Primary cutaneous acral CD8 positive T‐cell lymphoma with extra‐cutaneous involvement: A long‐standing case with an unexpected progression

Primary cutaneous acral CD8+ T‐cell lymphoma (acral CD8+ TCL) is a new provisional entity characterized by acral skin lesions and an indolent course. We describe an extraordinary case characterized by relapsed nodules with CD8+ cytotoxic infiltrates on the left ear. After 35 years, the skin lesions spread to other acral sites, and a mass with the same histological features as the other skin lesions appeared on the nose. Multiple courses of chemotherapy led to stable disease. Histological examinations carried out at different times showed the gradual transformation of the neoplastic cells, with an increased proliferation index. Genomic analysis revealed losses in the regions harboring the genes involved in cell cycle control. This is the first case of an acral CD8+ TCL with a very long history of indolent nodular lesions progressing to extra‐cutaneous sites.     

Extrafacial indolent CD8‐positive cutaneous lymphoid proliferation with unusual symmetrical presentation involving both feet

Indolent CD8+ cutaneous lymphoid proliferation represents a recently described entity among cutaneous T‐cell lymphomas that typically presents with solitary skin lesions on the face or at acral sites and usually follows an indolent clinical course. Histopathologically, this entity is characterized by a dense dermal infiltrate of non‐epidermotropic, small‐ to medium‐sized pleomorphic CD8+ T‐cells of the non‐activated cytotoxic phenotype showing a clear‐cut grenz zone and a low proliferation index. Distinction from otherwise aggressive T‐cell lymphomas bearing a cytotoxic CD8+ phenotype is fundamental. We herein present an unusual case of indolent CD8+ cutaneous lymphoid proliferation presenting in bilateral symmetrical distribution on both feet and lacking the otherwise described grenz zone. Our case widens the spectrum of possible clinical and histomorphological variations of this entity. Taking into account the distinctive and unique clinical and microscopic features of all hitherto published cases of indolent CD8+ cutaneous lymphoid proliferation we suppose that this lymphoma subtype has to be included as a new and distinct entity in the World Health Organisation (WHO)‐/European Organisation for Research and Treatment of Cancer (EORTC)‐classification of cutaneous lymphomas.     

Distinctive acral erythema occurring during therapy for severe myelogenous leukemia

A distinctive acral erythema developed in four patients with myelogenous leukemia, subsequent to blood transfusions and intensive chemotherapy with cytarabine. The clinical and histopathologic features of the eruption were suggestive of a drug-induced toxic eruption. To our knowledge, only one previous similar case has been reported in the literature. For patients in whom this self-limited condition develops, reassurance should serve as the mainstay of therapy.     

Jessner's lymphocytic infiltration of the skin: a CD8+ polyclonal reactive skin condition

BACKGROUND: Jessner's lymphocytic infiltration of the skin (JLIS) is a clinically and histologically distinct disease entity. Conflicting results have been reported concerning its differentiation from cutaneous lupus erythematosus and polymorphous light eruption, its relationship to palpable migratory arciform erythema and its classification as a B-cell or a CD4+ T-cell lymphoproliferative disease. OBJECTIVE: Our study was performed in order to re-evaluate JLIS clinically and by immunohistochemical and molecular analyses. METHODS: Stringent inclusion/exclusion criteria were used to collect a cohort of 34 patients with JLIS that did not overlap with lupus erythematosus or polymorphous light eruption. Clinical data were analysed, and immunohistochemical and molecular studies were performed including TCR-gamma PCR GeneScan software analysis of tissue and peripheral blood samples. RESULTS: In the majority of the patients, the lesions consisted only of papules and plaques while in 12% annular lesions were also seen. The lesions were found on the face (38%), on the trunk and arms (50%) or at both sites (12%). Immunohistochemical analyses revealed a clear predominance of T cells in all patients, and of CD8+ T cells in 77% of the patients. As judged by TCR-gamma PCR GeneScan analysis, 98 and 79% of the tissue and peripheral blood samples, respectively, showed a polyclonal T-cell population; identical T-cell clones were not detected concomitantly in both the skin and the peripheral blood of the same patient. CONCLUSIONS: JLIS occurs at 2 major predilection sites, that is the face and trunk. Therefore introduction of palpable migratory arciform erythema as a separate entity is not justified. The lymphoid infiltrates are dominated immunohistochemically by CD8+ T cells that do not show clonality on molecular analysis. Thus, JLIS represents a characteristic CD8+ polyclonal reactive skin condition.     

