脑脊液和血清肿瘤标志物β-hCG、αFP、PLAP及s-kit（CD117）对中枢神经系统生殖细胞肿瘤的诊断价值
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摘要
[研究目的]
中枢神经系统生殖细胞肿瘤,通常也称作颅内生殖细胞肿瘤(intracranial germ cell tumors, ICGCTs),分为生殖细胞瘤(germinoma)和非生殖细胞瘤性生殖细胞肿瘤(nongeminomatous germ cell tumors, NGGCTs)两大类。虽然病理亚型是决定预后的最主要因素,但早期积极而规范的诊治无疑也是非常重要之因素。多学科综合诊断平台是获得早期(病程半年内)确诊的基础,通过手术明确病理是建立平台的瓶颈。虽然肿瘤标志物是平台重要组成部分,但其临床诊断价值在国内外均未得到充分研究。当前数种分泌性肿瘤标准的判断依据并未建立在组织病理和脑脊液细胞学基础上。目前关于颅内生殖细胞瘤肿瘤标志物的研究仅限于非生殖细胞瘤特异性的人绒毛膜促性腺激素β亚单位(0subunit of human chorionicgonadotropin, β-hCG)和甲胎蛋白(alpha-fetoprotein, a FP)。而对生殖细胞瘤特异性肿瘤标记物—胎盘碱性磷酸酶(placental alkaline phosphatase, PLAP)和CD117(干细胞因子受体分子,跨膜形式为c-kit,可溶性形式为s-kit)未常规开展测定和进一步的研究。因此需要建立综合平台,以组织病理和脑脊液细胞学为基础,评估脑脊液和血清中肿瘤标志物—β-hCG、α FP及PLAP、s-kit对颅内生殖细胞肿瘤的诊断价值。
[研究方法]
1.将1991年3月至2011年9月20年期间我院32例经组织病理／脑脊液细胞学确诊的颅内GCTs患者(既往组)及在多科综合诊断平台基础上,自2011年9月至2012年12月期间我院26例患者(研究组)的诊断情况进行比较：包括患者基本情况、确诊情况、延迟诊断情况、肿瘤标志物染色和脑脊液细胞学情况、CSF和血清中肿瘤标志物测定水平。
2.结合两组可用同步CSF和血清肿瘤标志物数据,观察β-hCG、αFP水平的分布差别；评价当前不同的诊断标准的优劣；以朗格汉斯细胞组织细胞增生症组(langerhans cell histiocytosis. LCH,12例)和其余颅内肿瘤组(5例)为对照,用受试者工作曲线(receiver operating characteristic, ROC)计算p-hCG及α FP在CSF和血清中相应的新诊断切点,并评估新标准的诊断价值；评价男性不完全性性早熟／隐匿性低促性腺激素性高雄激素血症患者中肿瘤标志物对于早期诊断的提示意义。
3.用ELISA法测定研究组、LCH组、其余颅内肿瘤组和海马硬化组(5例)的CSF和血清中PLAP和s-kit水平,用ROC曲线分别计算两者合理诊断切点；并评估新标准的诊断价值
4.使用SPSS11.5作为数据统计的工具；正态分布数值资料、非正态分布数值资料(经对数变换后)使用独立样本T检验,或单因素方差分析(One-Way ANOVA)比较统计学差异；分类资料行wilcoxon signed-ranks test或卡方检验；ROC曲线计算诊断切点；P<0.05认为有统计学差异。
[研究结果]
1.既往组和研究组男女比例分别为1.1：1和1.9：1,平均确诊年龄分别为19±7岁和13±4岁；单纯鞍区病变比例分别为59.4%和38.5%,单纯松果体区病变比例分别为从3.1%和15.4%；手术确诊比例从71.9%增至96.2%；最终病理中,生殖细胞瘤比例从90.6%减至65.4%；4种肿瘤标志物免疫组化染色比例从9.4%-46.9%增至100%；β-hCG和α FP在CSF及血清肿瘤标志物测定率从50%-57.7%增至100%；早期确诊比例从6.3%增至19.2%(卡方值仍>0.05)。
2.CSF及血清中β-hCG≥50IU/L标准在既往组和研究组的总体诊断敏感性分别为18.8%和30.8%,特异性均为100%；而αFP≥10ng/mL标准在两组诊断敏感性分别为13.3%和23.1%,特异性分别为66.7%和83.3%,虽然α FP≥25ng/mL标准诊断敏感性分别为6.3%和19.2%,但特异性均为100%。
3.经ROC曲线分析,当CSF β-hCG≥8.4IU/L时,敏感性为44%；血清β-hCG≥2.2IU/L时,敏感性为33.3%,特异性均为100%；虽然αFP阳性病例数不足,但CSF α FP在3.8ng/mL时,仍能有效诊断颅内GCTs病例,血清α FP数值中未发现较25ng/mL标准更低的病例。
4.研究组CSF β-hCG诊断敏感性从26.9%增加至61.5%,高于同组血清β-hCG敏感性42.3%(主要用于诊断含STGC肿瘤)；CSF a FP诊断敏感性也从7.7%提高至19.2%；研究组总体诊断敏感性从38.5%提高至65.4%,其中最主要的比重来自于CSF β-hCG。
5.既往组中占男性比例17.6%的病例为高β-hC6血症所致的隐匿性低促高雄患者；研究组中占男性比例52.9%的病例为高β-hCG血症所致的性早熟或隐匿性低促高雄患者。
6.对既往组中有66.7%、研究组中有16.7%的病例根据CSF或血清α FP完善了混合性GCTs的最终诊断。
7.血清肿瘤标志物水平大于CSF中水平可证实BBB受损：以血清β-hCG≥2.2IU/L且≥CSF中水平；或血清α FP≥25ng/mL且≥CSF中水平为判断标准,两者均受损则为BBB严重受损：既往组中比例均为0%；研究组中由β-hCG和α FP证实BBB受损病例分别占18.8%(3例)和100%(5例),严重受损者1例,占β-hCG阳性病例的6.3%,占α FP阳性病例的20%。
