肉芽肿性蕈样肉芽肿

肉芽肿性蕈样肉芽肿是蕈样肉芽肿的一种罕见的组织学变异。复习文献闹述肉芽肿性蕈样肉芽肿的临床表现、组织病理变化、免疫组化染色、发病机制、诊断和鉴别诊断与预后。     

Th17和Treg细胞与蕈样肉芽肿相关性研究

目的 探讨调节性T（Treg）细胞和Th17细胞在蕈样肉芽肿不同分期中的变化。 方法 流式细胞仪检测28例蕈样肉芽肿、13例大斑块型副银屑病、17例扁平苔藓患者及10例健康对照外周血Treg细胞和Th17细胞百分率,同时应用免疫组化法检测40例蕈样肉芽肿、13例副银屑病、17例扁平苔藓及10例健康对照蜡块组织中叉头状转录因子P3（FOXP3）和白细胞介素17（IL-17）的表达。 结果 蕈样肉芽肿、副银屑病、扁平苔藓患者外周血Treg细胞百分率分别为（8.09 ± 1.68）%,（6.53 ± 1.67）%,（2.84 ± 1.16）%较健康对照［（1.01 ± 0.35）%］升高,差异均有统计学意义。蕈样肉芽肿、副银屑病患者外周血Treg细胞百分率亦高于扁平苔藓（均P < 0.05）;蕈样肉芽肿与副银屑病患者差异无统计学意义（P > 0.05）。外周血Th17细胞百分率在蕈样肉芽肿较副银屑病、扁平苔藓患者比健康人升高［（3.22 ± 0.82）%比（2.46 ± 0.79）%,（1.38 ± 0.47）%和（0.59 ± 0.30）%,均P < 0.05］。FOXP3阳性率在蕈样肉芽肿、副银屑病及扁平苔藓均高于正常皮肤组织［（14.94 ± 4.46）%,（11.95 ± 4.72）%,（6.32 ± 2.81）%比（3.43 ± 1.79）%,均P < 0.05］,蕈样肉芽肿及副银屑病比扁平苔藓高（均P < 0.05）,蕈样肉芽肿比副银屑病差异无统计学意义（P > 0.05）。IL-17阳性率在蕈样肉芽肿、副银屑病、扁平苔藓和正常组织中分别为（15.89 ± 4.27）%,（12.02 ± 3.34）%,（4.84 ± 1.93）%和（2.62 ± 0.89）%,其中,蕈样肉芽肿均高于副银屑病、扁平苔藓组织及正常组织（均P < 0.05）。蕈样肉芽肿、副银屑病外周血Th17/Treg细胞比率比扁平苔藓、健康对照低（0.41 ± 0.11,0.39 ± 0.12比0.50 ± 0.06,0.57 ± 0.19（均P < 0.05）。早期蕈样肉芽肿Th17细胞与Treg细胞呈正相关（r = 0.423,P < 0.05）,肿瘤期蕈样肉芽肿Th17细胞有所下降,而Treg细胞继续升高,但蕈样肉芽肿各期差异无统计学意义,且二者在肿瘤期无相关性。 结论 Treg和Th17细胞失衡可能参与了蕈样肉芽肿的发生与发展。     

肿瘤微环境对蕈样肉芽肿生物学行为的影响

蕈样肉芽肿是原发于皮肤的、具有独特临床表现、组织病理、免疫表型和遗传特征的皮肤T细胞淋巴瘤.蕈样肉芽肿肿瘤微环境由肿瘤细胞、局部浸润的免疫细胞、间质细胞及其所分泌的细胞因子等组成.树突细胞(包括朗格汉斯细胞)在蕈样肉芽肿发展的不同阶段发挥着双向作用,成熟树突细胞介导了抗肿瘤免疫反应,未成熟树突细胞诱导了免疫耐受反应.调节性T细胞与Th17细胞的功能失衡也决定了蕈样肉芽肿的进程,细胞因子特别是趋化因子在蕈样肉芽肿亲表皮现象中发挥重要作用,白介素10导致局部免疫抑制与蕈样肉芽肿预后密切相关.肿瘤微环境的改变决定了蕈样肉芽肿的病程发展规律与生物学行为.     

