Cutaneous EBV‐positive γδ T‐cell lymphoma vs. extranodal NK/T‐cell lymphoma: a case report and literature review

Primary cutaneous γδ T‐cell lymphoma and extranodal natural killer (NK)/T‐cell lymphoma (ENKTL), nasal type are two distinct lymphoma entities in the World Health Organization (WHO) classification. We report the case of an aggressive cutaneous lymphoma of γδ T‐cell origin showing overlapping features of both lymphomas. A 78‐year‐old female presented with confluent erythematous plaques with ulcerations over her right thigh. Microscopically, section of the skin showed a diffuse dermal and subcutaneous lymphocytic infiltration with tumor necrosis and angioinvasion. The medium‐ to large‐sized tumor cells expressed CD3, CD8, cytotoxic molecules and T‐cell receptor (TCR)‐γ but not CD4, CD20, CD30, CD56 or βF1. In situ hybridization for Epstein‐Barr virus‐encoded mRNA (EBER) was diffusely positive. Polymerase chain reaction‐based clonality assay showed a clonal TCR‐γ chain gene rearrangement. The features compatible with γδ T‐cell lymphoma include dermal and subcutaneous involvements, cytotoxic phenotype, expression of TCR‐γ, as well as an aggressive course. On the other hand, the diffuse EBER positivity, angioinvasion, tumor necrosis and cytotoxic phenotype may also fit in the diagnosis of an ENKTL of T‐cell lineage. We review the literature on EBER‐positive γδ T‐cell lymphoma and discuss the diagnostic dilemma using the current WHO classification system.     

Pagetoid reticulosis tumor cells with double expression of TCRγδ and TCRαβ: an off‐target phenomenon or genuine expression?

Pagetoid reticulosis (PR) is a low‐grade primary cutaneous T‐cell lymphoma showing localized patches or plaques with an intrapeidermal proliferation of neoplastic T‐cells with heterogeneous immunophenotype. We describe a 73‐year‐old woman with a 8‐year history of gluteal lesions of PR, whom large blast cells were CD4/CD8 double negative T‐cells with an activated cytotoxic profile. The case was investigated using a broad panel of monoclonal antibodies including TCRγM1, a new available antibody that recognizes the γ chain subunit of the T‐cell receptor (TCR) in formalin‐fixed paraffin‐embedded tissue. Large blast cells were simultaneously positive for TCRαβ and TCRγδ with an activated cytotoxic phenotype. It is worldwide accepted the mutual exclusive expression of TCRαβ and TCRγδ but six different studies, dealing with TCRγδ expression in various types of extra‐nodal lymphomas, reported cases whom tumor cells expressed simultaneously TCRαβ and TCRγδ. Our data and those of similar reports, suggest the possibility of existence of a subset of extra‐nodal T‐cell lymphomas showing simultaneous expression by tumor cells of TCRγδ and TCRαβ with an immunoprofile consistent with an origin from TCRγδ+ T lymphocytes. This unusual subset has preferential, but not exclusive, skin localization and variable epidermotropism.     

Expression of T-cell receptor-γδ in normal human skin, inflammatory dermatoses and mycosis fungoides

Background: T cells expressing the γδ T‐cell receptor (TCR) (γδ T cells) are found in normal epithelial tissues such as the skin. However, the proportions of γδ T cells that may be observed in commonly encountered cutaneous diseases with a prominent lymphocytic infiltrate have not been elucidated. Methods: Our pathology database was searched for cases of mycosis fungoides, erythema multiforme, graft‐versus‐host disease, lichen planus, lupus panniculitis and spongiotic dermatitis. Immunostaining for CD3, βF1 and the TCR γ chain was performed on formalin‐fixed paraffin‐embedded specimens retrieved from these cases to determine the normal range of γδ T cells in these diseases. Results: In 100 of the 101 cases studied (99.0%), γδ T cells accounted for less than 10% of the T‐cell infiltrate. Furthermore, γδ T cells were essentially absent in 74 cases (73.3%). Conclusions: These results suggest that γδ T cells very rarely account for more than 10% of the lymphocytic infiltrate in common inflammatory or infiltrative processes of the skin. Any case of suspected mycosis fungoides or interface dermatitis that possesses more than 10% γδ T cells should raise consideration for further investigation. Hocker TL, Wada DA, el‐Azhary R, Gibson LE. Expression of T‐cell receptor‐γδ in normal human skin, dermatitis and mycosis fungoides.     

