Erythema multiforme‐like lesions in primary cutaneous aggressive cytotoxic epidermotropic CD8+ T‐cell lymphoma: A diagnostic and therapeutic challenge

Primary cutaneous aggressive cytotoxic epidermotropic CD8+ T‐cell lymphoma is an extremely rare, rapidly progressing, cutaneous lymphoma, with frequent systemic involvement and poor prognosis, that still represents a diagnostic and therapeutic challenge, especially in the early stage. Herein, we report a case of an elderly woman with a fulminant course, who at onset presented with clinical and pathological features mimicking erythema multiforme (EM) and treated with cyclosporine that led to rapid deterioration with fatal outcome 6 months after disease onset. Histopathology showed a lichenoid, epidermotropic and nodular, angiocentric, dermal and subcutaneous infiltrate of sF1, CD8+, CD45RA+ small to medium‐sized atypical lymphoid cells, which strongly expressed cytotoxic markers. Monoclonal T‐cell‐γ receptor was clonally rearranged and array‐CGH showed numerous chromosomal imbalances. This case evidences the clinical, pathological and therapeutic challenges involved in this tumor. The first biopsy showed an interface dermatitis‐like pattern, revealing the deceptive features that early cutaneous infiltrates of this aggressive lymphoma may have. A high suspicion for aggressive CTCL and a low threshold for repeat biopsies should be maintained when faced with rapidly progressing and/or ulcerative EM‐like lesions, especially if immunomodulatory therapy is being considered.     

Dermal infiltrates of cutaneous T‐cell lymphomas with epidermotropism but not other cutaneous lymphomas are abundant with langerin+ dendritic cells

Background The Langerhans cell (LC) hypothesis suggests that cutaneous T‐cell lymphomas (CTCL) are diseases of chronic T‐cell stimulation by LC‐mediated antigen presentation. Objective To investigate a broad panel of CTCL and cutaneous B‐cell lymphomas (CBCL) for the spatial association of langerin⁺ dendritic cells (DC) with T and B cells in the skin, respectively. Methods Fifty‐five specimens of CTCL and 10 of CBCL were double‐stained with monoclonal antibodies against langerin and CD3 or CD20, respectively, and evaluated by confocal laser scan microscopy. Results Dermal infiltrates in mycosis fungoides (n = 38), primary cutaneous CD4+ small/medium‐sized pleomorphic T‐cell lymphoma (n = 3) and primary cutaneous peripheral T‐cell lymphoma, unspecified (n = 3) were characterized by a high frequency of dermal langerin⁺ DCs. These cells were exclusively present in the malignant infiltrates. No direct co‐localization of CD3 and langerin could be resolved. Dermal langerin⁺ cells were detected only in one of six primary cutaneous anaplastic large cell lymphomas (C‐ALCL), characterized by epidermotropism. In other C‐ALCL cases (five of six), in lymphomatoid papulosis (n = 3), subcutaneous panniculitis‐like T‐cell lymphoma (n = 2), and all variants of CBCL no dermal langerin⁺ DCs could be found. Conclusions Langerin⁺ DCs are abundant in the dermal infiltrates of T‐cell lymphomas with specific involvement of the epidermis. This might indicate that immature LC and neoplastic T cells interact and gives rise to further studies to characterize the phenotype of the langerin⁺ cell population described here and its role in the pathology of CTCL.     

32例皮肤T细胞淋巴瘤外周血染色体分析

报告32例皮肤T细胞淋巴瘤(CTCL)患者外周血染色体分析。MF23例、非向表皮性T细胞琳巴瘤8例、Sézary综合征1例。其中26例外周血细胞有异常核型,受检细胞共320个,有异常核型为48个(15%)。结构畸变略多于数量畸变,前者主要表现为染色体缺失,后者主要表现为非整倍体。畸变率与CTCL之类型、病期及皮损范围无明显关联,但在MF肿瘤期畸变率显著升高,提示染色体崎变与病情、预后有一定关联。     

The role of αEβ7 integrin (CD103) and E-cadherin in epidermotropism in cutaneous T-cell lymphoma