8.除1例鞍区转移性肺癌病例CSF中PLAP明显升高(1684pg/mL)以外,研究组和所有对照组病例对应数值均低于最小可测值；研究组和海马硬化组血清中s-kit水平之间无统计学差异(40.5±9.7ng/mL vs36.1±12.1ng/mL,P>0.05)；CSF中s-kit≥3.0ng/mL时,诊断敏感性为30.8%,特异性为100%,可将研究组总体诊断敏感性从64.6%提高至76.9%。
[结论]
1.通过建立和完善颅内生殖细胞肿瘤综合诊断平台有助于此病早期确诊；在此平台中,以组织病理和CSF细胞学为基础是本研究得以深入开展的关键。
2.本研究明确了分泌型颅内GCTs诊断标准之一：CSF/血清中β-hCG≥50IU/L和／或α FP≥25ng/mL的合理性；
3.本研究进一步制订出新的β-hCG临床诊断切点：CSFβ-hCG≥8.4IU/L血清β-hCG≥2.2IU/L；CSFαFP诊断标准下调为3.8ng/mL,血清中标准不变。
4.CSF或血清β-hCG对于以性早熟起病的男童或隐匿性低促高雄男性有提高早期临床诊断敏感性的作用；CSF或血清α FP对混合性GCTs有提高完善诊断敏感性的作用；β-hCG和α FP还可用于评估血脑屏障损伤及程度。
5.CSF中PLAP诊断颅内GCTs价值有限。
6.CSF中s-kit可用于诊断纯生殖细胞瘤,临床诊断切点为3.0ng/mL。
Objective
Germ cell tumors (GCTs) from the central nervous system (CNS), usually called intracranial germ cell tumors(ICGCTs) are traditionally classified into germinoma and nongeminomatous germ cell tumors (NGGCTs). Although the pathologic subtype is the most important factor to predict prognosis, normalized diagnostic and therapeutic algorithm as early as possible is also very important. A multiple-disciplinary diagnostic platform is the basis for early diagnosis (in half a year from onset of disease), and histopathological or cytological confirmation by surgical or cerebrospinal fluid (CSF) management is the most important part of it. Tumor markers are indispensible in this platform, however, their clinical values have not been comprehensively investigated. The current several kinds of diagnostic criterior of "secreting" tumors is not established on the basis of histopathology or cytology from lumber CSF, and the tumor markers are only limited to non germinoma specific β subunit of human chorionicgonadotropin (β-hCG) and alpha-fetoprotein (αFP), while the value of some germinoma-specific tumor markers, such as placental alkaline phosphatase (PLAP) and CD117(a stem cell factor receptor with several variants:the transmembrane form as "c-kit" and the soluble form as "s-kit"), has not been routinely measured and investigated further. Therefore, a multiple-disciplinary platform is needed to be established to evaluate tumor markers (β-HCG, αFP, PLAP and s-kit) in lumber CSF and serum in the diagnosis of CNS GCTs based on histopathology and CSF cytology.
Methods
(1) The study cohort was divided into two groups according to the date of their diagnoses. The PAST group included32patients with intracranial GCTs diagnosed by histopathology or CSF cytology between March1991and September2011. The PRESENT group included26patients, whose diagnoses were made based on the multiple-disciplinary diagnostic platform between September2011and December2012. Demographic information, diagnosis, duration from first symptom to diagnosis, immunohistology of tumor markers and lumber CSF cytology and level of tumor markers in CSF and serum were compared between the two groups.