Cutaneous gamma‐delta T‐cell lymphoma with central nervous system involvement: report of a rarity with review of literature

Primary cutaneous gamma‐delta (γδ) T‐cell lymphoma is an extremely rare and aggressive variant of cutaneous lymphoma. Central nervous system (CNS) involvement, a rare finding, and hemophagocytic syndrome are two complications that are commonly fatal. We describe a 58‐year‐old patient presenting with skin plaque who subsequently developed subcutaneous nodules diagnosed as cutaneous T‐cell lymphoma (CTCL), clinically resembling ‘mycosis fungoides’. The patient was treated with repeat topical radiation therapies but had frequent relapsed disease. Approximately 4.5 years after, the patient presented with third and sixth cranial nerve palsies and was found to have CNS involvement by lymphoma per positron emission tomography—computed tomography (PET/CT) and a biopsy of foramen magnum. Phenotypically, the tumor cells were CD3(+)/CD4(?)/CD8(?)/CD7(+)/CD5(?)/CD30(?)/TCRαβ(?)/TCRγδ(+). Despite aggressive strategies taken, the patient expired 3 months after the diagnosis of the CNS lesion. A retrospective investigation proved the original CTCL to be γδ T‐cell in origin, confirming an indolent cutaneous γδ T‐cell lymphoma with eventual CNS manifestation. We present this case to draw attention to the entity, which can occasionally present with misleading histopathologic and clinical features. In addition, we provide a review of the literature to summarize clinical and pathologic features of the reported similar cases.     

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.     

Epstein–Barr virus‐associated T‐cell lymphoproliferative disorder affecting skin and lung in an elderly patient

A 70‐year‐old man presented with papular skin lesions and was diagnosed with Epstein–Barr virus (EBV)‐associated T‐cell lymphoproliferative disorder (T‐LPD). The patient showed infiltration of a large number of EBV‐encoded RNA‐positive T cells in the skin and lung, presence of EBV load in the peripheral blood, and expansion of clonal EBV‐infected γδ T cells and CD8⁺ T cells in the blood and skin, as assessed by EBV‐terminal repeat Southern blot, T‐cell receptor polymerase chain reaction and flow cytometric analyses. In the Japanese or East Asian fatal cases of EBV‐associated T/natural killer (NK)‐LPD, there are two peaks in age at death, approximately 20 years and 60 years. The former age group is associated with chronic active EBV infection (CAEBV), and the latter group typically suffers from extranodal NK/T‐cell lymphoma. Our case is characterized not only by the unique skin and lung manifestations but also the late onset age of the disease, indicating that the skin manifestation of CAEBV can be seen even in elderly patients.     

Characterization of skin lesions induced by skin‐tropic α‐ and β‐papillomaviruses in a patient with epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is a rare, lifelong, autosomal recessive skin disease associated with an unusual susceptibility to infections with ubiquitous β‐human papillomaviruses (β‐HPVs), and in some cases also skin‐tropic α genotypes. In this case report, HPV infection patterns were correlated with pathology and clinical manifestations of skin lesions from a patient with EV, without loss‐of‐function mutations in the EVER genes. HPV infection was investigated by both polymerase chain reaction (PCR) and laser capture microdissection (LCM) PCR, alongside immunofluorescence for the viral proteins E4 and L1. Analysis of eyebrow hair bulbs revealed multiple β‐genus HPV infections, including HPV20 and HPV24, which were consistently found in all 11 skin lesions on the patient. Six lesions were also positive for the skin tropic α‐genotype, HPV27. Clear‐cut differences between two wart‐like lesions, one caused by a skin‐tropic α‐genotype and the other by β‐genotypes (as detected by LCM PCR) are shown, including the high cellular proliferation rate in β‐HPV‐induced lesions. Widespread expression of the early protein E4 was also evident in skin lesions positive for HPV20 by LCM PCR in both tumours and nearby intraepidermal proliferative areas. L1 expression was restricted to areas of intraepidermal proliferation showing productive infection. The patient's inability to control HPV infections is conclusive to the uncontrolled replication of few genotypes from both α and β genera, which cause proliferative lesions with clear‐cut clinical and histological features.     