Adhesion molecules such as integrins and cadherins are thought to play a critical role in T-cell migration and localization within the epidermis (epidermotropism). The purpose of this study was to correlate T-cell expression of the integrin GD103 and E-cadherin in cutaneous T-cell lymphoma (CTCL). Serial sections of skin biopsies from 22 patients with CTCL and 13 with benign reactive dermatitis were stained with antibodies to CD4, CD103, and E-cadherin by the avidin-biotin peroxidase technique. CD 103 was expressed on single epidermotropic CD4+ T-cells in 9/9 early stage (patch/plaque) CTCL and 6/10 reactive dermatitis biopsies. Less than 30% of dermal T-cells expressed CD103. All 4/4 late stage (tumor) CTCL were GD103–. Epidermal aggregates of CD4+T-cells (Pautrier's microabscesses) were CD103–. E-cadherin was expressed on epidermal keratinocytes and follicular and sweat gland epithelia but not on T-cells.
We conclude that CD 103 expression on cutaneous T-cells parallels the degree of epidermotropism exhibited in both neoplastic and inflammatory disorders of the skin. E-cadherin is not expressed on T-cells infiltrating the skin. Further investigation is necessary to further elucidate the interaction between CD103 and E-cadherin in facilitating trafficking of T-cells into the epidermis.     

Increased CCL18 expression in patients with cutaneous T‐cell lymphoma: association with disease severity and prognosis

Background CC chemokine ligand (CCL) 18 is expressed by monocytes and dendritic cells (DCs), and has potent chemotactic activity for T cells, B cells and DCs. CCL18 expression is up‐regulated in lesional skin of atopic dermatitis and bullous pemphigoid, suggesting its important roles in the development of these skin diseases. Objective To investigate roles of CCL18 in cutaneous T‐cell lymphoma (CTCL). Methods The CCL18 messenger RNA (mRNA) expression in CTCL skin (n = 21) and in normal skin (n = 7) was examined by quantitative RT‐PCR. CCL18 expression was also examined by immunohistochemistry. Serum CCL18 levels were measured in 38 patients with CTCL and 20 healthy controls by enzyme‐linked immunosorbent assay. We also analysed correlation between serum CCL18 levels and other clinical and laboratory data. Results The CTCL lesional skin contained higher levels of CCL18 mRNA than normal skin. CCL18 was expressed by dermal macrophages and DCs in CTCL skin. Serum CCL18 levels in patients with CTCL were significantly higher than those of healthy controls and correlated with types of skin lesions. They also significantly correlated with modified severity‐weighted assessment scores, serum sIL‐2R, LDH, IL‐4, IL‐10, IL‐31, CCL17 and CCL26 levels. Patients with high serum levels of CCL18 showed significantly poor prognosis compared with those with low CCL18 levels. Conclusion CCL18 mRNA is up‐regulated in CTCL lesional skin, and serum CCL18 levels are significantly increased and correlated with the severity of CTCL. These results suggest that CCL18 may be associated with the development of CTCL.     

Hematopoietic stem cell transplantation in advanced cutaneous T‐cell lymphoma

We retrospectively reviewed data pertaining to five patients with cutaneous T‐cell lymphoma (CTCL) who had received hematopoietic stem cell transplantation (HSCT) between 2004 and 2015 at Kurume University Hospital, along with their clinical data until March 2016. For patients with advanced CTCL eligible for HSCT, autologous HSCT was performed when they responded well to chemotherapy, and allogeneic HSCT was selected for patients with advanced mycosis fungoides (MF)/Sézary syndrome (SS) and CTCL other than MF/SS with poor chemosensitivity. Two patients (primary cutaneous anaplastic large cell lymphoma and primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T‐cell lymphoma) who responded well to chemotherapy received autologous HSCT: one patient was alive in partial remission and the other died due to therapy‐related acute myeloid leukemia without disease relapse. In the remaining three patients with MF or SS, allogeneic HSCT was performed. Although one patient with MF died due to disease progression, the remaining two patients were alive in complete remission. Although there were two deaths in this study, the outcomes were considered satisfactory.     

Cutaneous presentation of nasal/nasal type T/NK cell lymphoma: clinicopathological findings of four cases

