皮肤T细胞淋巴瘤的治疗选择

皮肤T细胞淋巴瘤是一种少见的淋巴细胞增生性疾病,依据疾病的分类及分期不同,治疗选择有很大差异性。多数的皮肤T细胞淋巴瘤病程进展缓慢,诸如早期的蕈样肉芽肿和淋巴瘤样丘疹病,只需要选择皮肤局部治疗的方案。侵袭性或顽固性如Sézary综合征、复发性CTCL等,则需系统治疗,包括化疗。本文对国内现有药物及最新治疗方法进行综述。     

Cutaneous T cell lymphoma: update of treatment

The state-of-the art therapy of cutaneous T cell lymphoma (CTCL) is reviewed. Commonly used treatments for early-stage (patch/plaque) mycosis fungoides (MF) include topical corticosteroids, mechlorethamine, carmustine, ultraviolet light B and PUVA. Total skin electron beam (TSEB) therapy is indicated for widespread infiltrated plaque and tumor stage disease. Low-dose methotrexate is often useful for resistant patch/plaque MF and erythrodermic CTCL. Interferon alpha (IFN-alpha) is indicated for methotrexate failures and recurrent tumors following TSEB therapy. Photopheresis may be helpful for early-stage erythrodermic CTCL but is very costly. Retinoids may be of value for early and moderately advanced CTCL particularly in combination with other agents such as IFN-alpha and PUVA. Systemic disease usually requires combination chemotherapy such as that used for non-Hodgkin's lymphoma; however, responses are usually short lived.     

Follicular cutaneous T-cell lymphoma: a clinicopathological study of nine cases

Nine patients with follicular cutaneous T-cell lymphoma (CTCL), a recently described variant of lymphoma, are presented. On the basis of clinical manifestations and disease course, three groups of patients were distinguished: (i) two patients with follicular CTCL not associated with conventional lesions of mycosis fungoides (MF) and showing no evolution towards MF in follow-up periods of 3 and 6 years; (ii) one patient with follicular CTCL that evolved into conventional MF within 3 years; (iii) six patients showing conventional MF lesions either before or concurrently with the follicular lesions and thus representing follicular CTCL of the true MF type. The follicular lesions included hair-devoid patches or plaques with spiky hyperkeratotic papules (four patients), keratosis pilaris-like lesions (four), comedo-like lesions (four), follicular papules with alopecia (three) and milia-like lesions (three). Histopathological examination showed perifollicular and intrafollicular lymphocytes, without mucin deposition and with minimal or no involvement of the overlying epidermis. Significant syringotropism was also observed in three cases. Immunohistochemical analysis showed the predominance of CD4 + T cells, deletion of CD7 in some cases, Ki-67 + lymphocytes confined mainly to the follicular epithelium, and expression of keratinocyte intercellular adhesion molecule-1 exclusively in the hair follicle. T-cell receptor gamma gene rearrangement was positive in the one case studied from each group. Different treatment modalities were employed, the most commonly used as monotherapy being phototherapy: psoralen ultraviolet A in four patients, two of whom showed a complete clinical and histopathological remission, and ultraviolet B in one patient, who showed a complete remission (both clinical and histopathological). This study indicates that follicular CTCL is more common than reflected in the literature, has heterogeneous clinical manifestations, and is either an expression of or closely related to MF. The influence of the follicular involvement on the therapeutic response remains to be clarified. However, our therapeutic experience clearly suggests that some patients with follicular CTCL can benefit from phototherapy.     