蕈样肉芽肿皮损及外周血人类疱疹病毒1、2、4、5型DNA的检测

目的　探讨蕈样肉芽肿与人类疱疹病毒 1型 (单纯疱疹病毒 1型 )、2型 (单纯疱疹病毒 2型 )、4型 (ep stein barr病毒 )、5型 (人类巨细胞病毒 )间有无相关性。方法　酚 氯仿法提取皮肤组织 (蕈样肉芽肿 3 2份、正常皮肤 2 9份、慢性湿疹与慢性单纯性苔藓 2 4份 )及外周血白细胞 (蕈样肉芽肿 15份、健康献血员 40份、慢性湿疹与慢性单纯性苔藓 11份 )中基因组DNA。采用聚合酶链反应技术检测病毒DNA ,扩增产物回收后以限制性内切酶BamHⅠ、SmaⅠ酶切鉴定。结果　蕈样肉芽肿皮损及外周血中 ,各有 2份检测到人类疱疹病毒 1型DNA ;蕈样肉芽肿皮损中有 5份存在人类疱疹病毒 4型DNA ;健康献血员外周血以及正常皮肤、慢性湿疹与慢性单纯性苔藓患者皮损组织及外周血中未检测到此4种病毒DNA。结论　蕈样肉芽肿与人类疱疹病毒 1、2、4、5型间可能不具有相关性。     

蕈样肉芽肿与扁平苔藓、银屑病浸润细胞的免疫组化比较

目的 探讨免疫表型对蕈样肉芽肿与扁平苔藓、银屑病鉴别诊断的意义.方法 应用ABC免疫组化技术检测15例蕈样肉芽肿,17例银屑病和17例扁平苔藓,6例正常人皮肤的CD1a、CD4、CD8、ICAM-1、LFA-1、HLA-DR(树枝状细胞)、CD30和CD7的表达情况.结果 蕈样肉芽肿表皮CD1a,CD30,ICAM-1(单一核细胞P<0.001,树枝状细胞P<0.01)的阳性细胞密度明显高于扁平苔藓、银屑病、正常人皮肤.蕈样肉芽肿表皮CD4,CD8,HLA-DR的阳性细胞密度明显高于扁平苔藓.蕈样肉芽肿真皮中CD1a阳性细胞的线性密度(P<0.01),真皮内ICAM-1和LFA-1阳性细胞百分比亦较扁平苔藓增多(P<0.05).蕈样肉芽肿表皮CD7阳性细胞与扁平苔藓、银屑病比较差异无统计学意义.银屑病和扁平苔鲜真皮内CD7阳性细胞百分比高于蕈样肉芽肿和正常人皮肤.结论 蕈样肉芽肿和扁平苔藓、银屑病皮损CD1a、CD4、CD8、ICAM-1、LFA-1、HLA-DR、CD30和CD7免疫表型有差异,其结果可为探讨发病机制提供线索.     

光线性角化病向鳞状细胞癌转化的分子机制研究进展

光线性角化病（AK）是皮肤鳞状细胞癌（SCC）的癌前病变,AK向SCC转化的分子机制一直是研究热点,但尚未完全清楚。围绕染色体变异、基因突变、信号通路和其他因子机制4个部分,概述了染色体3p、9p、9q、13q、17p和17q基因选择性突变、18q杂合性缺失,p53、p16和Ras基因突变,转化生长因子β1信号通路、Fas/FasL信号通路活性异常,及基质金属蛋白酶因子异常表达在AK向SCC进展中的机制研究进展,为进一步研究提供参考。     

持续性色素性紫癜性皮炎样蕈样肉芽肿1例

蕈样肉芽肿（mycosis fungoides,MF）是一种向表皮性低度亚性的T淋巴细胞淋巴瘤,除典型表现外,还有少数特殊的临床变异,如肉芽肿性MF,大疱性MF,色素异常性MF,紫癜性MF和持续性色素性紫癜性皮炎样蕈样肉芽肿（persistent pigmcnted purpuric dermatitis mycoais fungoides ,PPPD MF）。现将笔者诊治的1例PPPD MF报告如下。     