(2)To investigate the synchronized relationship of0-hCG and a FP between CSF and serum; to evaluate several different diagnostic criteria in current use; a receiver operating characteristic (ROC) curve was made by using patients with langerhans cell histiocytosis (LCH)(n=12) and other intracranial tumors(n=5) as controls. Based on this curve, new cutoff value for β-hCG and a FP in diagnosis of GCTs were investigated; to evaluate tumor markers in early diagnosis of GCTs in male patients with incomplete precocious puberty/latent hypogonadotropic hyperandrogenemia.
(3) The levels of PLAP and s-kit in CSF and serum were measured by ELISA. The difference between PRESENT group, LCH group, other intracranial tumors group and hippocampal sclerosis group (n=5) were compared. ROC curve was used to calculate the reasonable cutoff value of PLAP and s-kit for diagnosis and the new diagnostic criteria was evaluated.
(4) All data were analyzed with SPSS11.5. Independent t test or One-Way ANOVA were used to compare differences between two groups for normal distributed variable and non-normal distributed variable (logarithmic transformed). Wilcoxon signed-ranks test or chi-square test were used for categorical variables; ROC curves were used to calculate the cutoff value for diagnosis; P<0.05is considered as statistically significant.
Results
1. In PAST group and PRESENT group, the ratios of male:female were1.1:1and1.9:1respectively, the average ages of diagnosis were19+7years and13±4years respectively. Incidence rates of isolated sella mass were59.4%and38.5%, and incidence rates of isolated pineal mass were3.1%and15.4%respectively. The rates of diagnosis confirmed by surgical biopsy were71.9%and96.2%respectively. In the final pathological diagnosis of all patients, the incidence of germinomas decreased from90.6%to65.4%. Immunohistochemistry for four tumor markers was stained in9.4%-46.9%patients in PAST group, while it was conducted in100%of PRESENT group; In PAST group, β-hCG and a FP in CSF and serum were measured in50%-57.7%patients, while it increased to100%in PRESENT group; Early diagnosis rate increased from6.3%in PAST group to19.2%in PRESENT group (though chi-square test P>0.05).
