Wolf's Isotopic Response: Report of a Case and Review of Literature.

"Wolf's isotopic response" refers to the occurrence of a new dermatosis at the site of previously healed dermatosis. A number of factors including viral, neural, vascular, and immunologic factors have been implicated in the causation of this peculiar response but none has been proven conclusively. Here, we report a case where lichen planus developed at the site of dermatofibrosarcoma protruberans that had been previously treated with surgery and radiotherapy. We also put forth a hypothesis on the genesis of isotopic response considering the above mentioned factors.

What was known?

Various factors such as viral, neural, immunologic and vascular have been described in the pathogenesis of Wolf's isotopic response.

Various infective, granulomatous, immunologic and neoplastic dermatoses have been reported to present as Wolf's isotopic response.

Introduction

The term “Wolf's isotopic response” describes the occurrence of a new unrelated disease at the same location as a previously healed disease.[1] Although several cases exhibiting this phenomenon have been reported in the literature, yet the precise pathomechanisms leading to the occurrence of this peculiar response still eludes our understanding. In this manuscript, we report a case of Wolf's isotopic response at the site of dermatofibrosarcoma protuberans that had been treated with surgery and radiotherapy. We put forth a plausible hypothesis linking the various viral, immunologic, vascular, and neurohumoral events leading to Wolf's isotopic response. In addition we review the cases that have been reported in the past decade [Table 1].[2345678910111213141516171819202122232425262728293031323334353637383940414243444546474849505152] We also examine the related phenomenon like reverse isotopic response and isoradiotopic response.

Table 1

Reported cases of isotopic response in the last decade

An extensive literature search was performed to collect data on Wolf's isotopic response. Relevant literature published from January 2001 to April 2012 was obtained from two bibliographical databases: PubMed and EMBASE. Keywords: “Wolf's isotopic response”, “isotopic response”, “reverse isotopic response”, “isoradiotopic response”, or “herpes zoster” were used for literature search. The search and selection of the literature was restricted to publications written in English, Dutch, German, or French. All reviews, case series, case reports, and letters to the editor mentioning this phenomenon were reviewed. Reference lists in the selected articles were scrutinized to identify other relevant articles that had been overlooked in initial search.

Report of a Case

A 48-year-old lady presented with a painful nodule on right lower back for 1 year. The lesion began as a single small papule which slowly increased in size to form a large tender nodule. For this she consulted a surgeon who biopsied the lesion. Histopathology of the nodule revealed dermatofibrosarcoma protuberans. The patient underwent local excision of the nodule with excision of a generous margin of healthy skin. Postoperatively, she received 50 Gy of radiotherapy. Nearly 5 months after the last dose of radiotherapy, she reported to our department with an eruption on the same site, that is, on the right side of the lower back. This time, the lesions started as small itchy papules that gradually increased in size and number. On examination, a big scar measuring 10 × 8 cm in size was observed, reminiscent of the previous surgery. At the margin of scar and within its confines, multiple well- to ill-defined lichenoid plaques of variable size were present. On the surface of the lesions, there were whitish striae [Figure 1]. A diagnosis of lichen planus was considered. Histopathologic examination of a skin biopsy specimen showed epidermal hyperkeratosis, basal cell degeneration, and few Civatte bodies. Band like lymphomononuclear infiltrate at the dermoepidermal junction was observed, Thus, the features were consistent with lichen planus [Figure 2]. The patient was prescribed topical clobetasol propionate 0.05% ointment for twice daily application with which the lesions cleared after 8 weeks of therapy.

Figure 1

Lesions of lichen planus at the margin of the scar and within it

Figure 2

Epidermis showing hyperkeratosis, basal cell degeneration and few Civatte bodies with band like lymphomononuclear infiltrate at the dermoepidermal junction (H and E, ×20)

Discussion and Review of Literature

In 1955, Wyburn-Mason[53] for the first time described the occurrence of a new skin disease at the site of another skin disease that had already healed. Such cases continued to mark their presence in literature till Wolf and Wolf[54] in 1985 gave it a term; “isoloci response” (same locus). It was modified to “isotopic response” (same place) by Wolf et al.,[55] and finally reframed as Wolf's isotopic response by Ruocco et al.[1] Although the terminology has evolved over time, yet the definition remains the same as first defined by Wolf. Dermatoses which appear after exposure to external agents like chemicals and radiation should not be included in isotopic response.