Eruptive pseudo‐angiomatosis lesions are associated with intravascular neutrophils and do not harbour Epstein–Barr virus

Background Eruptive pseudo‐angiomatosis (EPA) is a rare, relatively newly described cutaneous disorder characterized by the sudden onset of several bright red, angioma‐like papules surrounded by blanched halo. Its aetiology is unknown; however, viral infection or mosquito bites have been speculated as possible causes. Objective This study aims to determine the clinical and histopathological features of EPA, and whether it is associated with Epstein–Barr virus (EBV) infection. Methods We conducted a retrospective chart review of 25 EPA cases from 2006 to 2008. In order to determine latent EBV infection, EBV‐encoded small RNA (EBER) in situ hybridization was performed in 18 subjects. To determine EPA's distinguishing histological characteristics, we compared the cases with 22 control cases of perivascular lymphocytic infiltration for haematoxylin and eosin, CD3, CD4, CD8, CD31 and c‐kit staining patterns. Results The patient sample's female‐to‐male ratio was 2.1 : 1, and the patients’ age ranged from 5 to 79 years (average 46 years). The lesions appeared during the months of July to September in all but 3 patients. Skin biopsies demonstrated capillary ectasia with perivascular mononuclear cellular infiltrates in the upper dermis. Most patients were otherwise healthy, and routine laboratory results were all normal except in one patient who had diabetes. The skin lesions faded without any treatment in 1–2 weeks. Results of EBER in situ hybridization were all negative. The only histological distinguishing feature of EPA was the presence of intravascular neutrophils, which was found to be present in 19 of the 20 EPA cases (95%), in contrast to only 3 of the 22 control subjects (14%) (P < 0.0001). Conclusion The sudden onset of lesions during the summer months among our patients supports the ‘paraviral eruption’ concept of this probably underdiagnosed condition. The significant presence of intravascular neutrophils may be a diagnostic clue of EPA in South Korea.     

Hydroa vacciniforme-like primary cutaneous CD8-positive T-cell lymphoma

An 8-year-old Taiwanese girl had a 6-month history of a relapsing papulovesicular eruption on her face that resembled hydroa vacciniforme (HV). Histologically, there was a dense infiltration of large atypical lymphocytic cells expressing CD8. TCR-gamma gene rearrangement study revealed a monoclonal band present in the DNA extracted from the specimen. A diagnosis of CD8+ cutaneous T-cell lymphoma (CTCL) was made. The patient was treated with Chinese herbal drugs and her skin lesions waxed and waned. At this writing, 11 months after establishment of the diagnosis, the skin lesions have been limited to the facial area and no definite evidence of systemic involvement is noted. To our knowledge, this is the first case of CD8+ primary CTCL with clinical features resembling HV.     

In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption

Background Although a severe form of fixed drug eruption (FDE) clinically and histologically mimics toxic epidermal necrolysis (TEN), subsequent evolution of the two conditions is quite different. It remains unknown, however, which factors determine whether these lesions resolve spontaneously or subsequently progress to TEN. Objectives Because epidermal injury in TEN can be locally reproduced in the evolving FDE lesions, we sought to investigate how epidermal damage can be induced in the evolving FDE lesions and how disease progression to TEN can be prevented, by analysing the FDE lesions induced by clinical challenge with the causative drug. Methods We immunohistochemically investigated in vivo dynamics of T‐cell trafficking and activation that occur in the evolving FDE lesions using sequential biopsy specimens obtained at multiple time points from the FDE lesions. Results Intraepidermal CD8+ T cells, which are resident in the lesional epidermis as a stable homogeneous population of memory T cells, transiently acquire a natural killer‐like phenotype and express cytotoxic granules upon activation. The influx into the epidermis of CD4+ T cells including Foxp3+ regulatory T cells (Tregs) during the evolution serves to ameliorate epidermal damage induced by activation of the intraepidermal CD8+ T cells. Interleukin‐15 derived from the lesional epidermis could maintain the survival of the intraepidermal CD8+ T cells even in the absence of antigenic stimulus over a prolonged period of time (> 4 years). Conclusions Whether Tregs could migrate to the lesions upon activation of intraepidermal CD8+ T cells would determine whether the inflammation becomes resolved spontaneously or progresses to TEN.     

