Hematopathology diagnosis and education

在血液病理学学会（SH）和欧洲血液病理学协会（EAHP）的主持下，对世界卫生组织（世卫组织）的《造血和淋巴组织肿瘤分类》进行了修订和更新，形成了新的版本（第4版）。这一举措是2001年世卫组织分类的延续，在过去几年中，世界各地的病理学家和临床医生在广泛接受和普遍使用方面取得了重大进展。这种分类的成功是由于所有参与者之间建立的主要共识，该建议是生物学上合理的，临床相关的，并且在全球不同的临床环境中实际上易于使用。目前世界卫生组织分类的主要原则，主要根据其谱系对肿瘤进行分层，并根据形态学、免疫表型、遗传和分子特征以及临床表现的结合对不同的临床相关疾病进行定义，被认为是一个坚实的框架，其中应纳入新的知识和观点。过去几年产生的新知识突出了世卫组织现行分类中需要修订和更新的几个方面，包括需要澄清一些定义不清的类别，纳入新的定义实体，以及考虑新的概念和信息。新的分类完善了已确立的疾病的定义，如慢性淋巴细胞白血病（CLL）、淋巴浆细胞性淋巴瘤和Waldestrom巨球蛋白血症和t细胞淋巴瘤，如间变性大细胞淋巴瘤（ALCL）和皮下泛膜炎样t细胞淋巴瘤。对旧的争议的共识包括认识到区分滤泡性淋巴瘤（FL）的1级和2级在临床上没有相关性，但区分3b级和3a级是很重要的，因为它可能对应的类别可能比传统的FL更接近弥漫性大b细胞淋巴瘤（DLBCL）。弥漫性大b细胞淋巴瘤的类别已经认识到接受这两种类型的基因表达谱的重要贡献生发中心分子亚型和活化b细胞衍生的DLBCL。然而，除了微阵列表达谱之外，用可靠的工具诊断这些亚型的困难阻碍了在临床实践中推荐使用这些类别。不同的亚型和新的实体已经被接受，特别是在终末b细胞分化的DLBCL中，如ALK阳性DLBCL，与慢性炎症相关的DLBCL，浆母细胞淋巴瘤，HHV-8相关多中心Castleman病引起的大细胞淋巴瘤，以及老年人的EBV+ DLBCL。在外周t细胞淋巴瘤中，间变性大细胞淋巴瘤（ALCL） ALK阳性是一种特殊的实体，应与形态和表型相似但ALK阴性的肿瘤区分开来，后者被认为是不同的临时类别。皮下泛膜炎样t细胞淋巴瘤的诊断现在仅限于具有α / β表型的病例，因为具有γ / δ表型的类似肿瘤被重新分类为原发性皮肤γ / δ t细胞淋巴瘤，这一类别似乎更具侵袭性，经常全身传播。新概念该分类识别了早期病变和惰性形式的淋巴瘤，可能对应于淋巴瘤发生的早期阶段，如单克隆b细胞淋巴细胞增多症，或滤泡性淋巴瘤和套细胞原位淋巴瘤。这些情况的识别对于研究淋巴瘤形成的早期机制具有概念意义，但也具有临床重要性，因为这些患者可能需要更保守的治疗方法。一些新的分类已经纳入其中，患者的年龄是一个主要的标识符。因此，儿童滤泡性淋巴瘤和淋巴结边缘区淋巴瘤或儿童ebv阳性淋巴瘤和老年人ebv阳性大细胞淋巴瘤是一种临床病理情况，提示年龄相关的生物学因素可能影响某些淋巴样肿瘤的发病和表现。在某些结外淋巴瘤，如MALT、原发性纵隔淋巴瘤、脾淋巴瘤和某些原发性皮肤淋巴瘤中，已经认识到特定地形位置作为某些淋巴瘤的重要特征的重要性。这一观点现在已经扩展到附加的B细胞和t细胞原发性皮肤，中枢神经系统DLBCL，并且也认识到起源于十二指肠或皮肤的滤泡性淋巴瘤是具有特定临床病理特征和治疗要求的类别。地形与特定疾病实体之间的这种关系可能与特定的致病机制（传染病）、特定的起源淋巴样细胞（小行星细胞）、部位相关的免疫功能（免疫避难所）或肿瘤-宿主相互作用（淋巴样细胞的归巢）有关。新的分类也确认了两类不同实体之间具有重叠特征的淋巴瘤：b细胞淋巴瘤，无法分类，其特征介于DLBCL和Burkitt淋巴瘤之间；b细胞淋巴瘤，无法分类，其特征介于DLBCL和经典霍奇金淋巴瘤之间。这些类别可能不对应于特定的实体，但重要的是要在临床上被识别，因为这些患者可能需要从更传统的类别中区分出来，以适应不同的临床发展和治疗策略。这些患者需要进一步的调查，有趣的是，这些肿瘤可能代表了淋巴样细胞可塑性的临床例子，可能比最初想象的更广泛。未解决的问题和临时实体在新的分类中有些问题没有得到解决。有几个类别仍然被认为是临时的或正在出现的，因为不清楚它们是否可能对应于其他实体的特殊变体。这些类型包括脾红髓弥漫性b细胞淋巴瘤及其与毛细胞白血病变异的可能关系、原发性皮肤侵袭性表皮性CD8阳性细胞毒性t细胞淋巴瘤、原发性皮肤小/中等CD4阳性t细胞淋巴瘤和ALCL alk阴性等。最后，在更新分类的过程中讨论了新的具有挑战性的观点，但认为在采用常规诊断使用之前需要进一步调查。这些主题包括生物标志物在淋巴瘤预后中的作用，以及微阵列表达谱研究在鉴定新的淋巴瘤亚型或特定分子发病途径的潜在临床价值中产生的信息。

The World Health Organization (WHO) Classification of Tumours of the Haematopoietic and Lymphoid Tissues has been revised and updated for a new edition (4th Edition) under the auspices of the Society of Hematopathology (SH) and the European Association for Haematopathology (EAHP). This initiative is a continuation of 2001 WHO classification that represented a major advance in terms of broad acceptance and general use during the last years by pathologists and clinicians from all over the world. The successes of this classification was due to the major consensus built among all the players based on a proposal that was biologically sound, clinically relevant and practically ease to use worldwide in different clinical settings. The major principles of the current WHO classification, stratification of the neoplasms primarily according to their lineage and the definition of distinct clinically relevant diseases based on a combination of morphology, immunophenotype, genetic and molecular features and clinical manifestations, are considered a solid framework in which the new knowledge and perspectives should be incorporated. The new knowledge generated over the last years has highlighted several aspects of the current WHO classification that need revision and update, including the need for the clarification of some poorly defined categories, the inclusion of new defined entities, and the consideration of new concepts and information Refinement in definitions, advances in old controversies, and new categories The new classification has refined the definition of well established diseases such as chronic lymphocytic leukemia (CLL) lymphoplasmacytic lymphoma and Waldestrom macroglobulinemia and T-cell lymphomas such as anaplastic large cell lymphoma (ALCL) and subcutaneous panniculitis-like T-cell lymphoma. Consensus on old controversies includes the recognition that it is not clinically relevant to distinguish between grades 1 and 2 of follicular lymphoma (FL) but it is important to segregate grade 3b from 3a since it may correspond to a category that may be closer to diffuse large B-cell lymphoma (DLBCL) than conventional FL. The category of diffuse large B-cell lymphoma has recognized the important contribution of gene expression profiling accepting the two molecular subtypes of germinal center and activated B-cell derived DLBCL. However, the difficulties to diagnose these subtypes with reliable tools other than microarray expression profiling prevents from