Though the two dermatoses are not related in terms of their morphology, the seeds of second disease may be sown during the healing process of the first disease. This is because the healed skin may continue to show microscopic and physiologic changes for a long time after the initial insult and some of these changes may in fact be responsible for occurrence of new dermatosis.[56] In other words, the sequel left over by first disease may have a bearing on occurrence of second disease, and thus not totally unrelated. We propose that the original definition be modified as “the occurrence of a new unrelated disease that appears at the same apparently normal looking location as a previously healed disease.” The dermatoses which present as a consequence of isotopic response have been classified as granulomatous reactions, malignant tumors, leukemic infiltrates, dermatoses secondary to immunologic dysfunction, infections, comedonic reactions, and other miscellaneous conditions.

Isotopic response vs isomorphic response

Heinrich Koebner, in 1872, first described the phenomenon where in typical skin lesions of an existing dermatosis appeared at sites of injuries.[57] This was termed as “isomorphic response of Koebner”. The isotopic response in comparison has been defined quite recently. While the names may appear analogous, the differences are obvious. The former response; classically seen in psoriasis, lichen planus, and vitiligo; emphasizes on the presence of lesions of same morphology whereas the latter response describes a new lesion (i.e. of different morphology) but at the same site of previously healed lesion. In spite of the clear cut definitions, there are still few areas of overlap-like appearance of a drug eruption at the site of previous herpes zoster as an isotopic or isomorphic response or recall phenomenon.[5859] Recall phenomenon refers to the drug-induced (mostly chemotherapeutic drugs) or contact-induced reactivation of tissue toxicity initially induced by sun exposure, radiotherapy, or previous allergen reactions. Since drug-induced erythema multiforme with photorecall phenomenon is not uncommon, Mizukawa et al.,[58] opined that some cases of erythema multiforme showing isotopic response may infact be triggered by drugs. They further elaborated that the localization of drug-induced erythema multiforme to the sites of healed herpes zoster infection can be explained by persistence of skin resident T cells after effective viral clearance.

Reverse isotopic response

This refers to the sparing of healed skin previously affected by herpes zoster virus (HZV) infection by a second generalized dermatosis. This phenomenon was first reported by Katayama et al.,[60] as a case of contact dermatitis sparing the eruption of herpes zoster and its periphery. It has also been reported with erythrodermic cutaneous T cell lymphoma (CTCL), Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), erythema multiforme, and erythrodermic drug reactions [Table 2].[6061626364] The pathogenesis of such a response, as of Wolf's isotopic response, is not entirely clear. It has been suggested that HZV infection may lead to depletion of cutaneous Langerhan's cells[64] and these cells are of prime importance for epidermotropism in CTCL, for severe drug reactions like erythroderma and SJS/TEN and also in the pathogenesis of contact dermatitis. Twersky et al.,[64] reported a relative paucity of CD1a+ staining cells in the spared epidermis. Kannangara et al.,[61] suggested that altered keratinocyte function may contribute to this sparing phenomenon. Antigen presenting function of keratinocytes may be interfered with due to downregulation of major histocompatibility complex (MHC)-I, MHC-II, and intercellular adhesion molecule (ICAM)-I expression in HZV-infected keratinocytes.[63]

Table 2

Reported cases of reverse isotopic response

Isoradiotopic response

This refers to the appearance of a skin disease confined to the site of radiation exposure.[65] It may represent a Koebner's response to radiation injury or an isotopic response. While in isoradiotopic response, the lesions of new dermatosis will be confined to the irradiated area, the lesions of similar morphology should be present elsewhere too in cases of Koebner's response to radiation injury. However, Wolf argued against the inclusion of such cases in isotopic response so as to ensure homogeneity. A variety of dermatosis have been described in the radiation site like lichen planus, bullous pemphigoid, pemphigus, SJS, chronic graft-versus-host disease (GVHD), comedones, etc.[6667686970717273]

Pathogenesis of Isotopic Response

What we already know

Various theories have been proposed to explain this phenomenon. These include the viral hypothesis, vascular hypothesis, immunologic hypothesis, and perhaps the most acceptable, the neural hypothesis.

