Commentaries 11 Terushkin V, Dusza SW, Scope A et al. Changes observed in slowgrowing melanomas during long-term dermoscopic monitoring. Br J Dermatol 2012; 166:1213–20.
cd T-cell-rich benign cutaneous disorders: good or bad? DOI: 10.1111/bjd.13597 ORIGINAL ARTICLE, p 372 Gamma delta (cd) T cells represent a small subset of T cells in humans and mice, but the importance of these cells in maintaining tissue homeostasis, host defence and disease pathogenesis is increasingly being appreciated. In the past few decades, it has been well documented that cd T cells play critical roles in infection, tumours, inflammation and autoimmune diseases.1,2 Primary cutaneous T-cell lymphoma originating from cd T cells has also been described.3 Chronic immunosuppression and prolonged antigenic exposure probably cause the clonal expansion of mature and activated cytotoxic cd T cells.4 Although primary cutaneous cd T-cell lymphoma is very rare, its aggressive clinical behaviour and poor prognosis make it one of the worst human malignancies. However, it remains unclear whether or not this is the same for other benign cutaneous disorders featuring cd T-cell-rich infiltration, which hampers early diagnosis and appropriate therapy for these patients. In this issue of BJD, Martinez-Escala et al.5 present a retrospective 5-year study determining the characteristics of a predominant cd T-cell infiltration in the lesions of the representative inflammatory skin disease pityriasis lichenoides (PL) and the low-grade lymphoproliferative disease lymphomatoid papulosis (LyP). By examining T-cell receptor (TCR) c expression in paraffin-embedded skin biopsies, four of 23 patients with PL and six of 16 patients with LyP were identified as having a cd Tcell-rich phenotype (> 20% infiltration in the lesions). The median follow-up was 16 months. Unlike those with primary cutaneous cd T-cell lymphomas, all of these patients showed an indolent clinical course. Papular eruptions were the major clinical presentation and no mucosal involvement was noted in all cases. Histologically, the infiltrating lymphocytes showed TCRc positivity and were predominantly CD8+ or double negative (CD4 /CD8 ). Coexpression of at least one of the cytotoxic markers studied (CD56, T-cell intracellular antigen-1, granzyme B) was detected in almost all of the cases. However, TCR clonal rearrangement was shown in only some of the patients’ blood or skin samples. The treatments applied included topical steroids, oral antibiotics, narrowband ultraviolet radiation and surgical excision. Patients either achieved complete remission or retained minimal residual lesions. None of the patients was reported to develop lymphoma. This was a retrospective study with small sample sizes from a single academic centre. The results presented in patients with
© 2015 British Association of Dermatologists
315
LyP are not that surprising. In addition to the first case reported by Morimura et al.,6 Rodrıguez-Pinilla et al.7 also found a good prognosis in patients with TCRc+ type D LyP. Interestingly, the current study found that the cd T-cell-rich phenotype was also shown in PL lesions, which is the first clear report of this phenotype to date. The infiltrated cd T cells in PL or LyP could be a result of an antigen-specific response, as Epstein–Barr virus has been implicated in PL pathogenesis.8 Although all of the cases in this study were negative for Epstein–Barr virus-encoded RNA, other unknown antigens could also be involved in the local immune response. In recent years, a new concept of cd T-cell regulation via innate signals has been established based on the findings from a series of sophisticated studies on murine and human cd T cells.9,10 A good example is that interleukin (IL)-17-producing cd T cells are well regulated by IL-23 and IL-1b. Therefore, it is also possible that these infiltrated cytotoxic