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

Introduction

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].

Volume Contributors

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].

General Changes

Taxonomy

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).

Table 1.

WHO Eye5: subsection headings and definitions*

Definition

A concise statement/description of the nature of the tumor

ICD-0 coding

ICD-11 coding

Related terminology

Synonyms, older terms, and eponymous terms are listed as either “acceptable” or “not recommended”

Subtypes (formerly known as “variant”)

A tumor variant in which one or two parameters (e.g., clinical, location, histopathological, and/or molecular) make it desirable to recognize it as being distinct from other subtypes but still related to the parent type (tumor “entity”)

Localization

Clinical features (including imaging)

Epidemiology

Etiology

Known risk factors and genetic factors

Pathogenesis

Explicates how the causes described in the “Etiology” subsection lead to tumor formation

Macroscopic appearance

Histopathology

H&E appearance and variation in pathological appearance (morphologic patterns)

Description of recognized histopathological subtypes

Diagnostic immunohistochemistry (IHC)

Grading (where applicable)

Differential diagnosis

Cytology (when clinically relevant)

Diagnostic molecular pathology

Analytic signature of the tumor that is diagnostically useful

Essential and desirable diagnostic criteria

Essential criteria – minimal criteria that are mandatory for diagnosis

Desirable diagnostic criteria – recommended criteria that are not mandatory for diagnosis

Staging

Staging system relevant to tumor, such as American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM classification, Lugano, etc.

Prognosis and prediction

Includes evidence-based information on prognostic and predictive biomarkers, when available

*Adapted from https://bboss.iarc.fr/instructions.php.

Nomenclature

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].

Table 2.

WHO Eye5: definitions of tumor type, subtype, and pattern*

Type (formerly known as “entity”)

Separate entity in which multiple parameters (e.g., clinical, location, histopathological, and/or molecular) differ from those of other types

Subtype (formerly known as “variant”)

A variant of a tumor type in which one or two parameters (e.g., clinical, location, histopathological, and/or molecular) make it desirable to recognize it as being distinct from other subtypes but still related to the parent type

Pattern

Morphologic or immunohistochemical pattern in a tumor, without distinct clinical, molecular, or prognostic parameters that make it desirable to be recognized as a subtype

*Adapted from https://bboss.iarc.fr/instructions.php.

Online version

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.

Specific Changes

Tumors of the Conjunctiva and Caruncle (Table 3)

Table 3.

WHO Eye5: tumors of the conjunctiva and caruncle [2]

Tumor-like lesions and choristomas of the conjunctiva

Cysts of the conjunctiva and caruncle

Epithelial conjunctival inclusion cyst

Reactive, epithelial, and degenerative conjunctival lesions

Reactive epithelial hyperplasia

Papillary and follicular conjunctivitis

Pterygium and pinguecula

Choristomas

Epibulbar choristoma (dermoid; dermolipoma; complex)

Epibulbar osseous choristoma

Epithelial tumors of the conjunctiva

Benign epithelial tumors

Conjunctival squamous papilloma

Conjunctival oncocytoma

Hereditary benign intraepithelial dyskeratosis

Premalignant and malignant epithelial tumors of the conjunctiva

Conjunctival squamous intraepithelial neoplasia

Conjunctival squamous cell carcinoma

Adenosquamous carcinoma

Melanocytic conjunctival tumors

Benign melanocytic conjunctival tumors

Benign epithelial melanosis of the conjunctiva

Junctional, compound, and subepithelial naevi

Inflamed juvenile conjunctival nevus

Blue nevus of the conjunctiva

WNT-activated DPN

Combined nevus of the conjunctiva

Premalignant and malignant melanocytic conjunctival tumors

Conjunctival melanocytic intraepithelial lesions

Conjunctival melanoma

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.

Table 4.