Viral hypothesis: This is the least favored one. In spite of the viral DNA being isolated initially in few cases (by Claudy et al.),[74] this theory suffered from its lack of reproducibility on further research. Serfling et al.,[75] failed to demonstrate viral DNA in any of the lesions arising as isotopic response at 4-200 weeks after resolution of herpetic infection.

Vascular hypothesis: It has been proposed that the local microcirculation damaged by inflammation may remember the experience and if insulted again in future, may localize the inflammation to the previous site of damage.[55]

Immunologic hypothesis: The immune system can be considered as a double edged sword. On one hand, it protects us from any foreign antigens but on the other hand, if dysregulated can lead to tissue inflammation. A dermatosis affecting a certain body site may lead to changes in the regional immune system or formation of memory T cells which when triggered at a later date may give rise to a new dermatosis. This may be the explanation in cases of drug eruptions localized to the site of healed herpes zoster. The preferential occurrence of acyclovir-induced macular and papular lesions at the sites of previous herpes zoster may be due to the memory T cells, which may have appeared during the initial herpetic infection, and the accidental excessive activation of these cells by drugs could result in localized tissue injury.[45] Intraepidermal memory T cells are abundant in such lesions. This is supported by the observation that some fixed drug eruptions initially appear at the site of previously traumatized skin.[76]

Neural hypothesis: This theory is currently the most favored and has been explained in detail by Ruocco et al.[1] Although HZV causes destruction of the nerve fibers (myelinated Group Aδ and unmyelinated Group C) in mid and lower dermis,[77] the neurohumoral factors may contribute to the pathogenesis of a new disease either directly by release of various neuropeptides or indirectly by aberrant activation of immune system:[1]

Direct effect: Spontaneous firing of the denervated central nervous system (CNS) neurons with associated release of neuropeptides may initiate the events for a new disease.

Indirect effect: Immune cells express cell membrane receptors for various neuropeptides and neurotransmitters produced by the brain or peripheral nerves and hence may be activated by abnormal release of such peptides.

What we propose

Composite theory of pathogenesis of Wolf's isotopic response: None of the above hypothesis can singularly explain the pathogenesis of isotopic response. One or more, or in fact all the factors play a role in the causation of a new disease along “locus minoris resistentiae”, that is, the area of lessened resistance although one factor may predominate over the other in individual cases. Development of the new skin disease occurs in a stepwise fashion where one event leads to another [Figure 3]. Although HZV DNA could not be isolated from most cases, yet the association between previous herpes zoster and isotopic response is too strong to be coincidental. In other instances where the first disease is not herpes zoster, other common dermatoses is erythema multiforme, the most common cause of which is herpes simplex infection. Even if not directly, herpes virus because of its ability to invade neural tissue is important in isotopic response. Herpetic infection prepares the ground for a new dermatosis by causing neurovascular alterations in the affected area.

Figure 3

Chain of events leading to isotopic response

Neuropeptides and nerve signals from damaged nerve endings are the initiating event in isotopic response. These neuropeptides include substance P, bradykinin, serotonin, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and α-melanocyte stimulating hormone (MSH). The peptides may have both pro- and antiinflammatory action and the balance between the two determines whether a new dermatosis will occur or not. Although these peptides may alone be responsible for producing certain symptoms like itching and pain, their main role is abnormal activation of immune system. In some cases, the second dermatosis has shown correlation with post herpetic neuralgia. Kim et al.,[16] reported a case of cutaneous mucinosis over previously healed HZV site. The mucinosis improved proportionally to that of postherpetic neuralgia, suggesting that nerve fiber damage caused by HZV may be closely related to mucin production. They suggested that the neuropeptides released by peripheral nerves may stimulate the B cells to produce excess glycosaminoglycans.