Ichthyosiform mycosis fungoides: an atypical variant of cutaneous T-cell lymphoma

BACKGROUND: Acquired ichthyosis is a known paraneoplastic sign of lymphoproliferative malignancies, with histopathologic findings that are nonspecific, revealing no insinuation of the underlying neoplasm. Ichthyosiform eruption as a specific manifestation of mycosis fungoides (MF), ie, ichthyosiform MF, is, however, regarded as rare and to date has been reported in only a few cases. OBJECTIVE: We sought to study the clinical, histopathologic, immunohistochemical, and genotypic features of patients with ichthyosiform MF. METHODS: The files of patients with MF seen during the past 8 years in our department were reviewed to search for cases of ichthyosis-like MF. RESULTS: Seven patients, comprising 3.5% of the patients seen with MF, had an ichthyosiform eruption with histopathologic features characteristic of early MF. In 2 patients it was the sole manifestation of the disease and in 5 patients it appeared either in conjunction with conventional patches and/or plaques or with follicular lesions. Immunohistochemically, all showed a predominance of CD3+ CD4+, except for 1 patient in whom the epidermotropic T cells were predominantly CD8+. In 3 of the 7 patients clonality could be demonstrated by polymerase chain reaction. None had extracutaneous involvement. All had an indolent course of the disease and responded well to skin-targeted therapies. CONCLUSIONS: Ichthyosiform MF is yet another atypical clinical variant of cutaneous T-cell lymphoma that is not as rare as reflected in the literature. It may be the sole manifestation of the disease but also may appear in conjunction with conventional or follicular MF lesions.     

Successful desensitization to fixed drug eruption: the presence of CD25+CD4+ T cells in the epidermis of fixed drug eruption lesions may be involved in the induction of desensitization

BACKGROUND: Fixed drug eruption (FDE) is a distinct type of drug-induced eruption, in which intraepidermal CD8+ T cells in the lesional skin are the final effector cells in the epidermal injury of FDE. Desensitization is a unique approach for the management of drug eruption, which has been reported to be effective in treating FDE. However, the mechanisms underlying desensitization to FDE are quite unknown. OBJECTIVE AND METHODS: We reported a case of successful desensitization to allopurinol-induced FDE. To clarify the mechanisms underlying desensitization to FDE, we examined the phenotype of T cells in the epidermis of FDE lesions before and after desensitization using flow cytometry. RESULTS: The overwhelming majority of intraepidermal T cells in the FDE lesion before desensitization consisted of CD8+ T cells, whereas a significant number of CD25+CD4+ T cells were present in the epidermis of FDE lesions after desensitization. CONCLUSION: The presence of CD25+CD4+ T cells in the epidermis of FDE lesions may be involved in the induction of desensitization to FDE.     

Necrolytic acral erythema in a Chinese patient with hepatitis C and hepatitis B virus coinfection

Necrolytic acral erythema is a distinct erythema that has been described as an extrahepatic manifestation of hepatitis C virus infection. Most reported cases have been in Africa, especially Egypt. We report the first case (to the best of our knowledge) of necrolytic acral erythema in a Chinese patient with HCV and HBV coinfection. We aim to increase awareness for recognizing this condition in the Chinese population.     

Disseminated CD8‐positive,CD30‐positive cutaneous lymphoproliferative eruption with overlapping features of mycosis fungoides and primary cutaneous anaplastic large cell lymphoma following remote solitary lesional presentation

CD8‐positive, CD30‐positive cutaneous lymphoproliferative disorders constitute a rare subset of T‐cell lymphoproliferative conditions, including variants of primary cutaneous anaplastic large cell lymphoma (ALCL), mycosis fungoides, lymphomatoid papulosis type D, cutaneous gamma‐delta T‐cell lymphoma and cutaneous peripheral T‐cell lymphoma. These entities share overlapping clinical, histopathologic and immunophenotypic features, presenting both a clinical and pathological diagnostic challenge. Presented here is a 73‐year‐old man with a disseminated, indolent CD30+, CD8+ cutaneous lymphoproliferative disorder with overlapping clinical and histopathological features of both mycosis fungoides and primary cutaneous ALCL, as well as features of lymphomatoid papulosis. To our knowledge, this is the first case of a generalized CD8+, CD30+ eruption with features of both mycosis fungoides and primary cutaneous ALCL arising following an episode of solitary primary cutaneous CD8‐positive ALCL.     