CD45RA+ immunophenotype in mycosis fungoides: clinical, histological and immunophenotypical features in 22 patients

BACKGROUND: Mycosis fungoides (MF) is a cutaneous T-cell lymphoma (CTCL) usually characterized by a T-helper memory phenotype (CD3+, CD4+, CD8-, CD45R0+). Aberrant phenotypes are more commonly seen in the tumor stages. CD45RA expression has so far been documented in only a few cases of CD8+ or TCR gamma delta+ CTCL and in some pagetoid reticulosis cases. METHODS: Two hundred and fifteen MF patients were immunophenotyped in our laboratory between January 1992 and June 2000 and 22 cases of CD45RA+ MF (8.7%) were identified by immunohistochemical analysis. RESULTS: The majority of these CD45RA+ patients (20/22) showed a patch-plaque stage disease and an indolent clinical course, as expected in early-stage MF. The remaining 2 patients presented with stage IIB and IVA MF, and were characterized by an aggressive clinical course, with systemic spread. The immunohistochemical analysis revealed that CD45RA+ neoplastic cells belonged to the memory compartment, displaying a CD62L-, CD11a+, CD29+ phenotype. Most patients showed aberrant phenotypes, with a loss of T-cell lineage markers and expression of cytotoxic molecules or gamma-delta chain of the T-cell receptor. CONCLUSIONS: Our data show that CD45RA+ MF is a rare variant of CTCL and shares with the classic MF cases both the clinical features and disease course, even if it is characterized by a higher incidence of immunopathological abnormalities.     

Primary cutaneous CD30+ lymphoproliferative disorders

Primary cutaneous CD30⁺ lymphoproliferative disorders are the second most common group of cutaneous T‐cell lymphomas (CTCL) and include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T‐cell lymphoma (cALCL). Both disease entities share overlapping clinical, histopathological, and molecular features, thus representing a spectrum of cutaneous CD30⁺ lymphoproliferative disorders. LyP may be distinguished from cALCL by clinicopathological correlation. In some patients, both diseases may coexist at initial diagnosis or develop over the course of the disease. Mycosis fungoides (MF), the most common CTCL, is not considered a primary cutaneous CD30⁺ lymphoproliferative disorder, but may occur in some LyP patients. In addition, LyP‐like lesions may develop in MF patients. However, this is frequently a manifestation of MF rather than a representation of two different disease entities. Caution also has to be taken in the setting of transformed MF with lesions expressing CD30, as they may be mistaken for either LyP or cALCL, resulting in an inadequate therapeutic approach.     

Mycosis fungoides-type cutaneous T-cell lymphoma and neutrophilic dermatosis

BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). Patients with limited patch and/or plaque disease have a normal life expectancy. Neutrophilic dermatosis (ND) may be associated with various hematologic disorders. However, its association with CTCL is exceptional and has been reported only twice with leukemic forms of CTCL. OBSERVATIONS: Three patients with MF developed ND resistant to conventional therapies and responsible for an impaired quality of life due to constitutional symptoms and painful cutaneous lesions. All patients underwent an aggressive treatment course despite their varying initial clinical stages of MF, and all experienced a fatal outcome less than 18 months after the onset of ND. CONCLUSIONS: The association of MF with ND is exceptional and carries a poor prognosis, but the pathophysiologic nature of this association remains unclear. It may involve neutrophil chemoattractant cytokine production by tumor cells. A triggering role of interferon alfa is also possible.     

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.     

蕈样肉芽肿的治疗进展

蕈样肉芽肿是常见的原发皮肤T细胞淋巴瘤,典型临床表现分为红斑期、斑块期、肿瘤期,病程呈慢性进行性.本病的病因及发病机制尚不清楚,其治疗和预后与疾病分期有关,早期以局部治疗为主,如局部外用糖皮质激素、氮芥、光疗法和放射疗法;晚期则以联合治疗为主,如联合干扰素、维A酸类、化疗药物等.治疗虽然可使蕈样肉芽肿患者得到缓解,但中位持续缓解时间一般较短,容易复发或进展.近年来,随着对蕈样肉芽肿发病机制的研究,出现了一些新的治疗方法,如新的外用制剂及剂型、单克隆抗体、免疫偶联物、组蛋白去乙酰化酶抑制剂、蛋白酶体抑制剂、免疫系统哨点抑制剂等.     