cd T cells in the lesion are triggered by local proinflammatory cytokines such as IL-12 and IL-18, which lead to local expansion of cd T cells. cd T cells could also be trafficked into the lesion via released chemokines. It is worth noting that LyP and PL have been reported to be associated with each other. One case of PL in this study was found to be CD30+, which is a phenotype for LyP. It may be difficult to differentiate these two diseases appropriately, as LyP or PL can be present in one patient at different stages of disease progression.11,12 Alternatively, LyP and PL might overlap and belong to the same disease spectrum, as the authors suggest in their paper. More importantly, the infiltrated lymphocytes from PL are usually present as a pattern of responsive lymphocytes, while a finding of atypical tumour cells is one of the criteria for LyP diagnosis. In this study, the authors did not state very clearly whether the infiltrated cd T cells in LyP were atypical. TCRc+ cells from immunohistochemical staining in representative patients’ samples did not present a typical morphology of tumour cells, and were perhaps responsive T cells. Therefore, we speculate that the nature of the infiltrated cd T cells in the lesion might be the key to determining the outcomes of cutaneous lymphoid infiltrates. The responsive cd T-cell phenotype is more likely to be related to an indolent clinical course. More attention and long-term follow-up are needed if atypical infiltrated cd T cells are found in these patients. Nevertheless, this study provides new insights into the clinical features of cutaneous inflammation and lymphoproliferative disorders with predominant cd T-cell infiltration. Further larger studies are now needed, over longer periods of time and including paediatric cases. Conflicts of interest None declared. 1
Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of
Y. CAI1 J. ZHENG2
British Journal of Dermatology (2015) 172, pp313–322
316 Commentaries
Louisville, 505 South Hancock Street, Clinical & Translational Research Building, Room 327H, University of Louisville, Louisville, KY 40202, U.S.A. 2 Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China E-mail: [email protected]
References 1 Chien YH, Meyer C, Bonneville M. cd T cells: first line of defense and beyond. Annu Rev Immunol 2014; 32:121–55. 2 Vantourout P, Hayday A. Six-of-the-best: unique contributions of cd T cells to immunology. Nat Rev Immunol 2013; 13:88–100. 3 Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. Lyon: IARC Press, 2008. 4 Foppoli M, Ferreri AJ. cd T-cell lymphomas. Eur J Haematol 2014; DOI: 10.1111/ejh.12439. 5 Martinez-Escala ME, Sidiropoulos M, Deonizio J et al. cd T-cell-rich variants of pityriasis lichenoides and lymphomatoid papulosis: benign cutaneous disorders to be distinguished from aggressive cutaneous cd T-cell lymphomas. Br J Dermatol 2015; 172:372–9. 6 Morimura S, Sugaya M, Tamaki Z et al. Lymphomatoid papulosis showing cd T-cell phenotype. Acta Derm Venereol 2011; 91:712–3. 7 Rodrıguez-Pinilla SM, Ortiz-Romero PL, Monsalvez V et al. TCR-c expression in primary cutaneous T-cell lymphomas. Am J Surg Pathol 2013; 37:375–84. 8 Bowers S, Warshaw EM. Pityriasis lichenoides and its subtypes. J Am Acad Dermatol 2006; 55:557–72. 9 Cai Y, Shen X, Ding C et al. Pivotal role of dermal IL-17-producing cd T cells in skin inflammation. Immunity 2011; 35:596–610. 10 Wencker M, Turchinovich G, Di Marco Barros R et al. Innate-like T cells straddle innate and adaptive immunity by altering antigenreceptor responsiveness. Nat Immunol 2014; 15:80–7. 11 Vonderheid EC, Kadin ME, Gocke CD. Lymphomatoid papulosis followed by pityriasis lichenoides: a common pathogenesis? Am J Dermatopathol 2011; 33:835–40. 12 Miquel J, Fraitag S, Hamel-Teillac D et al. Lymphomatoid papulosis in children: a series of 25 cases. Br J Dermatol 2014; 171: 1138–46.
