virus (VZV) infection also includes atypical lymphoid proliferation,13 lymphoplasmacytoid lymphoma,14 T-cell lymphoma,15 leukemia
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Ferenczi et al. cutis,16,17 Kaposi sarcoma,18 pseudolymphoma,19 Candida infection and dermatophytosis.20 Among the diverse manifestations of cutaneous eruptions arising at the site of previous HZ, granulomatous reactions are the most frequently reported. Patients present with erythematous to violaceous papules and plaques in a zosteriform distribution, sometimes in association with post-herpetic neuralgia. In this study, we describe the spectrum of histopathologic findings in HZ granulomatous dermatitis observed in 26 patients with cutaneous lesions confined to the area of previous HZ eruption, and compare those to 25 specimens taken from patients with acute HZ. Methods A retrospective retrieval was performed using a database search to identify HZ granulomatous reaction specimens in the dermatopathology laboratories at Cleveland Skin Pathology Laboratory, MetroHealth Medical Center (Cleveland, Ohio) and University of California, San Francisco (San Francisco, CA). All specimens for which an HZ granulomatous reaction was suggested by the pathologist were reviewed and only those in which clinical history substantiated previous HZ infection at the site were included in the study. Approximately one fourth of the specimens were collected prospectively. Additional cases (one each) were contributed by the Hospital of the University of Pennsylvania (Philadelphia, PA), Roger Williams Medical Center (Rhode Island, RI) and Chonbuk National University Hospital (Korea). Twenty-six formalin-fixed, paraffin-embedded skin biopsy specimens from patients with an eruption at the site of prior HZ and 25 specimens from patients with acute HZ were included. For the patients with granulomatous reactions, clinical information, including age, gender and the time elapsed between the onset of HZ and presentation, was reviewed. Patients ranged from 5 to 85 years, consisting of 8 men and 18 women. Anatomic sites included head and neck (11), trunk (9) and extremities (6). The time interval from the onset of HZ to presentation was available in 58% of the patients, ranging from 5 weeks to 3 months. In one patient, the lesions were reported to be present years after the initial HZ; however, the patient had a history of several dermatologic problems, and no accurate documentation of the acute infection was available. The clinical features of the 26 patients with persistent HZ reactions were
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variable and included a combination of clinical diagnoses and morphologic descriptions. The following are the reported morphologic descriptions with the cumulative number of occurrences with additional descriptors in parentheses: papules, n = 14 (erythematous-5, pruritic-2, hyperesthetic-2, edematous-1, hyperpigmented-1, eroded-1); plaques, n = 5 (painful-1, eroded-1); hyperpigmentation, n = 2; nodules, n = 1 and erythematous and hypopigmented patch, n = 1. Clinical diagnoses most often stated persistent reaction to VZV, followed by scar, n = 4; arthropod bite reaction, n = 4; squamous cell carcinoma/basal cell carcinoma, n = 3; eczema/contact dermatitis, n = 3; sarcoidosis, n = 2; granuloma annulare, n = 2; granuloma, n = 2; lichen planus, n = 2; factitial, n = 1; lymphoma, n = 1; xanthoma, n = 1; vitiligo, n = 1 and drug reaction, n = 1. No patient presented with vesicles, and no patient reported new eruptions in areas that had been completely healed after an acute HZ infection. Analysis of the histopathologic features was performed. Polymerase chain reaction (PCR) for detection of herpes viral genome was performed from the paraffin block in five cases. Results The histopathologic features of 26 biopsy specimens taken from patients who presented with cutaneous lesions at the site of previous involvement by HZ are summarized in Table 1. Findings included the presence or absence of scarring/fibrosis, inflammatory constituents, perineural, perifollicular and/or perieccrine inflammation, elastophagocytosis, dermal mucin, vasculitis and band-like inflammation at the dermal–epidermal junction. Granulomatous inflammation was seen in all cases but varied in pattern, with epithelioid granulomas, multinucleated giant cells, loosely aggregated epithelioid histiocytes and single interstitial histiocytes all being observed (Fig. 1). The presence of a perineural infiltrate composed of lymphocytes and plasma cells was a distinctive and prominent finding observed in 23/25 cases (92%) in which nerves were identified (Fig. 2A). In some cases, the inflammation surrounding the nerves appeared to be secondary to the perivascular inflammatory infiltrate around the neurovascular bundle. However, in other biopsy specimens, the perineural infiltrate was striking and did not appear to be the consequence of extension of the inflammation from a perivascular location. In