Follicular mycosis fungoides

We describe a patient with follicular mycosis fungoides (MF), a rare folliculotropic variant of cutaneous T-cell lymphoma (CTCL). Follicular involvement in CTCL usually presents clinically as alopecia mucinosa associated histologically with follicular mucinosis. Follicular MF differs from alopecia mucinosa/follicular mucinosis associated with MF with regard to its clinical presentation, histology and, presumably, prognosis. Our patient presented with the characteristic findings of follicular MF, i.e. infiltrated plaques showing numerous enlarged, comedo-like follicular infundibula; histology was dominated by exclusive folliculotropism of atypical lymphocytes sometimes forming follicular Pautrier's microabscesses, and by lack of epidermotropism and follicular mucinosis. Despite photochemotherapy and treatment with oral retinoids and interferon alpha, the patient's follicular MF rapidly developed into a progressive CTCL with large tumorous lesions, but responded to electron beam therapy. The course of our patient's disease confirms the notion that follicular MF may be associated with a worse prognosis than classical MF. However, electron beam irradiation induced remission of follicular MF that was maintained by a combination therapy consisting of extracorporeal photopheresis and interferon alfa.     

Successful treatment of mogamulizumab‐resistant mycosis fungoides with mogamulizumab plus etoposide combined therapy: Investigation of the immunomodulatory effects of etoposide on the tumor microenvironment

Mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by antibody‐dependent cell‐mediated cytotoxicity (ADCC) in advanced cutaneous T‐cell lymphoma (CTCL) patients. Although mogamulizumab is used as one of the anchor drugs for the treatment of advanced CTCL, its efficacy is unsatisfactory, especially in mycosis fungoides (MF). Therefore, additional drugs to enhance the antitumor effects of mogamulizumab are needed to further optimize its use for the treatment of MF. In this report, two cases of mogamulizumab‐resistant MF successfully treated with additional administration of etoposide are presented. Moreover, the possible mechanisms of mogamulizumab‐etoposide combined therapy for the treatment of MF were investigated based on the modulation of chemokine profiles in vivo using an EL‐4 mouse T‐cell lymphoma model. Intraperitoneal administration of etoposide significantly increased the mRNA expressions of CCL17, CXCL5, and CXCL10, suggesting that CCR4+ CTCL cells gather around the tumor‐associated macrophagess. Furthermore, the immunomodulatory effects of etoposide on the mRNA expressions of these chemokines were validated using monocyte‐derived M2 macrophages in vitro. Since mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by ADCC that depends on the contact between the lymphoma cells and the effector cells, these chemokines could enhance the therapeutic effect of mogamulizumab.     

The Role of Tumor Microenvironment in Mycosis Fungoides and Sézary Syndrome

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphomas (CTCLs). Most cases of MF display an indolent course during its early stage. However, in some patients, it can progress to the tumor stage with potential systematic involvement and a poor prognosis. SS is defined as an erythrodermic CTCL with leukemic involvements. The pathogenesis of MF and SS is still not fully understood, but recent data have found that the development of MF and SS is related to genetic alterations and possibly to environmental influences. In CTCL, many components interacting with tumor cells, such as tumor-associated macrophages, fibroblasts, dendritic cells, mast cells, and myeloid-derived suppressor cells, as well as with chemokines, cytokines and other key players, establish the tumor microenvironment (TME). In turn, the TME regulates tumor cell migration and proliferation directly and indirectly and may play a critical role in the progression of MF and SS. The TME of MF and SS appear to show features of a Th2 phenotype, thus dampening tumor-related immune responses. Recently, several studies have been published on the immunological characteristics of MF and SS, but a full understanding of the CTCL-related TME remains to be determined. This review focuses on the role of the TME in MF and SS, aiming to further demonstrate the pathogenesis of the disease and to provide new ideas for potential treatments targeted at the microenvironment components of the tumor.     

