The 5th Edition of the World Health Organization Classification of Tumours of the Eye and Orbit

The WHO Classification of Tumours aims to provide an evidence-based taxonomy for tumors of each organ system to standardize diagnostic practice worldwide and to promote translational research on cancer [1]. The 5th edition of the WHO Classification of Tumours of the Eye and Orbit (WHO Eye5) builds and improves upon the 4th edition (WHO Eye4) by furnishing a comprehensive summary of all tumors of the eye and ocular adnexa that an ophthalmic oncologist and ophthalmic pathologist may encounter [2, 3]. It employs a standardized, evidence-based approach to integrate the salient epidemiologic, ophthalmic, genetic, diagnostic, and prognostic data into a format that allows the reader to grasp the site-specific information on each tumor type and allows cross-referencing with other WHO 5th edition volumes [1, 2]. This review outlines the major general and specific changes in the WHO Eye5, which is currently available online as a beta version ahead of print [2].

The goal of the WHO Classification of Tumours is to provide an up-to-date synthesis of information on cancer, based on expert consensus review of evidence-based published data [1]. Two hundred authors and editors have participated in the production of the WHO Eye5 [2]. The revision was led by the WHO Classification of Tumours Editorial Board, composed of standing and expert members. The standing members have been nominated by pathology organizations and are the equivalent of the series editors of previous editions. The expert members have been selected on the basis of informed bibliometric analysis and advice from the standing members and are equivalent to the volume editors of previous editions. In recognition of the increasingly multidisciplinary approach to cancer diagnosis, prognostication, and management, the 5th edition authors, expert members, and editorial board included oncologists, radiologists, molecular biologists, geneticists, and pathology experts from the overlapping pathology disciplines (head and neck, dermatopathology, soft tissue pathology, and hematopathology) to address WHO Eye5-specific needs [2].

The WHO Eye5 aims to provide the most comprehensive overview of the eye and orbit tumors an ophthalmic oncologist and pathologist may encounter, with cross-reference to other volumes as necessary. Although the WHO Eye5 continues to be organized by anatomical site (e.g., conjunctiva, eyelid, uvea), its major differences with the WHO Eye4 are incorporation of tumor lineage (e.g., epithelial, adnexal, melanocytic) into the classification system, and synthesis of ocular and periocular soft tissue and bone tumors, hematolymphoid tumors, metastases, and genetic tumor predisposition syndromes into separate chapters, following the structure of the other WHO 5th edition volumes [1, 2]. In line with the 5th edition format, the WHO Eye5 content logically progresses from non-neoplastic tumor-like lesions, to benign neoplasms and, finally, to malignant neoplasms. The standardized, systematic approach is adopted to illuminate each tumor, with addition of the ICD11-codes, imaging features when relevant, macroscopic appearance, cytology, diagnostic molecular pathology, essential and desirable diagnostic criteria, and staging (Table 1).

The WHO Eye5 aims to use the most recent evidence-based nomenclature for classification of tumors. One major change was adoption, where possible, of the terminology proposed in 2018 by the International Society for the Study of Vascular Anomalies (ISSVA) to classify vascular tumors and malformations [4]. The definitions of tumor “type,” “subtype,” and “morphologic pattern” are implemented to classify the tumors (Table 2) [1, 2]. The preference for “subtype” over “variant” stems from the need to differentiate this concept from the homonymous genetic term “variant” to avoid potential confusion. Where appropriate, the WHO 5th edition volumes use the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC) system for gene symbols and names (https://www.genenames.org/) [5] and the Human Genome Variation Society (HGVS) recommendations for sequence variants (http://varnomen.hgvs.org) [6]. Another notable change in the 5th edition volumes is conversion of the mitotic count from the traditional denominator, number of high-power fields, to a defined area expressed in mm²[7].

The WHO Classification of Tumours Online website, which currently features the WHO Eye4, was launched in 2019 [1]. The WHO Eye5 will replace this on the website. In addition to the text, tables, and figures, the online edition will provide a whole slide image library, which will allow a more detailed histopathologic representation of various tumors. The online format also allows easy cross-referencing of tumor entities across body sites and organ systems for non-site-specific details.