2. The total sensitivities of CSFand serum β-hCG>50IU/L as diagnostic criteria were18.8%and30.8%in PRESENT group and PAST group respectively, while the specificities were both100%; the sensitivities of α FP>10ng/mL as diagnostic criteria were13.3%and23.1%in each group respectively, while the specificities were66.7%and83.3%respectively; although the sensitivities of αFP>25ng/mL as diagnostic criteria were6.3%and19.2%in each group respectively, while the specificities were both100%.
3. In ROC curve analysis, CSFβ-hCG≥8.4IU/L had a sensitivity of44%, serum β-hCG≥2.2IU/L had a sensitivity of33.3%and both had a specificity of100%; although the number of patients with positive a FP was not enough, the diagnostic cretria for CSF a FP could be set at3.8 ng/mL and ICGCTs could be effectively diagnosed, no case was found with serum a FP less than25ng/ml.
4. The diagnostic sensitivity of CSF β-hCG increased from26.9%in PAST group to61.5%in PRESENT group, the sensitivity of CSFβ-hCG was higher than that of serum one, which was42.3%(mainly for diagnosis of tumors including STGC); the diagnostic sensitivity of CSF a FP improved from7.7%in PAST group to19.2%in PRESENT group; The total diagnostic sensitivity in PRESENT group increased from38.5%to65.4%, mainly due to CSF β-hCG.
5. The incidence rate of male patients with latent hypogonadotropic hayperandrogenemia was17.6%in PAST group and the incidence rate of male patients with precocious puberty or latent hypogonadotropic hayperandrogenemia was52.9%in PRESENT group caused by high serum level of β-hCG.
6. In PAST and PRESENT groups,66.7%and16.7%of the patients were finally properly diagnosed as mixed GCTs based on the supplementary information from CSF/serum a FP.
7. BBB impairment was demonstrated by higher serum levels of tumor markers than CSF levels. The following diagnostic criteria were used as indication for impaired BBB:serum β-hCG≥2.2IU/L and the concentration in serum is no less than in CSF, or serum a FP≥25ng/mL and the concentration in serum is no less than in CSF; when both criteria were met, impairment of BBB was severe:in PAST group, the incidence of severe impaired BBB was0%; in PRESENT group, the patients of BBB impairment demonstrated by β-hCG and a FP took up18.8%(3cases) and100%(1case) respectively, there was1patient with severely impaired BBB, which took up6.3%of β-hCG positive patients and20%of a FP positive patients.
8. Except in1case of lung cancer metastasized to the sellar area the level of CSF PLAP was significantly elevated (1684pg/mL), the levels were all under the minimum detected value in all studied patients. There was no significant difference of serum s-kit between the studied group and the hippocampus sclerosis group (40.5±9.7ng/mL vs36.1±12.1ng/mL, P>0.05); when CSF s-kit was≥3.0ng/mL, the diagnostic sensitivity and specificity for germinoma was30.8%and100%, respectively, the total diagnosis sensitivity can be increased from64.6%to76.9%with the addition of CSF s-kit in PRESENT group.
Conclusions
1. A multiple-disciplinary diagnostic platform has been established for the early diagnosis of CNS GCTs, the basis of the platform is histopathology and CSF cytology.
2. CSF/serum β-hCG>50IU/L and/or a FP>25ng/mL are confirmed to be more reasonable diagnostic criteria for secreting intracranial GCTs in our study.
3. A new diagnostic cutoff point for intracranial GCTs was made:CSF β-hCG≥8.4IU/L, serum β-hCG≥2.2IU/L; CSF a FP cutoff point is decreased to3.8ng/mL and serum a FP unchanged;
4. CSF or serum β-hCG is valuable for early diagnosis in precocious boy or latent hypogonadotropic hyperandrogenemic male. CSF and serum a FP may provide additional value to the final diagnosis of mixed GCTs; β-hCG and a FP may help to evaluate the severity of BBB impairment.