Dyshidrotic mycosis fungoides

Mycosis fungoides (MF) represents the most common type of cutaneous T-cell lymphoma (CTCL). CTCL often progresses through patch, plaque and tumor stages but can also manifest with varied clinical presentations. MF rarely presents in vesiculobullous fashion, in which vesicles or bullae develop in pre-existing plaques or on the trunk or proximal extremities. We report a patient who presented with a vesiculobullous eruption on the palms and soles, resembling dyshidrotic dermatitis, which we believe represents dyshidrotic MF.     

T-cell receptor β variable region (Vβ) usage in cutaneous T-cell lymphomas (CTCL) in comparison to normal and eczematous skin

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphoproliferative disorders. We investigated the variable region (Vβ) of the T-cell receptor (TCR) repertoire in CTCL and compared it to the Vβ repertoire in normal and eczematous skin. We used a panel of 21 anti-Vβ antibodies and investigated 84 biopsies of 71 CTCL patients (4 parapsoriasis en grandes plaques (PA), 1 lymphomatoid papulosis, 29 mycosis fungoides (MF), 13 Sezary syndrome (SS), 1 CD8+ CTCL, 11 pleomorphic CTCL (PLEO), 12 CTCL not classified). Six biopsies of normal skin and 6 of eczematous skin lesions served as controls. We determined the frequency of the Vβ in normal and inflamed skin and compared it to the percentage of the respective Vβ in the malignant clone of the CTCL patients. The percentage of the Vβ positive CD4+ cells in relation to the total number of T cells in normal skin and inflamed skin differed from the distribution of the Vβ families in the peripheral blood monoiiuclear cells (PBMC). Out of 71 CTCL cases, the clone was identified in 23 (32%). We identified the following clones : 1 V03.1 (1 MF), 7 V05.1 (1 CD8+ CTCL.l CTCL not classified, 1 MF, 1 PA, 3 SS), 1 V|36.7 (1 SS), 7 Vβ8.1/8.2 (2 CTCL not classified,! PLEO, 2 MF, 2 SS), 1 V012.1 (1 PLEO), 3 Vβl7.1 (2 CTCL not classified, 1 MF), 2 Vβ22.1 (1 CTCL not classified, 1 MF), 1 TCR8 (SS). The frequency of the malignant clone Vβ usage corresponded well to the repertoire of Vβ in eczematous skin but not to the repertoire in PBMC. In 6 patients, the malignant clone was mainly localized in the epidermis. In 17 cases, the clone-specific cells were distributed in epidermis and dermis equally. A retrospective analysis showed that preferential epidermal homing of the clone was associated with a non-aggressive clinical course. The Vβ usage of CTCL and eczema suggests a special cutaneous microenvironment which might be co-created by certain (bacterial?) superantigens. A preferential epidermal homing of the clone might have prognostic implications.     

Prevalence and severity of pruritus in cutaneous T cell lymphoma

Background The most common types of cutaneous T cell lymphoma (CTCL) are mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS). One of the hallmarks of MF and SS is pruritus that rarely responds to treatment. Little is known about the prevalence and severity of pruritus in MF and SS. Objectives A retrospective analysis was performed to assess the prevalence and severity of pruritus in MF and SS. Methods This study compared self‐reported pruritus in early‐stage (stage Ia–IIa) and late‐stage (stage IIb–IVb) disease, and in MF and SS, in patients presenting at our CTCL clinic between January 1, 2006, and June 30, 2010. Results Of the 551 eligible patients, 486 reported baseline pruritus values. Overall, 373 patients had early‐stage disease, 113 had late‐stage disease, and 72 had SS. The prevalence of pruritus was 66% in all patients, 62% in patients with early‐stage disease, 83% in those with late‐stage disease, 61% in those with MF, and 94% in those with SS. Mean pruritus values out of 10 were: 4.2 [standard error of the mean (SEM) = 0.18] in all patients; 3.4 (SEM = 0.19) in patients with early‐stage disease; 6.6 (SEM = 0.36) in those with late‐stage disease; 3.6 (SEM = 0.18) in MF patients, and 7.7 (SEM = 0.37) in SS patients. Differences between early‐ and late‐stage disease, and MF and SS, were statistically significant (P < 0.001). Conclusions Pruritus affects a large proportion of patients with CTCL and is significantly more severe in late‐ than in early‐stage disease and in SS than in MF. Little information exists on the full range of the symptom burden on the patient. This aspect of patient care requires further exploration.     