This chapter provides an update on pathogenesis and molecular genetics of melanocytic conjunctival lesions (Table 4) [2, 8‒27]. Spitz nevus is removed from this chapter because of the lack of molecularly well-documented cases of this tumor in the conjunctiva. Conversely, the WNT-activated deep penetrating/plexiform melanocytoma (nevus) (DPN) – the recently agreed terminology for DPN – is added as a new well-characterized entity in the conjunctiva. This follows the 5th edition WHO Classification of the Tumours of the Skin that acknowledges that melanocytomas are genetically “intermediate” between nevus and melanoma because they carry pathogenic mutations additional to the initiating mutation that is the sole alteration in a nevus. Unlike in the skin, a WNT-activated DPN in the conjunctiva is usually a part of a combined nevus (with a common nevocellular or an inflamed juvenile nevus; shown in Fig. 1) [2, 14‒17]. Another notable change is the evolving WHO classification of the conjunctival melanocytic intraepithelial lesions, based on the recent international study and on the WHO consensus editorial meeting between dermatopathologists and ophthalmic pathologists (Table 5) [2, 28, 29]. Non-neoplastic pterygium and pinguecula were added as “tumor-like lesions” to delineate them from conjunctival squamous intraepithelial neoplasia. The term adenosquamous carcinoma, introduced in the Eye4 as the preferred term for mucoepidermoid carcinoma, is now recommended to be applied only to neoplasms with bi-phenotypic differentiation comprising squamous cell carcinoma and adenocarcinoma with mucin-containing cells (shown in Fig. 2) [2, 30]. Tumors that do not form true neoplastic glands/ducts or confluent sheets of cells with intracytoplasmic mucin and, instead, show scattered or small clusters of cells with such mucin in a background of malignant squamous cells are designated as “squamous cell carcinoma with mucinous differentiation” (shown in Fig. 3) [2, 30]. Sebaceous carcinoma, covered in Tumors of the Eyelid chapter, has been removed. Soft tissue tumors, hematolymphoid neoplasms, and secondary tumors of the conjunctiva are discussed in separate chapters.

This chapter covers common benign and malignant eyelid tumors with attention to their site-specific features. Rare adnexal tumors with predilection for the eyelid, such as sebaceous neoplasms and endocrine mucin-producing sweat gland carcinoma (shown in Fig. 4), and lesions that are unique to the eyelid, such as intratarsal keratinous cyst (shown in Fig. 5a–c) and phakomatous choristoma (shown in Fig. 5d–f), are also illuminated in this chapter [31‒36]. The material is coordinated with the 5th edition WHO Classification of the Tumours of the Skin, particularly with regard to cutaneous melanocytic tumors.

This chapter is limited to the non-neoplastic iris lesions and uveal melanocytic tumors and tumor-like lesions. Entities that can involve any portion of the uveal tract are described according to their dominant site. The most notable update is addition of diagnostic cytopathology for benign and malignant melanocytic tumors of the iris, ciliary body, and choroid (Table 8) [2, 37‒42]. This chapter provides an update on pathogenesis of uveal melanocytoma, which harbors solitary GNAQ mutations without additional oncogenic alterations and thus distinct from cutaneous and conjunctival melanocytoma [43], and that of bilateral diffuse uveal melanocytic proliferation, which may involve autoantibodies to hepatocyte growth factor [44, 45]. Soft tissue tumors of the uveal tract, including hemangioma, peripheral nerve sheath tumors, and smooth muscle tumors are covered in chapters dedicated to these entities.

This chapter is devoted to the tumors and tumor-like lesions of the retina, retinal pigment epithelium, and the iris and ciliary body epithelia. Retinocytoma is classified as a premalignant tumor, considering the genetic data that these tumors carry biallelic RB1 mutations and clinical evidence that they can dedifferentiate into retinoblastoma [45, 46]. The chapter includes recent consensus protocols on screening of children at risk for retinoblastoma [47, 48] and data on MYCN-amplified, RB1 wild-type retinoblastoma (shown in Fig. 6) [49]. Novel molecular genetic methods, like liquid biopsies of tumor-derived cell-free DNA from aqueous fluid for prognostication and from plasma for prenatal testing and detection of nonocular primary malignancies in children with retinoblastoma, are discussed [50‒52]. Coverage of diagnostic cytopathology for tumors of the retina and neuroepithelium is a notable addition (Table 10) [2, 53‒60]. The spectrum of nodular and massive gliosis is described, nodular gliosis being the preferred term for vasoproliferative tumor [2]. True vascular lesions of the retina are covered in the chapters dedicated to vascular malformations and vascular neoplasms.

This chapter focuses on primary lesions of the optic disk and pre-chiasmal optic nerve. Optic nerve choristoma, a rare, benign, developmental/malformative lesion composed of smooth muscle and adipose tissue within and around the optic nerve, is added to this chapter [2, 61, 62] that is coordinated with the 5th edition of WHO Classification of the Tumours of the Central Nervous System [63].