Characterization of skin blister fluids from children with Epstein–Barr virus‐associated lymphoproliferative disease

Epstein–Barr virus (EBV)‐associated T‐ or natural killer (NK)‐cell lymphoproliferative disease (LPD) is a heterogeneous group of disorders characterized by chronic proliferation of EBV‐infected lymphocytes. Patients may present with severe skin manifestations, including hypersensitivity to mosquito bites (HMB) and hydroa vacciniforme (HV)‐like eruption, which are characterized by blister formation and necrotic ulceration. Skin biopsy specimens show inflammatory reactions comprising EBV‐infected lymphocytes. However, blister fluids have not been fully assessed in patients with this disease. Blister fluids were collected from three patients with EBV‐associated LPD: two with HMB and one with HV. Immunophenotyping of blister lymphocytes and measurement of tumor necrosis factor (TNF)‐α in blister fluids were performed. The patients with HMB and HV exhibited markedly increased percentages of NK and γδ T cells, respectively, in both peripheral blood and blister fluids. These NK and γδ T cells strongly expressed the activation marker human leukocyte antigen‐DR and were considered to be cellular targets of EBV infections. TNF‐α was highly elevated in all blister fluids. Severe local skin reactions of EBV‐associated LPD may be associated with infiltrating EBV‐infected lymphocytes and a high TNF‐α concentration in blister fluids.     

A case of vancomycin‐associated linear IgA bullous dermatosis and IgA antibodies to the α3 subunit of laminin‐332

Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disease, which is defined by the histopathological finding of subepidermal vesicles with neutrophilic infiltration and linear IgA deposits in the basement membrane zone, revealed by immunofluorescence study. We present a case of LABD in which vancomycin (VCM) administration triggered LABD, and immunoblot analysis showed IgA antibodies reactive to the 145‐ and 165‐kDa α3 subunits of laminin‐332. This is the first report of VCM‐associated LABD in which the target antigen was laminin‐332. In the present case, we were compelled to continue administration of VCM along with systemic steroids, which eventually led to the attenuation of the symptoms, normalization of the serum IgA level, and negative results on both indirect immunofluorescence of 1 mol L^?1 NaCl‐split skin and immunoblot analysis.     

Atypical Molluscum Contagiosum Accompanied by CD30‐Positive Lymphoid Infiltrates

Abstract: Atypical presentations of molluscum contagiosum require histophathologic examination and may show pleomorphic lymphocytic infiltrates of a reactive nature, mimicking cutaneous lymphoproliferative diseases. Serial sections of specimens or polymerase chain reactions to show T‐cell receptor clonality may be helpful for differential diagnosis. We report a case of atypical molluscum contagiosum accompanied by atypical lymphocytic infiltration showing CD30 positivity.     

Papuloerythroderma‐like cutaneous involvement of a CD62L− subclone of T‐cell prolymphocytic leukemia

We report the case of an 88‐year‐old Japanese man with erythrodermic involvement of T‐cell prolymphocytic leukemia (T‐PLL). He had a history of pharyngeal diffuse large B‐cell lymphoma successfully treated with polychemotherapy including cyclophosphamide and epirubicin, 6 years before the current illness. He presented with numerous reddish, coalescing, flat‐topped papules on the trunk and extremities, sparing the skin folds of the abdomen, the features of which mimicked those of papuloerythroderma. Immunohistochemistry showed perivascular and epidermotropic infiltration of CD3⁺ CD4⁺ T cells in the cutaneous lesion. However, flow cytometric analysis revealed that the skin infiltrating T cells were negative for surface CD4, and that CD3⁺ CD4^? CD8^? cells made up 92% of the T‐cell fraction of peripheral blood. The circulating atypical T cells had a round or oval nucleus and prominent nucleoli, and the deletion of chromosomes 6q, 13 and 17. These cytological profiles were consistent with those of T‐PLL and distinct from those of Sézary cells. The same T‐cell clone was detected in the cutaneous lesion and peripheral blood, but the expression of CD62L was absent in the skin infiltrates and present in the circulating cells. No specific mutation was detected in STAT3 or STAT5B. Although low‐dose oral etoposide had a beneficial effect on the skin rash, a fatal crisis of marked leukocytosis (169 × 10³/μL) occurred 19 months after the illness onset. CD62L‐leukemic cells of T‐PLL may infiltrate the skin to form papuloerythroderma‐like cutaneous lesions.     