WHO Eye5: melanocytic tumors of the conjunctiva [2]

Conjunctival melanocytic lesion	Molecular genetic alterations	References
Junctional, compound, and subepithelial nevi; inflamed juvenile nevus	BRAF c.1799T>A p.V600E, NRAS mutations	[7–11]
Blue nevus	GNAQ mutations	[10, 12]
WNT-activated DPN	BRAF c.1799T>A p.V600E and CTNNB1 mutations	[13–16]
Melanoma	High-frequency mutations: NF1 (50–33%), BRAF (46–29%), NRAS (26–11%), ATRX (25%), TERT promoter (up to 54%), CTNNB1 (17%) Other mutations: ACSS3, ET, TP53, CKIT, TET2, CDKN2A, MAPK2, RAC1, MET, SF3B1, GNAQ, GNA1 Multiple chromosomal alterations: 6p gain, 11q gain, 6q loss, 10q loss	[17–26]

Fig. 1.

Combined nevocellular and WNT-activated deep penetrating/plexiform melanocytoma (nevus) (DPN) of the conjunctiva. a Circumscribed variably pigmented nodule in plica semilunaris, associated with a feeder vessel. b DPN component of the lesion is composed of lightly pigmented spindle melanocytes with abundant cytoplasm (asterisk), associated with scattered darkly pigmented melanophages (arrowhead). Mostly amelanotic nevocellular nevus (arrow) is present in the periphery. The DPN component of the lesion is positive for HMB45 (red chromogen, c), nuclear cyclin D1 (brown chromogen, d), and cytoplasmic and nuclear beta-catenin (brown chromogen, e). The nevocellular nevoid component of the lesion is negative for these markers (arrows, c–e). No proliferative activity is highlighted with Ki-67 (f) [hematoxylin-eosin (b), HMB45 (c), cyclin D1 (d), beta-catenin (e), Ki-67 (f); all figures. ×200].

Table 5.

2022 World Health Organization Classification of Conjunctival Melanocytic Intraepithelial Lesions [2]

WHO	Acceptable alternative terminology	Increased cellularity	Histologic features	Risk of association with or progression to invasive melanoma
Not applicable	Benign melanosis c-MIN (grades (0–1) PAM without atypia	No/minimal	Conjunctival hypermelanosis (increased pigment in epithelial cells without melanocytic hyperplasia or atypia). Slight or focal melanocytic hyperplasia without atypia (parabasal melanocytes with condensed round nuclei, smaller than basal epithelial cell, inconspicuous nucleoli, and inconspicuous cytoplasm) may be seen	None
Low-grade CMIL	PAM with mild atypia c-MIN (grades 2–4)	Yes	Predominantly basilar melanocytic proliferation with low-grade atypia (dendritic or small to moderate size polyhedral, usually non-epithelioid melanocytes with round to irregular nuclear contours, often nuclear hyperchromasia, inconspicuous nucleoli, and inconspicuous or scant cytoplasm)	Lower
High-grade CMIL	PAM with moderate to severe atypia c-MIN (grade 5–10)	Yes	More confluent basilar and significant non-basilar proliferation of melanocytes with high-grade atypia (moderate to severe), evidence of intraepithelial nested and/or pagetoid growth, and epithelioid cell cytomorphology	Higher
	Melanoma in situ	Yes	The term melanoma in situ may be used for (1) the most atypical high-grade CMILs involving close to full thickness of the epithelium, (2) histologically obvious melanomas without documented evidence of subepithelial invasion	Highest

CMIL, conjunctival melanocytic intraepithelial lesion.

Fig. 2.

Adenosquamous carcinoma of the conjunctiva. a Leukoplakic mass in the inferior fornix. b The invasive adenocarcinoma component is composed of epithelial cells with focal intracytoplasmic mucin (arrow) arranged in glands, in a background of desmoplastic stroma. Intracytoplasmic and luminal mucin is highlighted with Alcian blue stain (inset). c Sheets of atypical goblet cells (arrow). d Squamous cell carcinoma component is composed of irregular islands and bands of squamous cells [hematoxylin-eosin (b–d); ×100 (b), ×200 (c, d)].

Fig. 3.

Squamous cell carcinoma with mucinous differentiation. a Irregular islands and bands of invasive nonkeratinizing squamous cell carcinoma with focal intracytoplasmic mucin (b), highlighted with Alcian blue stain (c) [hematoxylin-eosin. ×50 (b), ×400 (b, c)].