Why should we care if onychomycosis is truly onychomycosis? DOI: 10.1111/bjd.13532 ORIGINAL ARTICLE, p 380 Onychomycosis, or fungal nail infection due to dermatophyte fungi, is one of the most common infections, with prevalence rates of toenail infection varying from 3% to over 25%. These rates depend on the country and method of case ascertainment;1 the prevalence increases with age, with those aged over 70 years having infection rates, in some studies, of > 50%.1 Other covariates include climate, nature of work and British Journal of Dermatology (2015) 172, pp313–322
presence of underlying disease such as diabetes or psoriasis. It is a difficult infection to treat, as even the most effective measures, such as oral terbinafine combined with topical amorolfine, rarely produce clinical and mycological cures of more than 60–70% at follow-up.2 These figures depend critically on the methods used to assess end points, and complete cure rates may be lower, even after lengthy treatment.3,4 Therefore preventing relapse or anticipating infection through early intervention has long been a desirable strategy. Many dermatologists advise patients who have had onychomycosis to treat any new signs of interdigital or plantar tinea pedis at the earliest opportunity, or to seek advice if there are any new abnormal nail signs. This is founded on the belief that a new nail infection can be prevented by treating the infection on the foot or the nail by simple measures such as topical antifungals, before oral therapy becomes necessary. That all was not well with such advice was first apparent when two studies showed that, in patients with minimal primary onycholysis, and also in some with apparently normal nails, there was a small risk that dermatophytes could be identified by both microscopy and culture.5,6 This was subsequently confirmed in patients with clinically normal nails but symptomatic tinea pedis.7 The study by Shemer et al.8 in the current issue of BJD confirms and extends these earlier observations by showing that a small but significant number of patients with apparently normal nails, and without clinical infection on the skin of the foot, have dermatophytes in their nails. These studies suggest that preventing recurrence of the nail infection by treating tinea pedis or minimal nail abnormalities as soon as these appear might not be effective, as the clinical signs may not be accurate predictors of infection. One key observation mentioned by the authors is that the organisms present in normal nail identified in this study might not have evolved into a fully established nail infection. This might be confirmed, or not, by a difficult long-term followup study of the presence of fungi in both skin and nails at different time points after successful treatment of onychomycosis. Alternatively, certain genes are switched on when dermatophytes invade keratinized tissue and, if demonstrated in patients with dermatophytes in normal nails, the fungus would be in ‘invasive mode’. At least four such gene classes have been identified.9 These are (i) proteases that can degrade epidermal proteins including keratin; (ii) kinases involved in signalling; (iii) secondary metabolites such as polyketide synthases, involved in interactions between fungus and host; and (iv) LysM (lysin motif) proteins that help the organism evade host surveillance. But why is this important, as onychomycosis is not thought to be disabling? Although there are few direct studies there is indirect evidence that there is a strong medical need to deal with onychomycosis in at least two different populations: diabetics and the frail elderly. In diabetes, both tinea pedis and fungal nail infection are risk factors for diabetic foot.10 Onychomycosis is also common in elderly patients, potentially a larger source of concern and one that will increase over the © 2015 British Association of Dermatologists
cd T-cell-rich benign cutaneous disorders: good or bad? DOI: 10.1111/bjd.13597 ORIGINAL ARTICLE, p 372 Gamma delta (cd) T cells represent a small subset of T cells in humans and mice, but the importance of these cells in maintaining tissue homeostasis, host defence and disease pathogenesis is increasingly being appreciated. In the past few decades, it has been well documented that cd T cells play critical roles in infection, tumours, inflammation and autoimmune diseases.1,2 Primary cutaneous T-cell lymphoma originating from cd T cells has also been described.3 Chronic immunosuppression and prolonged antigenic exposure probably cause the clonal expansion of mature and activated cytotoxic cd T cells.4 Although primary cutaneous cd T-cell lymphoma is very rare, its aggressive clinical behaviour and poor prognosis make it one of the worst human malignancies. However, it remains unclear whether or not this is the same for other benign cutaneous disorders featuring cd T-cell-rich infiltration, which hampers early diagnosis and appropriate therapy for these patients. In this issue of BJD, Martinez-Escala et al.5 present a retrospective 5-year study determining the characteristics of a predominant cd T-cell infiltration in the lesions of the representative inflammatory skin disease pityriasis lichenoides (PL) and the low-grade lymphoproliferative disease lymphomatoid papulosis (LyP). By examining T-cell receptor (TCR) c expression in paraffin-embedded skin biopsies, four of 23 patients with PL and six of 16 patients with LyP were identified as having a cd Tcell-rich phenotype (> 20% infiltration in the lesions). The median follow-up was 16 months. Unlike those with primary cutaneous cd T-cell lymphomas, all of these patients showed an indolent clinical course. Papular eruptions were the major clinical presentation and no mucosal involvement was noted in all cases. Histologically, the infiltrating lymphocytes showed TCRc positivity and were predominantly CD8+ or double negative (CD4 /CD8 ). Coexpression of at least one of the cytotoxic markers studied (CD56, T-cell intracellular antigen-1, granzyme B) was detected in almost all of the cases. However, TCR clonal rearrangement was shown in only some of the patients’ blood or skin samples. The treatments applied included topical steroids, oral antibiotics, narrowband ultraviolet radiation and surgical excision. Patients either achieved complete remission or retained minimal residual lesions. None of the patients was reported to develop lymphoma. This was a retrospective study with small sample sizes from a single academic centre. The results presented in patients with