Effect of gammadelta T cell supernatant on human skin fibroblast proliferation and collagen production--possible role of transforming growth factor-beta and basic fibroblast growth factor

Background Perivascular mononuclear cell infiltration, vascular injury and diffuse interstitial fibrosis has been shown in systemic sclerosis (SSc). Objective To study a role of cellular immune mechanism inducing fibroblast proliferation and collagen synthesis. Methods The interaction of γδ T‐cell receptor bearing lymphocyte supernatant to human fibroblast proliferation and collagen synthesis was studied. Results The fibroblasts added with γδ T cell supernatant showed increased proliferation compared with those without it and that added with αβ supernatant. The endothelial cells added with γδ T cell supernatants, however, showed significantly decreased proliferation compared with those without it and that added with αβ T cell supernatant. The fibroblasts added with endothelial cell supernatant showed increased proliferation compared with those without it. A doubling of collagen synthesis was observed when human skin fibroblasts were maintained in all of the supernatant. The collagen synthesis was inhibited by antitransforming growth factor‐β antibody and antibasic fibroblast growth factor antibody. Conclusion γδ T–cell‐receptor bearing lymphocyte has proliferative and collagen synthesis activity to human skin fibroblasts, but suppressive to endothelial cells.     

Oral administration of β‐carotene or lycopene prevents atopic dermatitis‐like dermatitis in HR‐1 mice

Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease. Certain populations of patients are resistant to standard therapies with topical steroids and/or calcineurin inhibitors, and require systemic medication, such as immunosuppressants. Recently, several reports have shed light on the anti‐allergic effects of carotenoids. Therefore, we investigated the effect of p.o. administration of β‐carotene or lycopene on AD‐like symptoms of HR‐1 hairless mice fed with a low zinc/magnesium diet. Mice were divided into four groups: (i) fed with a standard diet (Co group); (ii) low zinc/magnesium diet (HR group); (iii) low zinc/magnesium and β‐carotene diet (HR‐C group); and (iv) low zinc/magnesium and lycopene diet (HR‐L group). They were then fed these diets for 8 weeks. Severities of dermatitis were assessed by their appearance, and histopathological and hematological observations. Mice in the HR group developed AD‐like dermatitis both clinically and histologically. HR‐C and HR‐L group mice also developed xerosis and wrinkle‐like skin changes, but they were milder than those of HR group mice. Histological analysis revealed that epidermis thickening and inflammatory cell infiltration in the skin of the HR‐C and HR‐L groups were both statistically less than those of the HR group. The concentration of thymus and activation regulated chemokine in the skin of the HR‐L group and the concentration of CCL27 in the skin of the HR‐C group were significantly lower than those of the HR group, respectively. In conclusion, p.o. administration of β‐carotene or lycopene prevents AD‐like symptoms in association with a suppression of T‐helper 2 chemokines in a murine model. Ingestion of carotenoids may be beneficial for patients with AD.     