Tumors of the Eyelid (Table 6)

Table 6.

WHO Eye5: tumors of the eyelid [2]

Tumor-like lesions, hamartomas, and choristomas of the eyelid

Eyelid cysts

Epidermal inclusion cyst

Intratarsal cyst

Choristomas of the eyelid

Phakomatous choristoma

Epithelial tumors of the eyelid

Benign and premalignant epithelial tumors of the eyelid

Molluscum contagiosum

Verruca vulgaris

Squamous papilloma

Seborrheic keratosis

Inverted follicular keratosis

Actinic keratosis

Malignant epithelial tumors of the eyelid

Basal cell carcinoma

Squamous cell carcinoma

Merkel cell carcinoma

Adnexal tumors of the eyelid

Benign adnexal tumors of the eyelid

Ductal hidrocystoma

Sebaceous hyperplasia, adenoma, and sebaceoma

Syringoma

Mixed tumor

Tubular adenoma

Syringocystadenoma papilliferum

Pilomatrixoma

Trichilemmoma

Malignant adnexal tumors of the eyelid

Sebaceous carcinoma

Adenoid cystic carcinoma

Signet-ring cell/histiocytoid carcinoma

Mucinous carcinoma

Endocrine mucin-producing sweat gland carcinoma

Microcystic adnexal carcinoma

Apocrine adenocarcinoma

Melanocytic eyelid tumors

Benign and premalignant melanocytic eyelid tumors

Nevi of the eyelid

Spitz naevus

In situ cutaneous melanoma

Malignant melanocytic eyelid tumors

Invasive cutaneous melanoma

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.

Fig. 4.

Endocrine mucin-producing sweat gland carcinoma of the eyelid. a Reddish dermal-based nodule in the lower eyelid along the eyelash line. b Expansile nests of cells in cribriform arrangement. c Cuboidal neoplastic cells have ovoid, mildly pleomorphic nuclei, inconspicuous nucleoli, and moderate amounts of eosinophilic cytoplasm. d Alcian blue stain highlights intracytoplasmic and extracellular mucin. e Strong diffuse nuclear expression of estrogen receptors and insulinoma-associated protein 1 (INSM1) (f) [hematoxylin-eosin (b, c), Alcian blue (d), ER (e), INSM1 (f), ×50 (b), ×200 (c–f)].

Fig. 5.

Tarsal cyst and phakomatous choristoma. a–c Tarsal cyst. a Tan-gray subepithelial tarsal-based nodules. b The cyst is lined by stratified squamous epithelium with eosinophilic corrugated delicately keratinized cuticle (arrow) and filled with keratin (asterisk). Meibomian gland lobules with associated ducts, lined by the epithelium morphologically similar to the cyst (arrowhead), are present in the adjacent tarsus. c Higher magnification of the cyst lining and delicate lamellated luminal keratin. d–f Phakomatous choristoma. d Cataractous-appearing tissue composed of bladder cells (arrowheads) and cuboidal lens epithelium associated with a prominent periodic acid-Schiff (PAS)-positive basement membrane, reminiscent of lens capsule (arrow). The lens epithelial cells express nuclear PAX8 (e) and cytoplasmic S100 (f) [hematoxylin-eosin (b, c), PAS (d), PAX8 (e), S100 (f), ×100 (b), ×1,000 (c), ×400 (c–f)].

Tumors of the Uveal Tract (Table 7)

Table 7.

WHO Eye5: tumors of the uveal tract [2]

Iris tumors

Benign lesions and hamartomas of the iris

Ectopic tissue

Implantation cyst

Pigmented epithelial cyst

Lisch nodule

Melanocytic tumors of the iris

Ocular melanocytosis

Melanocytic nevus

Iris melanoma

Ciliary body and choroid tumors

Benign melanocytic lesions of the choroid and ciliary body

Choroidal and ciliary body nevi

Uveal melanocytoma

BDUMP

Malignant melanocytic tumors of the choroid and ciliary body

Choroidal and ciliary body melanomas

BDUMP, bilateral diffuse uveal melanocytic proliferation.

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.

Table 8.