Mycosis fungoides associated with malignant melanoma and dysplastic nevus syndrome

BACKGROUND: The increased risk of second malignancies, including nonmelanoma skin cancers, in cutaneous T-cell lymphoma (CTCL) patients has been well documented. However, relatively few studies of malignant melanoma in CTCL patients have been reported. METHODS: A database of 250 CTCL patients registered over a 3-year period was searched to identify patients with diagnoses of both mycosis fungoides (MF) and malignant melanoma. RESULTS: We identified six cases of MF associated with malignant melanoma and one associated with dysplastic nevus syndrome, which is a marker of increased risk of melanoma. In four patients, melanoma was diagnosed along with or before MF. In the remaining two patients, MF was diagnosed prior to melanoma, although dysplastic nevi were noted at the time MF was diagnosed. These two patients received treatment for their MF (one with topical nitrogen mustard and another with radiation therapy and nitrogen mustard) prior to the histologic confirmation of melanoma. Six patients had early stages of MF (IA or IB), while one patient presented with simultaneous erythrodermic mycosis fungoides involving the lymph nodes as well as melanoma metastatic to the lymph nodes from an unknown primary. CONCLUSION: There is an elevated prevalence of malignant melanoma in MF patients compared to the general US population (P < 0.00001) with a relative risk of 15.3 for observing malignant melanoma in MF patients (95% confidence interval 7.0-33.8). Possible pathologic links between the two diagnoses include effects of mycosis fungoides therapies, immunosuppression secondary to mycosis fungoides, and genetic alterations in the p16 tumor suppressor protein.     

微小RNA在蕈样肉芽肿中的研究进展

蕈样肉芽肿是一种原发性皮肤T细胞淋巴瘤,临床表现多种多样,极易误诊.微小RNA(miRNA)是一种长约22个核苷酸的非编码小RNA,参与细胞分化、增殖、代谢、凋亡等生命活动,miRNA的功能失调对肿瘤的发生起作用.目前发现,一些miRNA在蕈样肉芽肿的发病、辅助诊断、判断预后起作用,并对蕈样肉芽肿的治疗具有潜在价值.如miR-155、miR-22、miR-150能促进蕈样肉芽肿的发病,miR-233、miR-200c则抑制蕈样肉芽肿.一组miRNA,miR-155、miR-203和miR-205,有助于鉴别诊断皮肤T细胞淋巴瘤和良性皮肤病.     

The relevance of peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation of patients with mycosis fungoides and Sézary syndrome