Lymphomatoid papulosis with associated cerebellar lesion of similar histology and T‐cell clonality

A 9‐year old boy presented with a 4‐month history of a truncal monomorphic eruption with self‐healing papulonecrotic lesions. A skin biopsy revealed a dermal infiltrate of CD4, CD8 and CD30‐positive T‐cells, consistent with lymphomatoid papulosis. He responded to 4 months of treatment with narrowband UVB phototherapy (311 nm) which stabilised his disease. Five years later he presented with an acute onset of nausea and vomiting, dizziness, headache and ataxia. Magnetic resonance imaging of the brain revealed a lesion in the cerebellum and stereotactic resection was undertaken. Histology showed CD4, CD8 and CD30‐positive T‐cells similar to his skin lesions, with a monoclonal T‐cell receptor (TCR) gamma gene rearrangement. Subsequent analysis of the skin detected a monoclonal band of the same size as the cerebellar lesion. Treatment was initiated for a primary central nervous system (CNS) lymphoma but ceased after one course of high‐dose methotrexate. Opinion on the pathology was divided as to whether the cerebellar lesion represented an atypical reactive T‐cell lymphoproliferative response or a T‐cell lymphoma. On follow‐up 2 years later, the patient remains clinically and radiologically clear, making CNS lymphoma unlikely.     

Role of epidermal γδ T‐cell‐derived interleukin 13 in the skin‐whitening effect of Ginsenoside F1

Ginsenoside F1 (GF1) is a metabolite of ginsenoside Rg1. Although GF1 has several benefits for skin physiology, the effect of GF1 on skin pigmentation has not been reported. We found that a cream containing 0.1% GF1 showed a significant whitening effect on artificially tanned human skin after 8 weeks of application. However, GF1 did not inhibit mRNA expression of tyrosinase or dopachrome tautomerase (DCT) in normal human epidermal melanocytes (NHEMs) or cocultured NHEMs/normal human epidermal keratinocytes. Interestingly, GF1 enhanced production of interleukin 13 (IL‐13) from human epidermal γδ T cells. IL‐13 significantly reduced the mRNA expression and protein amount of both tyrosinase and DCT and reduced melanin synthesis activities in NHEMs, resulting in visible brightening of NHEM pellet. These results suggest that enhancement of IL‐13 production by GF1 from epidermal γδ T cells might play a role in the skin‐whitening effect of GF1 via the suppression of tyrosinase and DCT.     

Role of IL‐10 and TGF‐β in melanoma

IL‐10 and TGF‐β are immunosuppressive cytokines expressed in tumors including melanoma and, therefore, deemed major cause for failing antitumor immune responses. Re‐evaluating their role, we compared their expression by quantitative RT‐PCR in melanoma and skin of healthy individuals, tested their induction in dendritic cells and T cells co‐cultured with tumor cells, and their effects on the immune cells. Both cytokines as well as their receptors were expressed in melanoma at significantly lower levels than in healthy skin. Consequently, the expressions of IL‐10‐responsive SOCS‐3 and TGF‐β‐responsive Smad‐7 were low in tumors but high in healthy skin. T cells co‐cultured with tumor cells developed an anergic state without increased IL‐10 or TGF‐β expression. In vitro tumor‐induced immature dendritic cells produced high IL‐10 levels and less efficiently induced T‐cell proliferation. Nonetheless, they could be induced to mature, and blocking IL‐10 did not alter the capacity of the resulting mature dendritic cells to stimulate T cells. Mature dendritic cells co‐cultured with tumor cells produced increased IL‐10 but decreased TGF‐β and more efficiently induced T‐cell proliferation. The lack of correlation of IL‐10 and TGF‐β with immune deficits in situ and in vitro suggests re‐evaluating their roles in cancer.     

Cutaneous lymphocyte antigen expression in benign and neoplastic cutaneous B- and T-cell lymphoid infiltrates