WHO Eye5: diagnostic cytology of melanocytic uveal tumors [2]

Uveal melanocytic tumor	Diagnostic cytology	References
Conventional nevus	Paucicellular sample with predominantly small spindle to round cells with or without pigmentation and with small or absent nucleoli. The cells are immunoreactive for melanocytic markers and show rare or no cells in cycle with Ki-67 immunostaining. Molecular genetic profiling may allow differentiation from melanoma in cytologically borderline lesions	[2]
Melanocytoma	Large, ovoid cells with small centrally located nuclei and heavily pigmented cytoplasm. Melanin can obscure nuclear detail. The cells are immunoreactive for melanocytic markers and show rare or no cells in cycle with Ki-67 immunostaining. Molecular genetic profiling may allow differentiation from melanoma in cytologically borderline lesions	[37]
Melanoma	Individually dispersed, or small cohesive groups of atypical cells demonstrating spindle-shaped or rounded pleomorphic nuclei with nucleoli, coarsely hyperchromatic chromatin, and eosinophilic cytoplasm that is spindle-shaped in spindle melanoma cells and ovoid in epithelioid melanoma cells. Variable numbers of cytoplasmic finely granular melanosomes are present. Binucleation and mitotic figures can be seen. Molecular genetic profiling of cytology material plays an important role in prognostication	[38–42]

Tumors of the Retina and Neuroepithelium (Table 9)

Table 9.

WHO Eye5: tumors of the retina and neuroepithelium [2]

Tumors of the neurosensory retina

Benign retinal tumors

Astrocytic tumors

Nodular and massive retinal gliosis

Premalignant and malignant retinal tumors

Retinocytoma

Retinoblastoma

Tumors of the retinal pigment epithelium (RPE)

Reactive and hamartomatous lesions of the RPE

Hamartoma of the RPE

Congenital hypertrophy of the RPE

Reactive hyperplasia of the RPE

Benign and malignant tumors of the RPE

Adenoma and adenocarcinoma of the RPE

Tumors of the iris and ciliary body neuroepithelium

Reactive and cystic lesions of the iris and ciliary body pigment epithelium

Reactive epithelial hyperplasia of the ciliary epithelium

Nodular hyperplasia of the ciliary epithelium

Glioneuronal hamartoma of the ciliary body

Benign and malignant tumors of the iris and ciliary body pigment epithelium

Adenoma and adenocarcinoma of the ciliary body

Medulloepithelioma of the ciliary body

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.

Fig. 6.

MYCN-amplified retinoblastoma. a Gross photograph of the eye enucleated for failure to respond to local therapy demonstrates calcific post-treatment regression scar (arrow) and diffuse involvement of the detached retina by viable-appearing tumor (black arrowheads). Focal choroidal invasion is present (white arrowhead). Hemorrhage and necrosis are present in subretinal space (asterisk). b Histopathology demonstrates discohesive undifferentiated retinoblastoma cells, which focally invade choroid (arrow). c Discohesive retinoblastoma cells with prominent central nucleoli and scant cytoplasm (arrow), with brisk apoptotic bodies. d Retained retinoblastoma 1 (RB1) protein expression in the tumor [hematoxylin-eosin (b, c), RB1 (d), ×100 (b), ×400 (C), ×200 (d)]. Images courtesy of Ralph C. Eagle, Jr. MD.

Table 10.

WHO Eye5: diagnostic cytology of tumors of the retina and neuroepithelium [2]