具有多种表现的蕈样肉芽肿1例

报告1例具有多种表现的蕈样肉芽肿。患者男,48岁。全身皮肤出现红斑、脱屑,并伴进行性皮肤松弛,四肢有斑块、破溃8年,秃发6个月。体格检查发现全身皮肤红斑,上覆大片状鳞屑和结痂;颈部两侧可见表皮松弛;四肢皮肤呈暗红色浸润的松弛性斑块和深在的溃疡;枕部头皮呈条片状胶质样秃发斑;颈项部、双上肢及胸部群集表面光亮的肤色丘疹和结节：左腹股沟可触及数个增大的淋巴结。诊断为蕈样肉芽肿,同时具有蕈样肉芽肿的多种表现：鱼鳞病样蕈样肉芽肿、肉芽肿性皮肤松弛症或肉芽肿性蕈样肉芽肿、毛囊性蕈样肉芽肿。     

直肠癌化疗后致蕈样肉芽肿进展1例

患者男,67岁。躯干、四肢红斑,伴瘙痒6年余。2年前行直肠癌根治术后化疗时皮疹由干燥脱屑发展为泛发全身的红斑,1年前出现浸润性斑块及肿块。诊断:蕈样肉芽肿。予阿维A、IFNα-2b、NB-UVB及肿块处UVA照射联合得宝松注射,皮疹完全消退,随访7个月无复发。该例蕈样肉芽肿患者病程中伴发实体肿瘤,化疗后蕈样肉芽肿进展,呈典型的临床和组织病理特征,提示蕈样肉芽肿可伴发第二肿瘤,针对实体肿瘤的化疗可诱发蕈样肉芽肿的病情进展。     

干扰素γ联合阿维A治疗出汗不良性蕈样肉芽肿一例

蕈样肉芽肿（MF）是原发于皮肤的低度恶性T淋巴细胞性淋巴瘤,早期MF治疗中,光化学疗法、维A 酸类、干扰素、白介素2 融合蛋白等免疫调节剂对早期蕈样肉芽肿均有较好的疗效,可不同程度减缓MF进展。目前国内少有干扰素γ（IFN-γ）联合阿维A治疗早期蕈样肉芽肿案例报道,我们将较为特殊的出汗不良性蕈样肉芽肿患者2年内治疗情况做一报道……     

Genomic aberrations and survival in cutaneous T cell lymphomas

Information on chromosomal aberrations in cutaneous T cell lymphomas (CTCL), is scarce. In this study, comparative genomic hybridization (CGH) was used to analyze chromosomal imbalances (CI) in 32 patients with CTCL. CI were detected in 21 patients (66%). Euchromatic loss (dim) was localized most frequently (>16%) at the chromosomal regions 17p (28%), 13q (25%), 10q (16%), and 6q (19%), and gain of chromatin (enh) at 7 (25%), 8q (25%), and 17q (16%). The pattern dim6q-enh7-enh8-dim13 was the most frequent combination of CI. The number of aberrations per tumor sample varied between 0 and 19 and correlated with clinical tumor stages: from none in stage Ia to 8.75+/-1.8 (mean+/-SEM) in stage IVa. CI occurred more frequently in aggressive subtypes (9.33+/-2.16) than in indolent (2.88+/-0.8) subtypes. A high number of CI (>/=5) was associated with shorter survival. Gain of chromatin in 8q and loss of 6q and 13q correlated with a significantly shorter survival, whereas the most frequently observed aberrations (loss in 17p and gain in 7) did not influence the prognosis. In summary, CGH analysis revealed a characteristic pattern of recurring chromosomal gains and losses in CTCL. The association of the imbalances with the clinical course of the disease suggests that genes encoded at these loci may influence tumor development and progression.     

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.     

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.     