Epstein–Barr virus (EBV)-associated T/natural killer (NK) cell lymphoma mainly shows nasal lesions, and has recently been shown to be associated with cutaneous T-cell lymphoma (CTCL). The detailed features of CTCL nasal metastasis have yet to be elucidated. We report clinicopathological findings for four cases of cutaneous T/NK cell lymphoma with metastasis to the nose. The four patients presented progressive involvement of nasal lesions of CTCL, an aggressive course and poor outcome. Their pathological and immunohistological findings were consistent with peripheral T/NK cell neoplasm and, in three of four cases, EBER-1 were apparently detected in lymphoma cells by in situ hybridization, and two of four cases were also positive for TIA-1. The polymerase chain reaction (PCR) results showed the identical band from the skin and nasal lesions of the two patients. We also reviewed the cases of similar clinical course and attempted to elucidate clinical, pathological, immunological and genotypic features. The 10 reported cutaneous T/NK cell lymphomas with nasal metastasis revealed a poor prognosis (nine of 10 died at 3–108 months). Six cases of nine showed a positive reaction to EBV, and six cases revealed T-cell receptor β or -γ rearrangement. These findings suggest that most cutaneous T/NK cell lymphoma with nasal metastasis are similar to nasal T-cell lymphoma associated with EBV infection. This type of cutaneous T/NK cell lymphoma likely to involve nasal lesions and skin cases seemed to have a poor prognosis.     

Serum soluble CD26 levels: diagnostic efficiency for atopic dermatitis,cutaneous T‐cell lymphoma and psoriasis in combination with serum thymus and activation‐regulated chemokine levels

Background CD26 is a multifunctional type II transmembrane glycoprotein, which also exists as a secreted isoform, soluble CD26 (sCD26). The CD26 expression on circulating T cells is decreased in some skin diseases such as cutaneous T‐cell lymphoma (CTCL) and psoriasis. It remains to be determined whether sCD26 can be used as a marker of skin diseases or not. Objective To investigate utility of sCD26 as a diagnostic marker of skin diseases in combination with thymus and activation‐regulated chemokine (TARC). Methods Serum sCD26 levels were measured using enzyme‐linked immunosorbent assay in 130 participants including 32 patients with atopic dermatitis (AD); 45 patients with CTCL; 26 patients with psoriasis; and 27 healthy controls. Results Serum sCD26 levels in patients with CTCL and psoriasis (162.1 ± 80.2 ng/mL and 125.4 ± 82.1 ng/mL respectively) were significantly lower than those of healthy controls (392.6 ± 198.7 ng/mL; P < 0.01 and 0.01 respectively). In patients with CTCL, serum sCD26 levels of patients with advanced stage were 135.0 ± 51.5 ng/mL and they were significantly lower than those with early stage (193.1 ± 96.0 ng/mL; P < 0.05). When we used serum sCD26 and TARC levels for diagnostic criteria, sensitivity, specificity, positive predictive value and negative predictive value for AD, CTCL and psoriasis were 65.2–73.7%, 81.4–97.6%, 65.2–94.4%, and 81.4–88.9% respectively. Conclusion Serum sCD26 levels, combined with serum TARC levels, are helpful in diagnosis of AD, CTCL and psoriasis.     

Cutaneous T‐cell lymphoma cells are sensitive to rapamycin

Please cite this paper as: Cutaneous T‐cell lymphoma cells are sensitive to rapamycin. Experimental Dermatology 2010; 19 : 800–805. Abstract: Cutaneous T‐cell lymphomas (CTCL) are characterised by clonal expansion of helper T lymphocytes that infiltrate the skin. Only a small number of cell lines exist to study cellular pathways leading to T‐cell transformation and to identify new targets for intervention. We wanted to investigate the inhibition of mTOR as a possible therapeutic target in CTCL. Primary cells of patients with Sézary syndrome (SS) and conventional CTCL cell lines were analysed. Constitutive activation of mTOR was found, and concomitantly, we could show that rapamycin, a specific inhibitor of mTOR, inhibits CTCL cell growth in vitro by induction of cell cycle arrest. Using a previously established animal model for CTCL, we additionally observed upon rapamycin treatment tumor growth inhibition in vivo. In summary, primary cells from patients with SS as well as CTCL cell lines allowed us to identify mTOR as an important target for intervention.     

皮肤T细胞淋巴瘤(附三例报告)

本文报告了3例皮肤T细胞淋巴瘤,经抗Leul,Leu2a,L,eu3a,Leu4及抗HLA-DR单克隆抗体检测,证明2例为向表皮性皮肤T细胞淋巴瘤,1例为非向表皮性皮肤T细胞淋巴瘤,并对其诊断与治疗加以讨论.     