5. CSF PLAP had no value for diagnosis of intracranial GCTs;
6. CSF s-kit was helpful for the diagnosis of pure germinoma and clinical diagnostic cutoff point is3.0ng/mL.
中枢神经系统生殖细胞肿瘤,通常也称作颅内生殖细胞肿瘤(intracranial germ cell tumors, ICGCTs),分为生殖细胞瘤(germinoma)和非生殖细胞瘤性生殖细胞肿瘤(nongeminomatous germ cell tumors, NGGCTs)两大类。虽然病理亚型是决定预后的最主要因素,但早期积极而规范的诊治无疑也是非常重要之因素。多学科综合诊断平台是获得早期(病程半年内)确诊的基础,通过手术明确病理是建立平台的瓶颈。虽然肿瘤标志物是平台重要组成部分,但其临床诊断价值在国内外均未得到充分研究。当前数种分泌性肿瘤标准的判断依据并未建立在组织病理和脑脊液细胞学基础上。目前关于颅内生殖细胞瘤肿瘤标志物的研究仅限于非生殖细胞瘤特异性的人绒毛膜促性腺激素β亚单位(0subunit of human chorionicgonadotropin, β-hCG)和甲胎蛋白(alpha-fetoprotein, a FP)。而对生殖细胞瘤特异性肿瘤标记物—胎盘碱性磷酸酶(placental alkaline phosphatase, PLAP)和CD117(干细胞因子受体分子,跨膜形式为c-kit,可溶性形式为s-kit)未常规开展测定和进一步的研究。因此需要建立综合平台,以组织病理和脑脊液细胞学为基础,评估脑脊液和血清中肿瘤标志物—β-hCG、α FP及PLAP、s-kit对颅内生殖细胞肿瘤的诊断价值。
[研究方法]
1.将1991年3月至2011年9月20年期间我院32例经组织病理／脑脊液细胞学确诊的颅内GCTs患者(既往组)及在多科综合诊断平台基础上,自2011年9月至2012年12月期间我院26例患者(研究组)的诊断情况进行比较：包括患者基本情况、确诊情况、延迟诊断情况、肿瘤标志物染色和脑脊液细胞学情况、CSF和血清中肿瘤标志物测定水平。
2.结合两组可用同步CSF和血清肿瘤标志物数据,观察β-hCG、αFP水平的分布差别；评价当前不同的诊断标准的优劣；以朗格汉斯细胞组织细胞增生症组(langerhans cell histiocytosis. LCH,12例)和其余颅内肿瘤组(5例)为对照,用受试者工作曲线(receiver operating characteristic, ROC)计算p-hCG及α FP在CSF和血清中相应的新诊断切点,并评估新标准的诊断价值；评价男性不完全性性早熟／隐匿性低促性腺激素性高雄激素血症患者中肿瘤标志物对于早期诊断的提示意义。
3.用ELISA法测定研究组、LCH组、其余颅内肿瘤组和海马硬化组(5例)的CSF和血清中PLAP和s-kit水平,用ROC曲线分别计算两者合理诊断切点；并评估新标准的诊断价值
4.使用SPSS11.5作为数据统计的工具；正态分布数值资料、非正态分布数值资料(经对数变换后)使用独立样本T检验,或单因素方差分析(One-Way ANOVA)比较统计学差异；分类资料行wilcoxon signed-ranks test或卡方检验；ROC曲线计算诊断切点；P<0.05认为有统计学差异。
[研究结果]
1.既往组和研究组男女比例分别为1.1：1和1.9：1,平均确诊年龄分别为19±7岁和13±4岁；单纯鞍区病变比例分别为59.4%和38.5%,单纯松果体区病变比例分别为从3.1%和15.4%；手术确诊比例从71.9%增至96.2%；最终病理中,生殖细胞瘤比例从90.6%减至65.4%；4种肿瘤标志物免疫组化染色比例从9.4%-46.9%增至100%；β-hCG和α FP在CSF及血清肿瘤标志物测定率从50%-57.7%增至100%；早期确诊比例从6.3%增至19.2%(卡方值仍>0.05)。
2.CSF及血清中β-hCG≥50IU/L标准在既往组和研究组的总体诊断敏感性分别为18.8%和30.8%,特异性均为100%；而αFP≥10ng/mL标准在两组诊断敏感性分别为13.3%和23.1%,特异性分别为66.7%和83.3%,虽然α FP≥25ng/mL标准诊断敏感性分别为6.3%和19.2%,但特异性均为100%。
3.经ROC曲线分析,当CSF β-hCG≥8.4IU/L时,敏感性为44%；血清β-hCG≥2.2IU/L时,敏感性为33.3%,特异性均为100%；虽然αFP阳性病例数不足,但CSF α FP在3.8ng/mL时,仍能有效诊断颅内GCTs病例,血清α FP数值中未发现较25ng/mL标准更低的病例。
4.研究组CSF β-hCG诊断敏感性从26.9%增加至61.5%,高于同组血清β-hCG敏感性42.3%(主要用于诊断含STGC肿瘤)；CSF a FP诊断敏感性也从7.7%提高至19.2%；研究组总体诊断敏感性从38.5%提高至65.4%,其中最主要的比重来自于CSF β-hCG。
5.既往组中占男性比例17.6%的病例为高β-hC6血症所致的隐匿性低促高雄患者；研究组中占男性比例52.9%的病例为高β-hCG血症所致的性早熟或隐匿性低促高雄患者。
6.对既往组中有66.7%、研究组中有16.7%的病例根据CSF或血清α FP完善了混合性GCTs的最终诊断。