Allelotyping in mycosis fungoides and Sézary syndrome: common regions of allelic loss identified on 9p, 10q, and 17p

Allelotyping studies have been extensively used in a wide variety of malignancies to define chromosomal regions of allelic loss and sites of putative tumor suppressor genes; however, until now this technique has not been used in cutaneous lymphoma. We have analyzed 51 samples from patients with mycosis fungoides and 15 with Sézary syndrome using methods to detect loss of heterozygosity. Micro satellite markers were selected on 15 chromosomal arms because of their proximity to either known tumor suppressor genes or chromosomal abnormalities identified in previous cytogenetic studies in cutaneous lymphoma. Allelic loss was present in 45% of patients with mycosis fungoides and 67% with Sézary syndrome. Loss of heterozygosity was found in over 10% of patients with mycosis fungoides on 9p, 10q, 1p, and 17p and was present in 37% with early stage (T1 and T2) and 57% with advanced disease (T3 and T4). Allelic loss on 1p and 9p were found in all stages of mycosis fungoides, whereas losses on 17p and 10q were limited to advanced disease. In Sézary syndrome high rates of loss of heterozygosity were detected on 9p (46%) and 17p (42%) with lower rates on 2p (12%), 6q (7%), and 10q (12%). There was no significant difference in the age at diagnosis or number of treatments received by those with loss of heterozygosity and those without, suggesting that increasing age and multiple treatments do not predispose to allelic loss. These results provide the basis for further studies defining more accurately chromosomal regions of deletions and candidate tumor suppressor genes involved in mycosis fungoides and Sézary syndrome.     

Early mycosis fungoides: molecular analysis for its diagnosis and the absence of p53 gene mutations in cases with progression

The histological diagnosis of initial mycosis fungoides (MF) and the molecular mechanisms that are responsible for its progression and transformation to the more highly malignant variants of MF remain largely unknown. Because of the rare occurrence of these tumours, the need for snap frozen skin biopsy specimens and the difficulty to obtain suitable material for karyotypic and genotypic analysis, specific cytogenetic and molecular lesions have not yet been identified. In particular the role of known oncogenes and tumour suppressor genes, including the p53 gene, in the pathogenesis and clinical progression of MF has not been extensively investigated. The present study was carried out using the polymerase chain reaction (PCR) technique combined with temperature gradient gel electrophoresis (TGGE) to detect mutations of the p53 gene in 58 patients with MF. TGGE analysis was also used in combination with clonality analysis by means of T-cell receptor gamma (TCRG) gene rearrangement studies to distinguish parapsoriasis en plaque and initial MF from patch/plaque stage MF. More than 83% of the diagnoses of initial MF could be confirmed using PCR-TGGE analysis. However, although the sensitive TGGE analysis was used for all exons, p53 gene polymorphisms were found in 4 and p53 gene mutation in only 1 of 58 biopsy specimens. It appears unlikely that p53 gene mutations play a role in either the pathogenesis of parapsoriasis and initial MF or their progression to advanced stages of MF. However, TCRG gene rearrangement studies by means of TCR-TGGE analysis may be useful for distinguishing histologically discordant cases of initial MF.     

Loss of heterozygosity on chromosome 4q32-35 in sporadic basal cell carcinomas: evidence for the involvement of p33ING2/ING1L and SAP30 genes

BACKGROUND: Studies on basal cell carcinoma (BCC) have demonstrated that patched gene and p53 gene located at 9q22.3 and 17p13 are the main genes responsible for the onset of this tumor. In order to identify a possible involvement of other tumor suppressor genes, we screened 19 cases of BCCs for loss of heterozygosity (LOH). METHODS: The analysis was performed on tumoral tissue and on corresponding normal tissue by using a panel of 37 polymorphic markers spanning 26 chromosomal regions. RESULTS: We observed that only four chromosomal regions, 4q32 (30.00%), 4q35 (27.27%), 9q21-22 (28.57%), and 9q22-qter (35.71%), demonstrated a significative LOH (>20%), even if others show a borderline percentage (15-20%) of imbalance (1q32, 3p24, 10p22.1, and 17q21.3). CONCLUSIONS: Our findings suggest that a new chromosomal region mapping in the long arm of chromosome 4 could be involved in sporadic BCC carcinogenesis. Further analyses indicate that the minimal deleted region in 4q32-35 includes p33ING2/ING1L and SAP30, whose deletion could impair the G1-phase checkpoint control and favor gene silencing, respectively.     