Dohi memorial lecture. Cutaneous T cell lymphoma

Cutaneous T cell lymphoma (CTCL) is a generic classification of clonally-derived malignancies of phenotypic helper/inducer T cells with a propensity to infiltrate the skin, migrate into the epidermis, localize in T cell zones of lymphoid structures and spare the bone marrow. One clinical presentation has a tendency to evolve into another as subclones of progressively less mature and less epidermotropic neoplastic cells arise and overgrow the relatively more mature other subclones. In this manner, localized, scaling plaques of typical parapsoriasis develop into more infiltrated plaques of classical mycosis fungoides which are themselves predecessors of tumor or erythroderma stage CTCL. With loss of epidermotropism, systemic dissemination occurs: first microscopically with blood involvement and seeding of internal organs and finally with visceral tumor formation. The relationship between CTCL and adult T cell lymphoma/leukemia is unclear because of tremendous overlap in the clinical and immunologic findings and because a fraction of patients with classical CTCL have low titers of anti-HTLV-1 antibodies. It is important to distinguish the skin-limited and systemic phases of CTCL in order to select appropriate treatments. New diagnostic techniques which are quite helpful include immunotyping with monoclonal antibodies, karyotype analysis and T cell receptor studies. Photopheresis, a very promising new therapeutic approach for the management of patients with systemically disseminated disease, and a suggested pathogenetic scheme are discussed.     

FULMINANT HEAD AND NECK CONGESTION IN ADVANCED CUTANEOUS T CELL LYMPHOMA: A POOR PROGNOSTIC INDICATOR

Background. Clinical factors associated with a poor prognosis in patients with cutaneous T cell lymphoma (CTCL) include the extent and type of skin involvement and the presence and extent of lymphadenopathy. Materials. We report retrospectively the clinical course and survival time of four patients with advanced CTCL after the development of fulminant head and neck congestion. Methods. All four patients presented with marked erythema and edema of the head and neck with marked cervical adenopathy. Treatment with multidrug chemotherapy and radiation induced only brief remissions. The clinical picture was felt to be due to extensive tumor infiltration of the skin as well as lymphatic compression due to cervical adenopathy rather than venous compression at the level of the mediastinum. Survival from onset of this fulminant head and neck congestion was 1–5 months. Conclusion. Development of this fulminant head and neck congestion in patients with advanced CTCL heralds a progressively deteriorating clinical course with a poor prognosis.     

Analyses of T-cell receptor β–chain genes by Southern blotting in known and suspected cutaneous T–cell lymphoma. A study of 67 samples from 32 patients

In this study we have investigated the configuration of the T–cell receptor (TCR) β–chain genes in benign cutaneous conditions (n= 5) and known (n= 22) or suspected (n= 5) cutaneous T–cell lymphoma (CTCL). Sequential biopsies from skin, lymph node, blood and/or bone marrow were available in 12 cases of the 22 confirmed CTCL, and a total of 67 samples were analysed. In the benign conditions, clonal rearrangements of the TCR β–chain genes were seen in neither skin nor blood samples. In contrast, in CTCL clonal rearrangements were detected in all skin samples from plaque or tumour lesions of mycosis fungoides. Clonal TCR rearrangements were also present in skin and blood samples from two patients with Sèzary's syndrome, and in skin and blood samples from three of five patients with clinically suspected CTCL. In 10 patients with large cell lymphomas, clonal rearrangements were detected in skin samples in half of the cases. In the remaining patients, clonal TCR rearrangements could not be detected in the skin, but only in the blood and/or bone marrow specimens. Results from the analyses of sequential biopsies showed identical patterns of rearrangement in 11 patients. In the remaining patient, the pattern of rearrangement differed between skin and lymph node. These data confirm and extend previous reports and indicate that analysis of TCR β–chain genes by Southern blotting forms a useful supplement to other methods for the diagnosis of known and suspected CTCL. They also emphasize the importance of studying not only skin, but also extracutaneous sites.     

Malignant T cells in cutaneous T‐cell lymphoma lesions contain decreased levels of the antiapoptotic protein Ku70