© 2015 British Association of Dermatologists
315
LyP are not that surprising. In addition to the first case reported by Morimura et al.,6 Rodrıguez-Pinilla et al.7 also found a good prognosis in patients with TCRc+ type D LyP. Interestingly, the current study found that the cd T-cell-rich phenotype was also shown in PL lesions, which is the first clear report of this phenotype to date. The infiltrated cd T cells in PL or LyP could be a result of an antigen-specific response, as Epstein–Barr virus has been implicated in PL pathogenesis.8 Although all of the cases in this study were negative for Epstein–Barr virus-encoded RNA, other unknown antigens could also be involved in the local immune response. In recent years, a new concept of cd T-cell regulation via innate signals has been established based on the findings from a series of sophisticated studies on murine and human cd T cells.9,10 A good example is that interleukin (IL)-17-producing cd T cells are well regulated by IL-23 and IL-1b. Therefore, it is also possible that these infiltrated cytotoxic cd T cells in the lesion are triggered by local proinflammatory cytokines such as IL-12 and IL-18, which lead to local expansion of cd T cells. cd T cells could also be trafficked into the lesion via released chemokines. It is worth noting that LyP and PL have been reported to be associated with each other. One case of PL in this study was found to be CD30+, which is a phenotype for LyP. It may be difficult to differentiate these two diseases appropriately, as LyP or PL can be present in one patient at different stages of disease progression.11,12 Alternatively, LyP and PL might overlap and belong to the same disease spectrum, as the authors suggest in their paper. More importantly, the infiltrated lymphocytes from PL are usually present as a pattern of responsive lymphocytes, while a finding of atypical tumour cells is one of the criteria for LyP diagnosis. In this study, the authors did not state very clearly whether the infiltrated cd T cells in LyP were atypical. TCRc+ cells from immunohistochemical staining in representative patients’ samples did not present a typical morphology of tumour cells, and were perhaps responsive T cells. Therefore, we speculate that the nature of the infiltrated cd T cells in the lesion might be the key to determining the outcomes of cutaneous lymphoid infiltrates. The responsive cd T-cell phenotype is more likely to be related to an indolent clinical course. More attention and long-term follow-up are needed if atypical infiltrated cd T cells are found in these patients. Nevertheless, this study provides new insights into the clinical features of cutaneous inflammation and lymphoproliferative disorders with predominant cd T-cell infiltration. Further larger studies are now needed, over longer periods of time and including paediatric cases. Conflicts of interest None declared. 1
Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of
Y. CAI1 J. ZHENG2
British Journal of Dermatology (2015) 172, pp313–322
316 Commentaries
Louisville, 505 South Hancock Street, Clinical & Translational Research Building, Room 327H, University of Louisville, Louisville, KY 40202, U.S.A. 2 Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China E-mail: [email protected]
References 1 Chien YH, Meyer C, Bonneville M. cd T cells: first line of defense and beyond. Annu Rev Immunol 2014; 32:121–55. 2 Vantourout P, Hayday A. Six-of-the-best: unique contributions of cd T cells to immunology. Nat Rev Immunol 2013; 13:88–100. 3 Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. Lyon: IARC Press, 2008. 4 Foppoli M, Ferreri AJ. cd T-cell lymphomas. Eur J Haematol 2014; DOI: 10.1111/ejh.12439. 5 Martinez-Escala ME, Sidiropoulos M, Deonizio J et al. cd T-cell-rich variants of pityriasis lichenoides and lymphomatoid papulosis: benign cutaneous disorders to be distinguished from aggressive cutaneous cd T-cell lymphomas. Br J Dermatol 2015; 172:372–9. 6 Morimura S, Sugaya M, Tamaki Z et al. Lymphomatoid papulosis showing cd T-cell phenotype. Acta Derm Venereol 2011; 91:712–3. 7 Rodrıguez-Pinilla SM, Ortiz-Romero PL, Monsalvez V et al. TCR-c expression in primary cutaneous T-cell lymphomas. Am J Surg Pathol 2013; 37:375–84. 8 Bowers S, Warshaw EM. Pityriasis lichenoides and its subtypes. J Am Acad Dermatol 2006; 55:557–72. 9 Cai Y, Shen X, Ding C et al. Pivotal role of dermal IL-17-producing cd T cells in skin inflammation. Immunity 2011; 35:596–610. 10 Wencker M, Turchinovich G, Di Marco Barros R et al. Innate-like T cells straddle innate and adaptive immunity by altering antigenreceptor responsiveness. Nat Immunol 2014; 15:80–7. 11 Vonderheid EC, Kadin ME, Gocke CD. Lymphomatoid papulosis followed by pityriasis lichenoides: a common pathogenesis? Am J Dermatopathol 2011; 33:835–40. 12 Miquel J, Fraitag S, Hamel-Teillac D et al. Lymphomatoid papulosis in children: a series of 25 cases. Br J Dermatol 2014; 171: 1138–46.