7.血清肿瘤标志物水平大于CSF中水平可证实BBB受损：以血清β-hCG≥2.2IU/L且≥CSF中水平；或血清α FP≥25ng/mL且≥CSF中水平为判断标准,两者均受损则为BBB严重受损：既往组中比例均为0%；研究组中由β-hCG和α FP证实BBB受损病例分别占18.8%(3例)和100%(5例),严重受损者1例,占β-hCG阳性病例的6.3%,占α FP阳性病例的20%。
8.除1例鞍区转移性肺癌病例CSF中PLAP明显升高(1684pg/mL)以外,研究组和所有对照组病例对应数值均低于最小可测值；研究组和海马硬化组血清中s-kit水平之间无统计学差异(40.5±9.7ng/mL vs36.1±12.1ng/mL,P>0.05)；CSF中s-kit≥3.0ng/mL时,诊断敏感性为30.8%,特异性为100%,可将研究组总体诊断敏感性从64.6%提高至76.9%。
[结论]
1.通过建立和完善颅内生殖细胞肿瘤综合诊断平台有助于此病早期确诊；在此平台中,以组织病理和CSF细胞学为基础是本研究得以深入开展的关键。
2.本研究明确了分泌型颅内GCTs诊断标准之一：CSF/血清中β-hCG≥50IU/L和／或α FP≥25ng/mL的合理性；
3.本研究进一步制订出新的β-hCG临床诊断切点：CSFβ-hCG≥8.4IU/L血清β-hCG≥2.2IU/L；CSFαFP诊断标准下调为3.8ng/mL,血清中标准不变。
4.CSF或血清β-hCG对于以性早熟起病的男童或隐匿性低促高雄男性有提高早期临床诊断敏感性的作用；CSF或血清α FP对混合性GCTs有提高完善诊断敏感性的作用；β-hCG和α FP还可用于评估血脑屏障损伤及程度。
5.CSF中PLAP诊断颅内GCTs价值有限。
6.CSF中s-kit可用于诊断纯生殖细胞瘤,临床诊断切点为3.0ng/mL。
Objective
Germ cell tumors (GCTs) from the central nervous system (CNS), usually called intracranial germ cell tumors(ICGCTs) are traditionally classified into germinoma and nongeminomatous germ cell tumors (NGGCTs). Although the pathologic subtype is the most important factor to predict prognosis, normalized diagnostic and therapeutic algorithm as early as possible is also very important. A multiple-disciplinary diagnostic platform is the basis for early diagnosis (in half a year from onset of disease), and histopathological or cytological confirmation by surgical or cerebrospinal fluid (CSF) management is the most important part of it. Tumor markers are indispensible in this platform, however, their clinical values have not been comprehensively investigated. The current several kinds of diagnostic criterior of "secreting" tumors is not established on the basis of histopathology or cytology from lumber CSF, and the tumor markers are only limited to non germinoma specific β subunit of human chorionicgonadotropin (β-hCG) and alpha-fetoprotein (αFP), while the value of some germinoma-specific tumor markers, such as placental alkaline phosphatase (PLAP) and CD117(a stem cell factor receptor with several variants:the transmembrane form as "c-kit" and the soluble form as "s-kit"), has not been routinely measured and investigated further. Therefore, a multiple-disciplinary platform is needed to be established to evaluate tumor markers (β-HCG, αFP, PLAP and s-kit) in lumber CSF and serum in the diagnosis of CNS GCTs based on histopathology and CSF cytology.