Background Malignant T cells in primary cutaneous T‐cell lymphoma (CTCL) are genetically unstable and exhibit prolonged lifespans potentially explained by dysregulation of apoptosis, yet are responsive to apoptosis‐inducing therapies. The heterodimeric protein Ku70/80 is known to play a role in DNA repair (Ku70 and Ku80) and inhibition of apoptosis (Ku70 only). Objectives To investigate the expression of Ku70/80 in CD3+ T cells derived from skin and blood in patients with CTCL and normal samples, as well as benign dermatoses. Methods Normal (n = 10), CTCL (n = 9) and benign dermatoses (n = 13) skin samples were stained for confocal imaging of Ku70/80 and CD3 and analysed using imaging software. Circulating CD4+ T cells in normal and CTCL peripheral blood were analysed by flow cytometry and Western blot for Ku70/80 expression (n = 6). Results Ku70 and Ku80 were significantly diminished in T cells of CTCL lesions relative to T cells of control skin. Decreased T‐cell Ku70 expression was not a feature of the benign dermatoses psoriasis and contact dermatitis, suggesting that loss of Ku70/80 in CTCL is not simply the result of cutaneous inflammation. Reduced Ku70 was also noted in circulating CD4+ T cells in patients with CTCL with peripheral blood involvement. Conclusions Deficient expression or lack of Ku70/80 may result in genomic instability and play a role in tumorigenesis, as well as account for the increased susceptibility of malignant T cells to apoptosis‐inducing treatment modalities in the setting of intrinsic resistance to apoptosis.     

Treatment of cutaneous T cell lymphoma with intermediate doses of interferon alpha 2a

In this study we treated 6 patients with epidermotropic cutaneous T cell lymphoma (CTCL) with intermediate doses of recombinant alpha 2a interferon (18-100 x 10(6) IU/week) for 2-6 months. One patient experienced complete clinical remission in spite of a persistent dense lymphocytic skin infiltrate. One patient was markedly improved and 2 patients were moderately improved. The clinical condition of the 2 remaining patients was unchanged by interferon treatment. In all cases lesions relapsed a few weeks after treatment was discontinued. This study shows that interferon can be used to treat epidermotropic CTCL. However, a 2- to 6-month treatment using moderate doses did not lead to the high percentage of remission previously reported by others with high doses of recombinant alpha 2a interferon, for longer periods. This result suggests that interferon should be used at high doses and/or for long time periods for clinical improvement of CTCL patients.     

Epidermotropic secondary cutaneous involvement by relapsed angioimmunoblastic T‐cell lymphoma mimicking mycosis fungoides: a case report

Angioimmunoblastic T‐cell lymphoma (AITL) is frequently associated with skin lesions, but epidermotropic cutaneous involvement has never been described. A 37‐year‐old man presented with erythematous and pruriginous plaques, clinically suggestive of mycosis fungoides, distributed all over the body, 3 weeks after the last line of a polychemotherapy, given for an AITL diagnosed 1 year earlier on a lymph node biopsy. Skin biopsy showed an epidermotropic CD4⁺ T‐cell lymphoma, so that a diagnosis of mycosis fungoides was first proposed. Further investigations showed that atypical lymphocytes strongly expressed CD10 and markers of follicular helper T cells (T_FH) including PD1, BCL‐6 and CXCL13. The diagnosis of an unusual epidermotropic cutaneous localization of the AITL was finally made, supported by the presence of the same T‐cell clone in the initial lymph node biopsy and the skin. We therefore recommend performing markers of T_FH cells in patients with unusual epidermotropic cutaneous T‐cell lymphomas, particularly if they have any clinical features suggestive of AITL.     

Cutaneous histopathology of Sézary syndrome: a study of 41 cases with a proven circulating T-cell clone

Sézary syndrome is an uncommon variant of cutaneous T-cell lymphoma (CTCL) characterized by erythroderma, pruritus, adenopathy, and circulating atypical T-lymphocytes with cerebriform nuclei. The definition of Sézary syndrome can be further refined by including only patients with a circulating peripheral blood population of clonal T-cells. We have evaluated 79 skin biopsies from such a group of 41 erythrodermic patients with circulating Sézary cells and a clonal population of T-cells detected by T-cell receptor-figene rearrangement on Southern analysis of peripheral blood mononuclear cells. Histopathologic features consistent with chronic dermatitis were observed in 26/79 (33%) skin biopsy specimens, emphasizing that a non-specific histologic appearance is common. Evidence of CTCL was lacking in 11/41 patients on biopsy of their erythrodermic skin. The survival of these patients was not significantly different from 30/41 patients in whom skin biopsies revealed changes diagnostic of CTCL, such as a dermal lymphocytic band with atypical lymphocytes (18/79, 23%) or a mycosis fungoides-like infiltrate (30/79, 38%). This study confirms that non-specific cutaneous hlstopathologic findings are common in Sézary syndrome, even when a circulating T-cell clone is present. This stresses the need for peripheral blood genetic analysis and for multiple or repeat skin biopsies in erythrodermic patients when there is high clinical suspicion of CTCL.