Herpes zoster granulomatous dermatitis Table 1. Summary of histopathologic findings in zoster-associated granulomatous dermatitis Biopsy interval after appearance of lesions (Number of patients/26 total)
Perineural inflammation (25 cases with nerves) Lymphohistiocytic Lymphoplasmacytic without epithelioid histiocytes Lymphoplasmacytic with loosely arranged epithelioid histiocytes Lymphoplasmacytic with epithelioid granulomas Vasculitis/venulitis Peri and intra-arrector pili granulomas (24 cases with arrector pili) Perieccrine inflammation (18 cases with eccrine glands) Lymphohistiocytic Lymphoplasmacytic without epithelioid histiocytes Lymphoplasmacytic with loosely arranged epithelioid histiocytes Lymphoplasmacytic with epithelioid granulomas Elastophagocytosis Perifollicular inflammation (18 cases with follicles) Acute suppurative Lymphohistiocytic Lymphoplasmacytic and suppurative Lymphoplasmacytic with loosely arranged epithelioid histiocytes Lymphoplasmacytic with epithelioid granulomas Cystic follicular change Interstitial granulomatous inflammation With multinucleated giant cells Without multinucleated giant cells Scar/fibrosis Perivascular inflammation Lymphoplasmacytic Lymphoplasmacytic with loosely arranged epithelioid histiocytes Lymphoplasmacytic with epithelioid granulomas
contrast to perineural inflammation, a perieccrine lymphoplasmacytic infiltrate was seen in 15/18 (83%) of the cases in which eccrine glands were included (Fig. 1E) and was almost always noted in the vicinity of a blood vessel, suggesting that it is most probably a secondary phenomenon. Elastophagocytosis was found in 18/26 cases (69%; Fig. 1C). Perifollicular inflammation was also common, being seen in 16/18 cases (89%) in which a follicle was present (Fig. 2C). Scarring was present in 11/26 specimens (42%). Intra-arrector pili and/or peri-arrector pili granulomatous inflammation was noted in 12 specimens (12/24, 50%, Fig. 2B). Other features included follicular infundibular dilatation and hyperkeratosis (9/18, 50%), dermal mucin (9/26, 35%) and band-like inflammation at the dermal–epidermal junction (5/26, 19%). A dermal perivascular lymphoplasmacytic and sometimes granulomatous infiltrate were noted in all the specimens. Vasculitis, including lymphocytic, neutrophilic and focally granulomatous
Less than 6 weeks: 5/26 6–9 weeks: 7/26 9–12 weeks: 3/26 Unknown: 11/26 24/25 1/25 11/25 9/25 3/25 6/23 12/24 16/18 1/18 8/18 6/18 1/18 18/26 16/18 1/18 2/18 1/18 9/18 3/18 9/18 23/26 18/23 5/23 11/26 26/26 20/26 7/26
vasculitis, was observed in 6/26 specimens (23%; Fig. 2D). Two specimens showed viral cytopathic effects within follicular epithelium (Fig. 3). PCR for the presence of VZV DNA was performed in five cases. VZV DNA was showed in only one specimen. No evidence of foreign body was noted by polariscopic examination in any of the specimens. Twenty-five specimens submitted with the clinical diagnosis of HZ showing herpes virus cytopathic effects were also evaluated. Of these specimens, 22/25 (88%) had perineural lymphocytic inflammation and 20/25 (80%) had plasma cells, which were usually inconspicuous. Interstitial histiocytes in an interstitial granulomatous dermatitis-like pattern were seen in 10/25 (40%). Early coalescing epithelioid granulomas, usually in a perivascular pattern, were seen in 16/25 (64%) specimens. Intra or peri-arrector pili histiocytes were seen in 6/25 (24%) specimens.
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Fig. 1. Spectrum of granulomatous inflammation in post-zoster granulomatous dermatitis. A) Epithelioid granulomas admixed with multinucleated giant cells. B) Interstitial granulomatous dermatitis composed of mononuclear histiocytes, with collagen degeneration and mucin deposition. C) Multinucleated giant cells with elastophagocytosis. D) Perineural inflammation with small epithelioid granulomas. E) Perieccrine inflammation with small epithelioid granulomas.