Background: Cutaneous lymphocyte‐associated antigen (CLA) is expressed in resident cutaneous T lymphocytes, high endothelial venules, peripheral monocytes, granulocytes and a small percentage of memory B cells. It has been postulated to be an important factor in homing of lymphocytes to the skin because of its function as a ligand for E‐selectin expressed on cutaneous endothelial cells. Design: We investigated the expression of CLA using the HECA‐452 antibody on paraffin‐embedded, formalin‐fixed tissue in a variety of reactive, neoplastic and preneoplastic cutaneous lymphoid infiltrates of T‐ and B‐cell derivation. Results: CLA was expressed at high levels in various types of inflammatory dermatoses with the exception of lupus erythematosus. High levels of CLA expression were seen in epidermotropic T‐cell dyscrasias and epidermotropic T‐cell lymphomas including mycosis fungoides (MF) and adult T‐cell leukemia/lymphoma (ATCLL). A loss of CLA in tumors normally positive for CLA was a feature of disease progression best exemplified by tumor‐stage MF and acute ATCLL. There was a lack of CLA expression in those lymphocytic infiltrates manifesting subcutaneous localization including lupus profundus, panniculitis‐like T‐cell lymphoma and atypical lymphocytic lobular panniculitis. CLA expression was not only observed in primary cutaneous anaplastic large cell lymphoma but also seen in cases of nodal anaplastic large cell lymphoma secondarily involving the skin and was negative in cases of nodal anaplastic large cell lymphoma without any established skin involvement. An oligodot pattern defined a novel reaction pattern in those aggressive systemic dyscrasias with a proclivity to involve the skin. CLA was negative in the majority of B‐cell lymphomas. Conclusions: CLA plays a role in the pattern of T‐cell lymphocyte migration in the skin and subcutis in both reactive and neoplastic states. An alteration in the expression of this marker, whether it is in the context of the acquisition of expression in a cell that is normally CLA negative or its loss of expression, may define a key event in determining cutaneous and extracutaneous hematopoietic cell distribution.     

Evolution of granuloma annulare to mid‐dermal elastolysis: report of a case and review of the literature

A 55‐year‐old healthy Caucasian female, on no medication, was seen by a dermatologist because of a patchy, slightly indurated and violaceous eruption involving her neck and trunk. The clinical impression was of granuloma annulare (GA). Over a period of several months the violaceous lesions became atrophic with loss of colour and eventual wrinkling of lesional skin. Sequential skin biopsies were obtained, which revealed a spectrum of changes. Those from early violaceous lesional zones displayed perivascular lymphocytic infiltrates and interstitial granulomatous inflammation, characteristic of interstitial GA. Samples from atrophic lesional areas appeared normal on routine sections but an Orcein–Giemsa (OG) stain, prompted by the clinical history of atrophy, revealed absence of elastic fibers in the mid‐reticular dermis. The combined clinicopathologic findings pointed to development of mid‐dermal elastolysis (MDE) at involutional sites of GA. Owing to consideration of a cutaneous T‐cell lymphoma in the differential diagnosis, genotyping in search of T‐cell monoclonality was performed and yielded a negative result. Our case supports the existing but scant evidence in the literature that the rare, enigmatic condition termed MDE is an end‐result of inflammatory destruction of dermal elastic fibers. GA is one form of dermatitis capable of culminating in this entity, but others have also been implicated.     

CD4+ T cells producing interleukin (IL)‐17, IL‐22 and interferon‐γ are major effector T cells in nickel allergy

Background It has been suggested that interleukin (IL)‐17 and IL‐22 play important roles in the elicitation of human allergic contact dermatitis; however, the frequencies of T cell subtypes producing IL‐17 and IL‐22 in human allergic contact dermatitis are unknown. Objectives To determine the frequencies of CD4⁺, CD8⁺ and γδ T cells producing IL‐17, IL‐22 and interferon (IFN)‐γ in the blood and skin from nickel‐allergic patients. Patients/materials/methods Blood samples were collected from 14 patients and 17 controls, and analysed by flow cytometry. Biopsies were taken from 5 patients and 6 controls, and analysed by immunohistochemistry and flow cytometry of skin lymphocytes. Results We found an increased frequency of γδ T cells in the blood, but no differences in the distribution of cytokine‐producing CLA⁺ T cell subtypes in nickel‐allergic patients as compared with controls. In nickel‐allergic patients, there was massive cellular infiltration dominated by CD4⁺ T cells producing IL‐17, IL‐22 and IFN‐γ in nickel‐challenged skin but not in vehicle‐challenged skin. Conclusion CD4⁺ T cells producing IL‐17, IL‐22 and IFN‐γ are important effector cells in the eczematous reactions of nickel‐induced allergic contact dermatitis in humans.