Neuropeptides like VIP, enhance the monocyte chemotaxis and inhibit natural killer (NK) cell activity and substance P causes proliferation of T cells.[78] This hyperactive immune system forms the basis of a variety of inflammatory and granulomatous skin diseases. Conversely, localized immunosupression may be responsible for cutaneous malignancies. In addition, the cytokines may also stimulate the peripheral nerves, thus forming a positive feedback cycle. Abraham et al.,[50] proposed that various immunological changes like an immune complex vasculitic process and delayed-type hypersensitivity reactions secondary to post herpetic immune dysregulation, may be responsible for occurrence of various granulomatous and infiltrative disorders like granuloma annulare and sarcoidosis. It has also been suggested that macrophage function may be altered secondary to herpes infection leading to necrobiosis and granuloma formation.[28] Immune instability may account for the reports of isotopic response in patients with HIV infection and myelodysplastic syndrome.[1416] It has also been suggested that, tumor necrosis factor-α may have a role in the Wolf isotopic response as it is an important mediator in a variety of inflammatory and granulomatous diseases.[22]

However, this inflammatory response is not generalized. As already mentioned, the local vasculature is altered due to the prior skin disease and this may provide a favorable environment for localization of immune cells to the same site by upregulation of adhesion molecules. Angiogenic factors may also interact with neural and immunologic factors in the occurrence of Kaposi sarcoma and tufted angioma at the site of previous herpes zoster.[26] The occurrence of a cutaneous angiosarcoma exactly at the site of a previous herpes zoster is a classic example of Wolf's isotopic response with a predominant local dysregulation of both angiogenic and immune mechanisms.[79] Neurovascular factors may also be responsible for the presence of rosacea localized to HZV scar site.[27]

Our case provides an example of how these events form a chain culminating in a new skin disease. Our patient developed a cutaneous tumor, that is, dermatofibrosarcoma protuberans (primary dermatosis) which was adequately treated with surgery and radiotherapy (a possible triggering agent; nonviral in this case). Later she developed lichen planus at the same site. Exposure of skin to ionizing radiations can lead to certain neural and immunologic alterations. These vary from sensory change/loss to chronic pain (as seen following breast cancer sugery/radiotherapy) and is associated with damage to nociceptive receptors.[80] In addition, ionization radiations have been known to produce cutaneous immunomodulation (primarily immunosuppression) due to their effect on T regulatory cells (immunologic component).[81] Upon induction by ultraviolet rays, T regulatory cells tend to migrate to local lymph nodes and thus may not inhibit the elicitation of cutaneous immune reactions.[82] Although changes in cutaneous nerves are of relatively less importance in the pathogenesis of lichen planus, Nissalo et al.,[83] showed an increase in nerve fiber density in oral lichen planus and lichenoid reactions compared to healthy mucosa which was compatible with sprouting and collateral formation (neural component).[83] The primary pathology in lichen planus is immune dysregulation as seen by increase in population of dermal CD4+ and CD8+ T cells with infiltration of epidermis with CD8+ T cells culminating in keratinocyte necrosis. The effect of ionizing radiation in the induction of lichen planus like lesions is not proven conclusively (as psoralen plus ultraviolet therapy has been used to treat lichen planus), but it is not unreasonable to assume that immunologic and neural changes that result in the aftermath of radiation damage may together lead to immune dysfunction and hence lichen planus. Altered vasculature as mentioned may help to limit the extent of this abnormal response (vascular component).

What to Look Forward in Future

Although much advances have been made in understanding the pathogenesis of Wolf's isotopic response, further insight into the exact neuropeptides, the role of tumour necrosis factor-α and other inflammatory mediators and the vascular factors is needed. Further, unfolding of pathogenesis of Wolf's isotopic response and reverse isotopic response will also enable us to understand the various factors responsible for the localization of numerous dermatological diseases.

What is new?

The present case and review adds another case of lichen planus to the meager literature on Wolf's isotopic response.

We also propose a plausible hypothesis which explains the interaction among factors already known to be responsible for Wolf's isotopic response.