Fig. 2. Distinctive histopathologic features of post-zoster granulomatous dermatitis. A) Perineural lymphoplasmacytic inflammation. B) Granulomatous inflammation within arrector pili muscle. C) Follicular dilatation with hyperkeratosis and perifollicular inflammation. D) Vasculitis.
Discussion Herpes viruses target cutaneous nerve endings and establish a life-long latency in the sensory ganglia following primary infection. Cutaneous HZ represents reactivation of a latent infection, presumably as a result of viral migration
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along peripheral nerves from the dorsal ganglia to the skin. After primary VZV infection and possibly following HZ, maintenance of viral latency and control of viral reactivation is influenced by both cellular and humoral arms of the immune system. The virus is known to stimulate
Herpes zoster granulomatous dermatitis
Fig. 3. Early post-zoster granulomatous dermatitis in the presence of persistent viral cytopathic effect. A) Scanning magnification shows superficial and deep inflammation. B) A central follicle shows viral cytopathic effect. C) Poorly formed perineural and perivascular epithelioid granulomas.
a dramatic increase in VZV-specific T-cells that recognize VZV glycoproteins (including gE, gB) and prevent disseminated infection. An increase in VZV IgG antibodies via induction of humoral-mediated immunity is also known to occur as a means of neutralizing the virus in case of reactivation (for review, see Ref. 21). The pathogenesis of granulomatous reactions occurring at the site of prior HZ lesions is not fully understood. Cell-mediated immune responses mediated by T lymphocytes reacting to local antigenic stimulus, especially VZV-specific T-cells which produce IFN-γ and TNF-α may be involved in their pathogenesis (for review, see Ref. 22). A delayed hypersensitivity reaction induced by the virus or tissue antigens altered by the virus has been suggested.22 It has been hypothesized that HZ granulomas may represent a reaction to minute amounts of persistent viral proteins in the absence of the viral genome.23 VZV DNA has been detected in HZ granulomas by PCR. Early lesions, particularly those developing less than one month after VZV infection, were found to contain viral DNA, but no DNA was found in late lesions.7 Nikkels et al. reported a high frequency of VZV major envelope glycoproteins gE and gB in monocytes-macrophages in granulomatous reactions that developed earlier rather than later after the previous VZV infection. This finding suggests that the development of granulomatous reactions in sites of resolved HZ may be as a result of persistence of viral envelope glycoproteins rather than complete viral particles.23
Granulomatous reactions arising in sites of previous HZ fall into a wide array of histopathologic patterns, including granulomatous vasculitis, sarcoidal and tuberculoid granulomas, granulomatous folliculitis, non-specific granulomatous dermatitis and granulomatous dermatitis mimicking granuloma annulare. While the histopathologic features of these granulomatous reactions are not detailed in some reports, a review of the first case report of granuloma annulare occurring in a site of HZ has photomicrographs showing features of interstitial granulomatous dermatitis with peri-adnexal inflammation, very similar to what we observed in our cases, but not typical of granuloma annulare, favoring an HZ granulomatous reaction.1 We observed all the reported patterns of granulomatous inflammation in our cases, suggesting that most of these reported cases represent persistent granulomatous reactions to the virus rather than unrelated granulomatous dermatitis occurring in HZ scars. Malignancy arising at the healed site of HZ was described by Wyburn-Mason in 1955, who postulated that disruption of innervation of affected tissues might predispose to the development of malignancy at the site.24 The description of this phenomenon was expanded upon by Wolf, who suggested that dermatoses occurring in the site of healed HZ virus infection represent an isotopic response, which is defined as ‘the occurrence of a new skin disorder at the site of another, unrelated and already healed skin disease’.25 This is to be distinguished from the isomorphic response of Koebner, in which
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Ferenczi et al. lesions of an existing skin disease (such as lichen planus or psoriasis) occur at a site of prior injury. While cutaneous neoplasms and secondary cutaneous involvement of hematopoietic malignancies may represent an isotopic response, our data strongly favor post-zoster granulomatous dermatitis as a persistent inflammatory reaction to viral proteins rather than an isotopic response. Several findings support this. All cases with a documented timeframe occurred 1–3 months after the onset of acute infection, with most cases reported as papules developing in resolving HZ lesions rather than in completely healed sites. In two of our cases, viral cytopathic changes were still present within follicular epithelium. Finally, the