Two separate chapters provide an update regarding molecular biology and diagnosis of benign and malignant epithelial lacrimal gland (Table 13) and lacrimal drainage system tumors and include new sections on diagnostic cytopathology [64‒106]. Obsolete entities, such as oncocytic carcinoma, have been removed. Tumors that are rarely encountered in the lacrimal gland or are controversial in this region, such as Warthin tumor, are also removed.

This new chapter, which focuses primarily on orbital teratomas, choristomas, and hamartomas, adopts, where possible, ISSVA terminology to classify vascular malformations of the eye and orbit [4]. Cavernous vascular malformation (cavernous hemangioma), combined lymphatic-venous malformation (lymphangioma), and orbital venous malformation (orbital varix) are discussed, with an update on their molecular genetics and pathogenesis [2]. Vascular neoplasms are covered in the chapter dedicated to soft tissue tumors.

In this chapter, reactive lesions of the eye and orbit, and intraocular and ocular adnexal hematolymphoid proliferations are presented separately. The chapter provides an update on the molecular genetics, diagnostic cytopathology, diagnostic molecular pathology, and essential and desirable diagnostic criteria of intraocular lymphomas (shown in Fig. 7, Fig. 8 and Fig. 9; Table 16) [107‒129]. Ocular adnexal lymphomas, myeloid neoplasms, and histiocytic and dendritic cell neoplasms are comprehensively discussed, emphasizing site-specific characteristics and the most up-to-date immunophenotypic, molecular genetic, and prognostic features [2, 130, 131]. The material is coordinated with the 5th edition of WHO Classification of the Hematolymphoid Tumours [132].

This chapter provides salient clinical, radiologic, etiological, pathogenic, diagnostic, and prognostic information on each ocular and ocular adnexal soft tissue tumor, with an emphasis on site-specific characteristics. Vascular lesions classified as benign neoplasms of blood vessels, in accordance with the ISSVA nomenclature [4], such as infantile hemangioma and lobular capillary hemangioma, are covered. Vascular malformations are discussed in the chapter dedicated to the tumors of the orbit. The material is coordinated with the 5th edition of WHO Classification of the Soft Tissue and Bone Tumours [133].

This chapter combines information from the prior edition on secondary and metastatic tumors to various ocular tissues into a separate section, Metastases to Intra-Ocular Structures[2]. Analogously, metastases to ocular adnexa are covered in a new section, Metastases to Ocular Adnexal Structures[2].

This chapter synthesizes the most up-to-date clinical, epidemiologic, genetic, diagnostic, and prognostic information on the genetic tumor predisposition syndromes of particular relevance to the ophthalmologist: the retinoblastoma syndrome, BAP1 tumor predisposition syndrome, von Hippel-Lindau syndrome, Sturge-Weber syndrome, neurofibromatosis type 1, Goldenhar syndrome, and Muir-Torre syndrome [2]. The information is coordinated with the upcoming new WHO Classification of Tumours volume, on genetic tumor syndromes, which will be last of the 14 vol making up the 5th edition.

In conclusion, the WHO Eye5 provides an up-to-date comprehensive taxonomy for the range of tumors occurring in the eye and orbit with an emphasis on their site-specific features. The information presented is standardized across the 5th edition volumes. This systematic approach not only facilitates cross-referencing the information presented with other volumes within the classification, but also highlights the remaining gaps in knowledge. As such, the classification will not only serve as a valuable reference for a practicing ophthalmic oncologist and pathologist, but also drive future research bridging various oncology and pathology disciplines. It is hoped that the information conveyed in this overview will help to distill the major changes in the latest edition and will facilitate more detailed study of the volume.

The authors acknowledge the International Agency for Research on Cancer (IARC) staff, IARC editorial board, and authors, who have directly and indirectly contributed to the WHO Eye5 edition and other 5th edition WHO volumes, on whose behalf this paper has been prepared.

Participants provided written informed consent for the publication of their details and any accompanying images.

The authors have no conflicts of interest to declare.

No funding received.

Study design and data acquisition (T.M., H.E.G., I.A.C., G.G.-L., T.T.K., S.E.C., H.S.M., C.G.E., R.M.V., S.H., A.J.G., A.A.R., B.E., M.J.J., V.A.W., and J.C.H.), manuscript drafting (T.M.), and manuscript review (T.M., H.E.G., I.A.C., G.G.-L., T.M., H.E.G., I.A.C., G.G.-L., T.T.K., S.E.C., H.S.M., C.G.E., R.M.V., S.H., A.J.G., A.A.R., B.E., M.J.J., V.A.W., and J.C.H.). The content of this article represents the personal views of the authors and does not represent the views of the authors’ employers and associated institutions. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.