recommending the use of these categories in the clinical practice. Different subtypes and new entities have been accepted, particularly among DLBCL with a terminal B-cell differentiation such as ALK positive DLBCL, DLBCL associated with chronic inflammation, plasmablastic lymphoma, large cell lymphoma arising in HHV-8 associated multicentric Castleman disease, and EBV+ DLBCL of the elderly. Among peripheral T-cell lymphomas, Anaplastic large cell lymphoma (ALCL) ALK positive is a specific entity that should be distinguished from tumors with similar morphology and phenotype but ALK negative, that are considered a different provisional category. The diagnosis of subcutaneous panniculitis-like T-cell lymphoma is now restricted to the cases with an alpha/beta phenotype since similar tumours with gamma/delta phenotype are reclassified as primary cutaneous gamma/delta T-cell lymphoma, a category that appears to be more aggressive with frequent systemic dissemination. New concepts The classification has recognized early lesions and indolent forms of lymphomas that may correspond to early stages of lymphomagenesis such as Monoclonal B-cell lymphocytosis, or follicular lymphoma and mantle cell lymphoma in situ. The identification of these situations are of conceptual interest to investigate the early mechanisms in lymphomagenesis but also of clinical importance since these patients may need a more conservative management approach. Several new categories have been included in which the age of the patients is a major identifier. Thus, pediatric follicular lymphomas and nodal marginal zone lymphomas or the EBV-positive lymphomas of the childhood and the EBV-positive large cell lymphoma of the elderly are clinico-pathologic situations that suggest the potential influence of age-related biological factors in the pathogenesis and manifestations of certain lymphoid neoplasms. The importance of specific topographic sites as an important feature of certain lymphomas had been recognized previously in certain extranodal lymphomas such as MALT, primary mediastinal, splenic, and certain primary cutaneous lymphomas. This idea has been now expanded incorporating additional B and T-cell primary cutaneous, CNS DLBCL, and also recognizing that follicular lymphomas originated in the duodenum or skin are categories with specific clinicopathologic features and management requirements. This relationship between topography and specific disease entities may be related to specific etiopathogenic mechanisms (infectious diseases), particular lymphoid cells of origin (asteroid cells), site related immunological functions (immunological santuaries) or tumor-host interactions (homing of lymphoid cells). The new classification has also recognized two categories that correspond to lymphomas with overlapping features between different entities, the B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma and the B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma. These categories may not correspond probably to specific entities but are important to be recognized clinically because these patients may need to be distinguished form the more conventional categories for the different clinical evolution and treatment strategies. These patients need further investigations and interestingly, these tumours may represent clinical examples of the plasticity of the lymphoid cells that may be broader than initially thought. Unresolved issues and provisional entities Some issues are not resolved in the new classification. Several categories are still considered provisional or emerging because it is not clear if they may correspond to peculiar variants of other entities. These categories include the diffuse B-cell lymphomas of the splenic red pulp and their possible relationship to hairy cell leukemia variant, primary cutaneous aggressive epidermotropic CD8 positive cytotoxic T-cell lymphoma, primary cutaneous small/medium CD4 positive T-cell lymphoma, and the ALCL ALK-negative among others. Finally, new challenging perspectives have been discussed during the process of updating the classification but it was felt that they require further investigations before being adopted for routine diagnostic use. These topics include the role of biomarkers in the prognosis lymphoma, and the information generated by microarray expression profiling studies in the identification new lymphoma subtypes or the potential clinical value of specific molecular pathogenetic pathways.