A review of the solitary cutaneous T‐cell lymphomas

Cutaneous T‐cell lymphomas (CTCL) account for almost 65‐92% of all cutaneous lymphomas, many of which usually present with multiple lesions. However, a number of well‐recognized and rare types of CTCL, including mycosis fungoides, can present in isolated fashion. These solitary lesions often run a relatively indolent clinical course but often pose diagnostic difficulties. We review histopathologically challenging solitary cutaneous T‐cell lymphomas, including criteria for diagnosis, clinical course and prognosis, particularly for primary cutaneous CD4+ small/medium pleomorphic lymphoma and indolent CD8+ lymphoid proliferation of acral sites. In addition, we suggest an algorithm and nomenclature to aid in the diagnosis of such problematic lesions.     

The effects of human herpesvirus 8 infection and interferon-gamma response in cutaneous lesions of Kaposi sarcoma differ among human immunodeficiency virus-infected and uninfected individuals

Background Kaposi sarcoma (KS) is associated with human herpesvirus 8 (HHV‐8). The cutaneous immune response in this tumour is not well established and a better understanding is necessary. Objectives To evaluate the HHV‐8 expression and immune response in cutaneous lesions of classic KS (CKS) and AIDS‐associated KS (AIDS‐KS). Methods We performed a quantitative immunohistochemical study of cells expressing HHV‐8 latency‐associated nuclear antigen (LANA), CD4, CD8 and interferon (IFN)‐γ in skin lesions from patients with CKS and AIDS‐KS (with or without highly active antiretroviral therapy, HAART). Results CKS showed higher LANA expression compared with AIDS‐KS, regardless of HAART. We also found higher LANA expression in nodules compared with patch/plaque lesions. The tissue CD4+ cell proportion was lower in AIDS‐KS patients without HAART than in patients with CKS. In CKS lesions, CD4+ and CD8+ cells expressed IFN‐γ, as shown by double immunostaining. AIDS‐KS presented low numbers of IFN‐γ‐expressing cells. CD8+ cell numbers were similar in all groups, which appeared unrelated to the clinical or epidemiological type of KS. Conclusions Our quantitative data on the pattern of KS lesions in selected groups of patients, as shown by in situ immune response, demonstrated a CD4+ T‐cell involvement associated with IFN‐γ, an environment of immune response‐modified human immunodeficiency virus (HIV) infection. In our sample, the promotion of KS in patients without HIV appears to be related to higher HHV‐8 load or virulence than in those with AIDS. This higher resistance may be explained by a sustained immune response against this herpesvirus, that is only partially restored but effective after HAART.     

HIV阳性药疹患者CD4+、CD8+T细胞水平以及临床特征分析

目的 探讨病毒感染在HIV阳性药疹患者发病中的作用及抗病毒治疗效果。 方法 回顾性分析接受“高效抗逆转录病毒治疗”的11例HIV阳性药疹患者及同期76例HIV阳性非药疹患者临床资料以及基线CD4+、CD8+T细胞计数和CD4/CD8比值。 结果 11例HIV阳性药疹患者均符合轻型药疹,潜伏期8 ~ 34（14.00 ± 8.10） d,其中7例出现肝功能损伤,与皮损严重程度不一致,未停用抗病毒药物并经抗过敏治疗后病情好转。11例HIV阳性药疹患者基线CD4+T细胞计数为42 ~ 810（493.00 ± 245.68）个/μl,高于75例HIV阳性非药疹患者［11 ~ 814（347.81 ± 167.00）个/μl,t = 647.50,P < 0.05］,基线CD4+T细胞计数降低者比例（3/11）低于HIV阳性非药疹患者［64.00%（48/75）,χ2 = 3.95,P < 0.05］。10例HIV阳性药疹患者基线CD8+T细胞计数［（1 472.30 ± 858.55）个/μl］与同期69例HIV阳性非药疹患者［（1 356.59 ± 684.06）个/μl］相比,差异无统计学意义（P > 0.05）,基线CD4/CD8比值（0.40 ± 0.27）与HIV阳性非药疹患者（0.29 ± 0.16）差异无统计学意义（P > 0.05）,基线CD4/CD8值低于正常下限者率（9/10）与HIV阳性非药疹患者［98.55%（68/69）］差异亦无统计学意义（P > 0.05）。 结论 接受“高效抗逆转录病毒治疗”的HIV阳性药疹患者具有更长的潜伏期,即使轻型药疹亦可伴肝功能异常等系统损害;相对较高CD4+T细胞计数可能是HIV阳性者药疹发生或加重的危险因素。     