Methods
(1) The study cohort was divided into two groups according to the date of their diagnoses. The PAST group included32patients with intracranial GCTs diagnosed by histopathology or CSF cytology between March1991and September2011. The PRESENT group included26patients, whose diagnoses were made based on the multiple-disciplinary diagnostic platform between September2011and December2012. Demographic information, diagnosis, duration from first symptom to diagnosis, immunohistology of tumor markers and lumber CSF cytology and level of tumor markers in CSF and serum were compared between the two groups.
(2)To investigate the synchronized relationship of0-hCG and a FP between CSF and serum; to evaluate several different diagnostic criteria in current use; a receiver operating characteristic (ROC) curve was made by using patients with langerhans cell histiocytosis (LCH)(n=12) and other intracranial tumors(n=5) as controls. Based on this curve, new cutoff value for β-hCG and a FP in diagnosis of GCTs were investigated; to evaluate tumor markers in early diagnosis of GCTs in male patients with incomplete precocious puberty/latent hypogonadotropic hyperandrogenemia.
(3) The levels of PLAP and s-kit in CSF and serum were measured by ELISA. The difference between PRESENT group, LCH group, other intracranial tumors group and hippocampal sclerosis group (n=5) were compared. ROC curve was used to calculate the reasonable cutoff value of PLAP and s-kit for diagnosis and the new diagnostic criteria was evaluated.
(4) All data were analyzed with SPSS11.5. Independent t test or One-Way ANOVA were used to compare differences between two groups for normal distributed variable and non-normal distributed variable (logarithmic transformed). Wilcoxon signed-ranks test or chi-square test were used for categorical variables; ROC curves were used to calculate the cutoff value for diagnosis; P<0.05is considered as statistically significant.
Results
1. In PAST group and PRESENT group, the ratios of male:female were1.1:1and1.9:1respectively, the average ages of diagnosis were19+7years and13±4years respectively. Incidence rates of isolated sella mass were59.4%and38.5%, and incidence rates of isolated pineal mass were3.1%and15.4%respectively. The rates of diagnosis confirmed by surgical biopsy were71.9%and96.2%respectively. In the final pathological diagnosis of all patients, the incidence of germinomas decreased from90.6%to65.4%. Immunohistochemistry for four tumor markers was stained in9.4%-46.9%patients in PAST group, while it was conducted in100%of PRESENT group; In PAST group, β-hCG and a FP in CSF and serum were measured in50%-57.7%patients, while it increased to100%in PRESENT group; Early diagnosis rate increased from6.3%in PAST group to19.2%in PRESENT group (though chi-square test P>0.05).
