New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center.
New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center.
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DOI：
10.1016/j.jtho.2018.04.023
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Girard N
中科院分区：
文献类型：
--
作者：
Galateau Salle F;Le Stang N;Nicholson AG;Pissaloux D;Churg A;Klebe S;Roggli VL;Tazelaar HD;Vignaud JM;Attanoos R;Beasley MB;Begueret H;Capron F;Chirieac L;Copin MC;Dacic S;Danel C;Foulet-Roge A;Gibbs A;Giusiano-Courcambeck S;Hiroshima K;Hofman V;Husain AN;Kerr K;Marchevsky A;Nabeshima K;Picquenot JM;Rouquette I;Sagan C;Sauter JL;Thivolet F;Travis WD;Tsao MS;Weynand B;Damiola F;Scherpereel A;Pairon JC;Lantuejoul S;Rusch V;Girard N
2015年WHO肿瘤分类将恶性间皮瘤分为上皮样、双相（BMM）和肉瘤样（SMM），以用于预后相关性和治疗决策。BMM的存活被怀疑与肉瘤样成分的量相关。肉瘤样成分的标准和病理学家之间鉴别该成分的观察者间变异性还没有很好的描述。在不明确的情况下，已经提出了“过渡”（TMM）亚型，但在2015年WHO分类中未被接受为特定亚型。本研究的目的是评估观察者之间在BMM诊断中的一致性，确定TMM亚型的性质和意义，并将肉瘤样成分的百分比与生存率联系起来。BRCA-1相关蛋白（BAP 1）和CDKN2A（p16）荧光原位杂交（FISH）染色的价值也进行了评估，相对于每个肿瘤成分。该研究由法国国家癌症研究所、罕见癌症网络（EURACAN）支持的国际间皮瘤小组与国际肺癌研究协会（IASLC）合作进行。患者病例包括一组随机的42例诊断为BMM的手术活检样本，由法国MESOPATH专家小组从1998年至2016年收集的971例BMM病例中选择SMM成分进行评价。14名具有间皮瘤专业知识的国际病理学家在不了解既往诊断或结局的情况下审查了数字扫描切片（苏木精和伊红染色和泛细胞角蛋白）。选择14名病理学家中至少有7名认识TMM特征的病例作为TMM组。从MESOBANK数据库中检索人口统计学、临床、组织病理学、治疗和随访数据。分别通过免疫组织化学（IHC）和FISH评估BAP 1（克隆C-4）缺失和CDKN2A（p16）纯合缺失（HD）。采用Kappa统计分析观察者间一致性，采用经年龄和性别校正的考克斯回归分析进行多变量分析以进行生存分析。14名小组成员共记录了544项诊断。观察者间相关性为中度（加权Kappa = 0.45）。在最初被MESOPATH分类为BMM的病例中，评审员同意71%的病例（544个意见中的385个），17%的病例（544个意见中的93个）被分类为纯上皮样，12%的病例（544个意见中的66个）被分类为纯肉瘤样。23%的病例仅根据形态学或IHC诊断BMM，77%的病例（402/544）进行了额外的IHC评估。42例BMM患者中位总生存期（OS）为8个月。BMM的OS与SMM和上皮样恶性间皮瘤有显著差异（p <0.0001）。在BMM中，小于80%的肉瘤样成分与更好的生存率相关（p = 0.02）。BMM与TMM之间的生存率有显著差异，显示中位生存期为6个月，而无TMM的患者为12个月（p <0.0001）。在50%（42例中的21例）的病例中观察到BAP 1丢失，在26%的病例中观察到两种成分的BAP 1丢失。我们还将TMM组与更具侵袭性的上皮样间皮瘤亚型（我们的大型MESOPATH队列的实体和多形性）进行了比较。移行型曲线持续接近肉瘤样成分的OS曲线。肉瘤样间皮瘤、移行性间皮瘤和多形性间皮瘤的组群非常接近。然后，我们考虑了BAP 1免疫染色和CDKN 2A（p16）的FISH损失的贡献。在50%（21/41）的病例中观察到BAP 1丢失，在27%（11/41）的病例中观察到两种成分的BAP 1丢失。TMM组和非TMM组之间BAP 1丢失无显著差异。HD CDKN2A（p16）在74%的病例中被检测到，在TMM组和非TMM组之间没有显著差异。在多变量分析中，TMM形态是预后不良的指标，风险比= 3.2; 95%置信区间：1.6 - 8.0; p = 0.003，即使与肉瘤样成分上存在HD CDKN 2A（p16）相比（风险比= 4.5; 95%置信区间：1.2 - 16.3，p = 0.02）。国际间皮瘤和法国间皮瘤小组之间的观察者一致性表明，双相间皮瘤的更新定义具有临床实用性，可以更好地将患者分层为治疗决策，全身抗癌治疗或选择手术或姑息治疗的风险组。我们还显示了CDKN2A（p16）HD的FISH检测与梭形细胞成分的BAP 1缺失相比，在良性华丽间质反应与双相间皮瘤的真正肉瘤样成分之间的模糊病例中分离的有用性。总之，我们的研究结果进一步验证了过渡模式作为一个不良预后指标的概念。
The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a “transitional” (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components. The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin – stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis. The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a signicant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 – 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 – 16.3, p = 0.02). The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator.
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影响因子：
3.3
作者：
Hasegawa S;Okada M;Tanaka F;Yamanaka T;Soejima T;Kamikonya N;Tsujimura T;Fukuoka K;Yokoi K;Nakano T
通讯作者：
Nakano T
影响因子：
4.6
作者：
Churg, Andrew;Galateau-Salle, Francoise
通讯作者：
Galateau-Salle, Francoise
DOI：
10.1038/modpathol.2011.146
发表时间：
2012-02
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.3
作者：
Combaz-Lair, Christelle;Galateau-Salle, Francoise;Lantuejoul, Sylvie
通讯作者：
Lantuejoul, Sylvie
影响因子：
5.6
作者：
Berg, Kyra B.;Churg, Andrew
通讯作者：
Churg, Andrew