Why should we care if onychomycosis is truly onychomycosis? DOI: 10.1111/bjd.13532 ORIGINAL ARTICLE, p 380 Onychomycosis, or fungal nail infection due to dermatophyte fungi, is one of the most common infections, with prevalence rates of toenail infection varying from 3% to over 25%. These rates depend on the country and method of case ascertainment;1 the prevalence increases with age, with those aged over 70 years having infection rates, in some studies, of > 50%.1 Other covariates include climate, nature of work and British Journal of Dermatology (2015) 172, pp313–322
presence of underlying disease such as diabetes or psoriasis. It is a difficult infection to treat, as even the most effective measures, such as oral terbinafine combined with topical amorolfine, rarely produce clinical and mycological cures of more than 60–70% at follow-up.2 These figures depend critically on the methods used to assess end points, and complete cure rates may be lower, even after lengthy treatment.3,4 Therefore preventing relapse or anticipating infection through early intervention has long been a desirable strategy. Many dermatologists advise patients who have had onychomycosis to treat any new signs of interdigital or plantar tinea pedis at the earliest opportunity, or to seek advice if there are any new abnormal nail signs. This is founded on the belief that a new nail infection can be prevented by treating the infection on the foot or the nail by simple measures such as topical antifungals, before oral therapy becomes necessary. That all was not well with such advice was first apparent when two studies showed that, in patients with minimal primary onycholysis, and also in some with apparently normal nails, there was a small risk that dermatophytes could be identified by both microscopy and culture.5,6 This was subsequently confirmed in patients with clinically normal nails but symptomatic tinea pedis.7 The study by Shemer et al.8 in the current issue of BJD confirms and extends these earlier observations by showing that a small but significant number of patients with apparently normal nails, and without clinical infection on the skin of the foot, have dermatophytes in their nails. These studies suggest that preventing recurrence of the nail infection by treating tinea pedis or minimal nail abnormalities as soon as these appear might not be effective, as the clinical signs may not be accurate predictors of infection. One key observation mentioned by the authors is that the organisms present in normal nail identified in this study might not have evolved into a fully established nail infection. This might be confirmed, or not, by a difficult long-term followup study of the presence of fungi in both skin and nails at different time points after successful treatment of onychomycosis. Alternatively, certain genes are switched on when dermatophytes invade keratinized tissue and, if demonstrated in patients with dermatophytes in normal nails, the fungus would be in ‘invasive mode’. At least four such gene classes have been identified.9 These are (i) proteases that can degrade epidermal proteins including keratin; (ii) kinases involved in signalling; (iii) secondary metabolites such as polyketide synthases, involved in interactions between fungus and host; and (iv) LysM (lysin motif) proteins that help the organism evade host surveillance. But why is this important, as onychomycosis is not thought to be disabling? Although there are few direct studies there is indirect evidence that there is a strong medical need to deal with onychomycosis in at least two different populations: diabetics and the frail elderly. In diabetes, both tinea pedis and fungal nail infection are risk factors for diabetic foot.10 Onychomycosis is also common in elderly patients, potentially a larger source of concern and one that will increase over the © 2015 British Association of Dermatologists