2. The total sensitivities of CSFand serum β-hCG>50IU/L as diagnostic criteria were18.8%and30.8%in PRESENT group and PAST group respectively, while the specificities were both100%; the sensitivities of α FP>10ng/mL as diagnostic criteria were13.3%and23.1%in each group respectively, while the specificities were66.7%and83.3%respectively; although the sensitivities of αFP>25ng/mL as diagnostic criteria were6.3%and19.2%in each group respectively, while the specificities were both100%.
3. In ROC curve analysis, CSFβ-hCG≥8.4IU/L had a sensitivity of44%, serum β-hCG≥2.2IU/L had a sensitivity of33.3%and both had a specificity of100%; although the number of patients with positive a FP was not enough, the diagnostic cretria for CSF a FP could be set at3.8 ng/mL and ICGCTs could be effectively diagnosed, no case was found with serum a FP less than25ng/ml.
4. The diagnostic sensitivity of CSF β-hCG increased from26.9%in PAST group to61.5%in PRESENT group, the sensitivity of CSFβ-hCG was higher than that of serum one, which was42.3%(mainly for diagnosis of tumors including STGC); the diagnostic sensitivity of CSF a FP improved from7.7%in PAST group to19.2%in PRESENT group; The total diagnostic sensitivity in PRESENT group increased from38.5%to65.4%, mainly due to CSF β-hCG.
5. The incidence rate of male patients with latent hypogonadotropic hayperandrogenemia was17.6%in PAST group and the incidence rate of male patients with precocious puberty or latent hypogonadotropic hayperandrogenemia was52.9%in PRESENT group caused by high serum level of β-hCG.
6. In PAST and PRESENT groups,66.7%and16.7%of the patients were finally properly diagnosed as mixed GCTs based on the supplementary information from CSF/serum a FP.
7. BBB impairment was demonstrated by higher serum levels of tumor markers than CSF levels. The following diagnostic criteria were used as indication for impaired BBB:serum β-hCG≥2.2IU/L and the concentration in serum is no less than in CSF, or serum a FP≥25ng/mL and the concentration in serum is no less than in CSF; when both criteria were met, impairment of BBB was severe:in PAST group, the incidence of severe impaired BBB was0%; in PRESENT group, the patients of BBB impairment demonstrated by β-hCG and a FP took up18.8%(3cases) and100%(1case) respectively, there was1patient with severely impaired BBB, which took up6.3%of β-hCG positive patients and20%of a FP positive patients.
8. Except in1case of lung cancer metastasized to the sellar area the level of CSF PLAP was significantly elevated (1684pg/mL), the levels were all under the minimum detected value in all studied patients. There was no significant difference of serum s-kit between the studied group and the hippocampus sclerosis group (40.5±9.7ng/mL vs36.1±12.1ng/mL, P>0.05); when CSF s-kit was≥3.0ng/mL, the diagnostic sensitivity and specificity for germinoma was30.8%and100%, respectively, the total diagnosis sensitivity can be increased from64.6%to76.9%with the addition of CSF s-kit in PRESENT group.
Conclusions
1. A multiple-disciplinary diagnostic platform has been established for the early diagnosis of CNS GCTs, the basis of the platform is histopathology and CSF cytology.
2. CSF/serum β-hCG>50IU/L and/or a FP>25ng/mL are confirmed to be more reasonable diagnostic criteria for secreting intracranial GCTs in our study.
3. A new diagnostic cutoff point for intracranial GCTs was made:CSF β-hCG≥8.4IU/L, serum β-hCG≥2.2IU/L; CSF a FP cutoff point is decreased to3.8ng/mL and serum a FP unchanged;
4. CSF or serum β-hCG is valuable for early diagnosis in precocious boy or latent hypogonadotropic hyperandrogenemic male. CSF and serum a FP may provide additional value to the final diagnosis of mixed GCTs; β-hCG and a FP may help to evaluate the severity of BBB impairment.
5. CSF PLAP had no value for diagnosis of intracranial GCTs;
6. CSF s-kit was helpful for the diagnosis of pure germinoma and clinical diagnostic cutoff point is3.0ng/mL.
引文
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