Acral lesions of vitiligo: why are they resistant to photochemotherapy?

Background Acral lesions of vitiligo are usually resistant to conventional lines of treatment as well as surgical interventions. Objective To clarify causes underlying resistance of acral lesions to pigmentation in vitiligo by studying some of the factors associated with mechanisms of repigmentation following photochemotherapy. Methods The study included twenty patients with active vitiligo. Skin biopsies were taken from lesional and perilesional skin of areas expected to respond (trunk and proximal limb) and skin of acral areas, before and after PUVA therapy. Sections were stained with H and E, Melan‐A, MHCII, CD1a, SCF and c‐kit protein. Results Before treatment acral areas showed significantly lower hair follicle density, melanocyte density, Langerhans cell (LC) density, epidermal MHCII expression, lesional SCF expression and perilesional c‐kit expression. Following treatment with PUVA in both non‐responsive acral and repigmenting non‐acral lesions identical immunohistochemical changes in the form of significant decrease in LC density, epidermal MHC‐II and SCF expression were observed. Conclusion The surprisingly similar histochemical changes in response to PUVA in acral and non‐acral lesions did not manifest with clinical repigmentation except in non‐acral ones. Factors such as inherent lower melanocyte density, lower melanocyte stem cell reservoirs and/or lower baseline epidermal stem cell factor may be considered as possible play makers in this respect.     

Lichen planus and lichenoid drug-induced eruption: a histological and immunohistochemical study

Introduction Lichenoid drug eruption (LDE) shares similar features with lichen planus (LP), that could reflect the same pathogenesis. In LP, an autoimmune attack is accepted and cytotoxic T‐lymphocytes (CD8+) predominate, especially in late lesions. Apoptosis of keratinocytes may be mediated by CD8+ T and NK cells in two distinct ways: by the release of cytotoxic molecules such as perforin and granzyme B or by the Fas/FasL system. The immunological mechanisms involved in LDE are not yet fully established. Objectives Investigate immunohistological features in LP and LDE to add clues to better understand their pathogenesis. Material and methods Twenty‐two patients fulfilled all clinical, laboratory, histopathological, and follow‐up features of lichen planus (n = 16) and lichenoid drug eruption (n = 6). Classic histological features favoring LP or LDE were evaluated by two observers. HAM56, MAC387, UCHL‐1, OPD4, CD8, Granzyme B, Perforin, and ICAM‐1 antibodies were used to decorate the immune infiltrate. Results were analyzed through Pearson correlation, Student’s t‐test, and linear discriminant analysis. Results A higher number of necrotic keratinocytes as well as plasma cells and eosinophils within inflammatory cells were associated with LDE diagnosis. Only in LDE, a correlation was found between the number of T and CD8+ cells and between the number of granzyme B+ cells and apoptotic keratinocytes. Conclusion Our findings suggest a more important role of CD8+ granzyme B‐containing cells in LDE group, being its synthesis associated with more intense apoptosis. So, LP and LDE may have a somewhat distinct pathogenesis.     

Primary cutaneous acral CD8+ T‐cell lymphoma of the ear: A case report

Primary cutaneous acral CD8+ T‐cell lymphoma (TCL) is a rare, distinct type of cutaneous TCL. Despite its worrisome histological appearance it has a benign clinical course. It is therefore important to recognize this as a distinct entity from other more aggressive CD8+ lymphomas, for which the management is very different.     

Acral subcutaneous steatocystoma multiplex: A distinct subtype of the disease?