BACKGROUND: There is evidence that a T-helper (Th) 2 cytokine pattern dominates in the peripheral blood as well as in tissue of patients with Sézary syndrome (SS), and that the malignant clone is of Th2 phenotype. However, there are conflicting studies on the cytokine pattern in the peripheral blood in different stages of cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To examine, by means of flow cytometry (FC), the Th1/Th2 cytokine profile [cytoplasmic interferon (IFN)-gamma/interleukin (IL)-4] in peripheral blood T cells from patients with mycosis fungoides (MF) and SS, the most common forms of CTCL, and to correlate their expression with clinical stage, clonality and T-cell immunophenotype changes in order to evaluate their relevance in CTCL progression. METHODS: We investigated by FC the percentage of CD3+ T cells expressing cytoplasmic IFN-gamma and IL-4 after stimulation in blood specimens of 43 CTCL patients (32 stage I-II and 11 stage III-IV), eight of whom were erythrodermic. Next, we compared cytoplasmic IFN-gamma and IL-4 expression between patients of different stages and controls, and correlated our findings to T-cell receptor (TCR)-gamma gene rearrangement, used as a marker of clonality, and changes in T-cell immunophenotype (CD4+, CD8+, CD4+/CD7-, CD4+/CD25+) and natural killer cells. Polymerase chain reaction amplification of the TCR-gamma gene was performed in 41 blood and 26 skin specimens. We also examined the cytokine expression pattern in patients with erythrodermic MF and SS. RESULTS: A significantly higher frequency of CD3+/IL-4+ T cells was found in late (III-IV) compared with early (I-II) CTCL patients (P = 0.002) or controls (P < 0.001). There were significant positive correlations between the percentages of CD3+/IL-4+ and the percentages of CD3+/CD4+ T cells (r = 0.385, P = 0.05), CD4+/CD7- T cells (r = 0.335, P < 0.05) and CD4+/CD25+ T cells (r = 0.433, P = 0.01); there was a negative correlation between the percentages of CD3+/IL-4+ and CD3+/CD8+ T cells (r = -0.463, P = 0.005) and a positive correlation between the percentages of CD3+/IFN-gamma+ and CD3+/CD8+ T cells (r = 0.368, P = 0.02). Increased percentages of CD3+/IL-4+, CD3+/CD4+ and CD4+/CD7- T lymphocytes were associated with the presence of clonality (P = 0.025, P < 0.001 and P = 0.0031, respectively). All independent variables showed a statistically significant difference between SS and erythrodermic MF patients, or controls, apart from cytoplasmic IL-4, which was high both in erythrodermic MF and SS patients compared with controls (P = 0.003 and P = 0.008, respectively). In multiple regression logistic analysis, the probability of belonging to advanced CTCL stages was associated only with increased cytoplasmic IL-4 (P = 0.007, odds ratio 1.13, 95% confidence interval 1.033-1.229). CONCLUSIONS: Increased T-cell cytoplasmic IL-4 is more frequent in late CTCL stages, correlates with T-cell immunophenotype changes found in advanced disease and is associated with clonality. Increased cytoplasmic IL-4 is frequent both in erythrodermic MF and SS patients, in contrast to other variables found increased only in SS, suggesting that IL-4 may be an early indicator of disease progression. Moreover, our results show that increased cytoplasmic IL-4 is the sole predictor of advanced CTCL disease and confirm the relevance of FC determination of IL-4 in the routine evaluation of CTCL cases.     

Transformed mycosis fungoides: clinicopathological features and outcome

BACKGROUND: Transformation of mycosis fungoides (T-MF) occurs in 8-55% of MF patients. Its early histopathological diagnosis is of tremendous importance to better define the management and to establish the prognosis. Recent studies have demonstrated that advanced-stage MF at diagnosis of transformation is the predominant risk factor of poor outcome. The 5-year survival rates for stage IIB and IV MF are 26.9% and 10.6%, respectively. The prognostic value of the immunophenotypic characterization of the infiltrate has not been thoroughly studied in the literature. OBJECTIVES: To retrieve clinical, histological and immunophenotypic features of T-MF in our patient population and analyse their prognostic value. PATIENTS AND METHODS: A register-based retrospective study was performed including all patients with cutaneous T-cell lymphoma (CTCL) registered in our two departments from January 2000 to December 2005. Among 208 patients with CTCL, 17 patients with proven transformation of their MF were studied. Clinical features and staging as well as immunophenotypic and pathological findings at the time of the initial diagnosis of MF and of the diagnosis of T-MF were analysed. RESULTS: Our results, in accordance with previously published material, indicate that the main clinical prognostic factor in T-MF is the stage of the initial disease at the time of the transformation. Patients with stage IIB-IV MF have a poor prognosis. In our study, strong expression of CD30 is linked to a better prognosis. CONCLUSIONS: We believe that pathological and immunopathological documentation of progressive MF is important in order to identify T-MF early; however, the differential diagnosis is sometimes difficult. Aside from already acknowledged prognostic factors such as older age, advanced initial disease and short delay to transformation, the CD30 immunophenotype could be regarded as a useful additional prognostic marker in T-MF.