presence of persistent viral proteins in granulomatous lesions favors an etiologic role of these proteins in the inflammatory process. In addition to the defining feature of a granulomatous dermatitis, we report the frequent occurrence of an inflammatory infiltrate composed of lymphocytes and plasma cells in a prominent perineural distribution. A similar infiltrate was seen around the vessels and eccrine coils in most cases. The perineural inflammation was observed in a large majority of cases of zoster-associated granuloma. The presence of perineural inflammatory changes in HZ granulomatous reactions was originally described by Araki et al. who reported granulomas in close association with peripheral nerves.26 More recently, Kapoor et al. have reported the presence of a lymphohistiocytic infiltrate with a perineurovascular and follicular pattern in five patients with post-herpetic granuloma annulare.27 The presence of inflammation composed of lymphocytes and plasma cells in a perineural distribution in delayed HZ reactions when viral particles are not typically showed could be as a result of residual viral proteins. In contrast, in acute HZ, a dense perineural inflammatory infiltrate is invariably described and is probably related to a cell-mediated immune reaction to reactivated VZV replicating in the skin.28 A distinctive finding in 50% of cases was the presence of intra-arrector pili granulomas. While secondary involvement of the muscle because of its proximity to the follicle or blood vessels is a possibility, VZV is known to directly infect skeletal muscle, particularly in HZ ophthalmicus, in which it may cause orbital myositis.29 Similar involvement of smooth muscle in skin could also occur, accounting for granulomas in arrector pili, and possibly vasculitis of larger cutaneous vessels containing smooth muscle.
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Another distinctive finding in our data is the presence of follicular infundibular dilatation and hyperkeratosis, which was seen in 50% of cases. This was frequently accompanied by prominent follicular inflammation. The follicular inflammation probably represents a persistent inflammatory reaction to follicular VZV infection, and the dilatation and hyperkeratosis may be a manifestation of the damage to the infected follicle.30 Granulomatous vasculitis has been reported to occur in sites of HZ.31 This finding was present in one of our cases, and an additional five cases showed foci of lymphocytic and neutrophilic vasculitis involving smaller vessels. The specimens in which vasculitis was observed tended to occur in patients presenting within a shorter interval from onset of HZ infection. Trends in the patterns of inflammation based upon the duration of lesions were noted. In early lesions (those present less than 6 weeks), an interstitial granulomatous dermatitis pattern with loosely aggregated epithelioid histiocytes predominated, and vasculitis was more likely to be present. These early findings appeared to represent a continuum of features seen with acute HZ. Later lesions were more probably to have well-formed epithelioid granulomas and multinucleated giant cells, probably representing evolution of the granulomatous reaction. This study of the histopathologic features of ‘post-zoster’ granulomatous dermatitis was undertaken with the notion that this inflammatory process represents an unusual immunologic reaction which becomes activated in response to persistent viral antigens. In our series, there were no instances of lesions developing in areas of completely healed HZ infection. Two of the patients in the series presented with lesions showing acute viral cytopathic effect in specimens also showing granulomatous reactions and perineural plasma cells. These findings lead us to conclude that the ‘post-zoster’ granulomatous dermatitis occurs in a continuum with the acute inflammatory response to the virus. To evaluate this premise further, we reviewed 25 biopsy specimens which were submitted with the clinical impression of HZ, confirmed by the identification of herpetic viral cytopathic effect. We found that 80% of specimens showing acute HZ have subtle perineural lymphoplasmacytic inflammation and over half to have a granulomatous component to the inflammation. Given the striking overlapping histopathologic features
Herpes zoster granulomatous dermatitis with our study specimens, these findings support the concept of a persistent inflammatory response to the virus, which tends to come to attention in patients with a greater than average duration of skin lesions. Based on the findings, we favor the diagnostic term ‘herpes zoster granulomatous dermatitis’, as in our experience, the commonly-used term ‘post-zoster
granulomatous dermatitis’ does not reflect the true nature of the pathologic process. Acknowledgements The authors acknowledge Dr Caroline S. Wilkel from Roger Williams Medical Center and Dr Chull-Wan Ihm at Chonbuk National University Hospital for their contribution of post-zoster granuloma cases.
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