Steatocystoma multiplex (SM) is a hamartomatous malformation of the pilosebaceous duct consisting of dermal cysts filled with a sebum‐like material. SM lesions are typically located in areas with sebaceous follicles, although atypical presentations involving sites lacking sebaceous follicles have exceptionally been described. We reviewed retrospectively a series of 32 histologically diagnosed SM observed in our department in the period 2006–2010, evaluating the kinds of lesions and their locations, and family history of SM and associated disorders, to focus on the clinical features of the acral subcutaneous variety of SM and to estimate its prevalence. We found five patients (four women and one man) with asymptomatic deep, skin‐colored nodules on the flexor surfaces of distal upper extremities with a mean age at diagnosis and at disease onset of 32.5 and 26 years, respectively. The prevalence was 15%. All five cases were sporadic. The male patient had eruptive syringomas as an associated condition, together with a family history of this tumour. Acral subcutaneous SM may represent a distinct disease variety by virtue of its distinctive clinical features. Dermatologists should be aware of this form, which has to be included in the wide panel of diseases involving subcutaneous tissue.     

Insect bite-like reaction associated with mantle cell lymphoma: clinicopathological, immunopathological, and molecular studies

A cutaneous eruption simulating insect bites has been repeatedly described in association with chronic lymphocytic leukemia (CLL). It was only rarely described with mantle cell lymphoma (MCL). Our study was performed to elucidate the clinical, histologic, immunopathological, and molecular characteristics of insect bite like reaction (IBLR) associated with MCL. The clinical presentation and histologic findings in 3 IBLR cases associated with MCL were found to be similar to 3 IBLR cases associated with CLL. The eruptions consisted of itchy erythematous papules, nodules, plaques, and vesicles. Non-vesicular lesions were characterized histologically by normal or mildly spongiotic epidermis. Vesicular lesions were characterized by marked spongiosis and intraepidermal spongiotic vesicles containing eosinophils, or marked subepidermal edema occasionally leading to a dermoepidermal separation. Most of the lesions were characterized by superficial and mid dermal to deep perivascular and interstitial, and occasionally periadnexal, inflammatory-cell infiltrate consisting of mononuclear cells and eosinophils. The densities of the infiltrates varied and the inflammatory-cell infiltrate extended often into the fat lobules. Neutrophils and nuclear dust were found more frequently and abundantly in the IBLR lesions associated with MCL. Immunophenotyping, direct immunofluorescence (DIF) tests, and IgH gene rearrangement studies were performed in the lesions associated with MCL only. The majority of the infiltrating lymphocytes were CD3+, CD5+ and CD43+, more CD4+ than CD8+, and only a small minority was CD20+. The cells did not stain for bcl-1 protein and CD30, and with no evidence of clonality. The DIF test result was negative. The IBLR eruption associated with MCL resembles clinically and histologically IBLR associated with CLL. The eruption seems to be reactive rather than neoplastic, because there is no evidence of MCL involvement in the skin lesions.     

CD30 expression on CD1a+ and CD8+ cells in atopic dermatitis and correlation with disease severity

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental stimuli, resulting in increased infiltration of inflammatory cells, IgE production and enhanced expression of costimulatory molecules, cytokines and chemokines. CD30, a TNF receptor superfamily member, is a costimulatory molecule expressed on activated T and B cells. A positive correlation between soluble CD30 (sCD30) levels in patient serum and AD disease severity has been described previously. However, the relative frequencies and identities of cells expressing CD30 in AD patients and the relationship between the frequency of CD30 positive cells and serum sCD30 levels with disease severity remained unknown. To address these questions, immunofluorescence analysis of AD skin lesions representing different disease stages, was conducted. In addition to the CD4+ T cells, CD1a+ Langerhans cells and CD8+ T cells were found to express CD30 in AD lesions and the cell numbers correlated with disease severity. FACS analysis of AD patient blood samples revealed expression of CD30 on memory T-cells and a correlation with disease severity was identified. Finally, serum analysis of soluble mediators revealed positive correlations between sCD30, IgE, MDC, TARC and PARC levels with disease severity. Combined, our data provide correlative evidence that CD30+ cells, including Langerhans cells and CD8+ T-cells, may contribute to AD disease severity and that therapeutic strategies targeting CD30+ cells may provide benefit to AD patients.