High frequency of loss of heterozygosity on chromosome region 9p21-p22 but lack of p16INK4a/p19ARF mutations in greek patients with basal cell carcinoma of the skin

Basal cell carcinoma of the skin is the most common neoplasia in humans. Previous studies have shown the existence of allelic imbalance (loss of heterozygosity and microsatellite instability) in BCC on several human chromosomes. Chromosome region 9p21-p22 harbors the CDKN2a/p16INK4a, p19ARF, and p15INK4b tumor suppressor genes. To determine the contribution of these genes to the development of basal cell carcinomas we looked for evidence of allelic imbalance in 67 sporadic basal cell carcinoma specimens from Greek patients and screened 28 of them presenting loss of heterozygosity at 9p21-p22 for germline mutations in p16INK4a and p19ARF genes. Chromosome regions 17q21 and 17p13 were also screened for allelic imbalance in all the 67 basal cell carcinoma specimens. Overall, 69% (46 of 67) of the specimens displayed loss of heterozygosity in at least one microsatellite marker, whereas only six of the 67 (9%) exhibited microsatellite instability. For the 9p21-p22 locus the overall frequency of loss of heterozygosity reached 55% (37 of 67) and is the highest reported. The overall frequency of loss of heterozygosity for the 17q21 locus is 34% (22 of 64) and for the 17p13 locus is 11% (seven of 65). Two of the 28 loss of heterozygosity positive cases were heterozygous for a previously described polymorphism, Ala148Thr, in exon 2 of the CDKN2a gene. This is the first demonstration of polymorphism in the CDKN2a gene in human basal cell carcinomas. No sequence variation in exon 1beta of the p19ARF gene was found. Our results provide evidence of a significantly high occurrence of loss of heterozygosity for the 9p21-p22 locus; however, lack of p16INK4a/p19ARF mutation suggests that these genes seem not to be implicated by mutational inactivation in the development of basal cell carcinoma. Other(s), yet unidentified, tumor suppressor gene(s) located in this locus may be related to this specific type of skin cancer.     

Spectral karyotyping demonstrates genetically unstable skin-homing T lymphocytes in cutaneous T-cell lymphoma

We initially established cell lines from skin biopsies from four patients (MF8, MF18, MF19 and MF31) in early stages of cutaneous T-cell lymphoma (CTCL) in 1999. After 3 weeks of culture, skin-homing T lymphocytes were stimulated with phytohaemagglutinin. Metaphase spreads were analysed using spectral karyotyping (SKY), a molecular cytogenetic technique. MF18 and MF19 had predominantly normal karyotypes. MF8 had recurrent numerical aberrations resulting in two T lymphocyte clones: one with trisomy 21 (12/20 cells) and the other with monosomy chromosome 22 (3/20 cells). MF8 also exhibited a clonal deletion, del(5)(p15.1), as well as multiple non-clonal structural aberrations. MF31 had a clonal deletion, del(17)(p12) and other non-clonal deletions involving chromosomes 2, 5, 10, 11. MF18 had a single abnormal cell that contained two reciprocal translocations t(1;2)(q32;p21) and t(4;10)(p15.2;q24). In 2001, three of the original patients had new skin biopsies taken and cell lines were established. SKY analysis revealed the continued presence of a T-cell clone in MF8 with trisomy 21 (4/20 cells). Additionally, a new clone was seen with a del(18)(p11.2) (17/20 cells). MF31 had only one aberrant cell with a del(17)(p12). MF18 had a clonal deletion, [del(1)(p36.1) in 3/20 cells] and non-clonal aberrations involving chromosomes 3, 4, 5, 6, 12, 13, 17 and 18. Thus, three of four patients continued to show numerous numerical and structural aberrations, both clonal and non-clonal, with only MF8 having a recurring T lymphocyte clone (+21). Our findings demonstrate high genetic instability among skin-homing T lymphocytes even in early stages of CTCL. We did not see genetic instability or evidence of clones in cell lines from a patient with atopic dermatitis and one with psoriasis.