Retinal and neuroepithelial tumor	Diagnostic cytology	References
Retinoblastoma	Generally, biopsy is avoided due to the risk of extraocular recurrence and metastasis. Cytological samples often have pitfalls (sampling of retinal neurons, scant material) that may be misleading. Diagnostic features of malignancy such as necrosis, mitoses, and nuclear atypia should be present when diagnosing retinoblastoma in a cytology. Consultation with an experienced ophthalmic cytopathologist is recommended if a biopsy is considered	[2]
Medulloepithelioma	The polymorphous nature of medulloepithelioma can reduce the sensitivity and specificity of aspiration cytology. In many reports, diagnosis is limited to a malignant round cell tumor, although more specific rosettes and focal epithelial-like fragments with cellular polarity and multilayering occasionally are observed. Immunohistochemical staining for medulloepitheliomas expresses LIN28A and PAX8 by immunohistochemistry (IHC), which may help distinguish these tumors from retinoblastoma	[53–57]
Adenoma and adenocarcinoma of the ciliary body epithelium (CBE)	CBE adenoma shows polygonal epithelial cells with bland round to oval nuclei and small nucleoli, with or without melanin granules. Adenocarcinoma demonstrates cohesive clusters of atypical cuboidal to large epithelioid epithelial cells with hyperchromatic, enlarged nuclei, and prominent nucleoli. The cells in adenoma and adenocarcinoma can be pigmented or non-pigmented. The presence of basement membrane material highlighted with periodic acid-Schiff (PAS) stain helps differentiate these tumors from melanoma, other stromal tumors, and metastases. PAX8 IHC is useful in distinguishing CBE adenoma and adenocarcinoma from melanocytic lesions. Adenomas and adenocarcinomas of pigmented CBE harbor BRAF c.1799T>A p.V600E mutations and lack GNAQ or GNA11 mutations (histopathology data), a profile that may favor adenoma/adenocarcinoma over melanocytic uveal neoplasm	[57–59]
Adenoma and adenocarcinoma of retinal pigment epithelium (RPE)	Adenocarcinoma of RPE and epithelioid melanoma cells can appear similar, and there is significant immunohistochemical overlap between RPE tumors and uveal melanoma. Documentation of PAS-positive basement material can be helpful in supporting the diagnosis of retinal pigment epithelial neoplasm. Correlation of cytologic findings with clinical and imaging findings is essential	[57], [60]

Tumors of the Optic Disk and Optic Nerve (Table 11)

Table 11.

WHO Eye5: tumors of the optic disk and optic nerve [2]

Malformations of the optic disk and optic nerve
Optic nerve choristoma
Primary neural tumors of the optic disk and optic nerve
Gliomas of the optic nerve
Pigment epithelial tumors of the optic disk and optic nerve
Medulloepithelioma of the optic disk and optic nerve
Meningeal tumors of the optic nerve
Meningioma of the optic nerve
Melanocytic tumors of the optic disk and optic nerve
Melanocytoma of the optic disk and optic nerve

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].

Tumors of the Lacrimal Gland and Lacrimal Drainage System (Table 12)

Table 12.

WHO Eye5: tumors of the lacrimal gland and lacrimal drainage system [2]

Tumors of the lacrimal gland

Epithelial tumors of the lacrimal gland

Cysts of the lacrimal gland

Dacryops cyst

Benign and premalignant epithelial tumors of the lacrimal gland

Pleomorphic adenoma (PA) of the lacrimal gland

Lacrimal gland oncocytoma

Myoepithelioma

Intraductal carcinoma

Malignant epithelial tumors of the lacrimal gland

Carcinoma ex PA

Adenoid cystic carcinoma

Primary ductal adenocarcinoma of the lacrimal gland

Secretory carcinoma

Mucoepidermoid carcinoma (MEC)

Epithelial-myoepithelial carcinoma (EMC)

Acinic cell carcinoma

Adenocarcinoma, NOS

Tumors of the lacrimal drainage system

Epithelial tumors of the lacrimal drainage system

Benign and premalignant epithelial tumors of the lacrimal drainage system  Papillomas (squamous and inverted)

Malignant epithelial tumors of the lacrimal drainage system

Squamous cell carcinoma

Lymphoepithelial carcinoma

MEC

Other salivary gland-type carcinomas of the lacrimal drainage system

Adenocarcinoma NOS of the lacrimal drainage system

Melanocytic tumors of the lacrimal drainage system

Melanoma involving the lacrimal drainage system

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.

Table 13.

WHO Eye5: epithelial tumors of the lacrimal gland [2]

Epithelial tumor of the lacrimal gland/ Definition	Molecular genetic alterations/ Diagnostic molecular pathology	Immunohistochemistry (IHC)	Essential and desirable diagnostic criteria	Ref
Pleomorphic adenoma (PA) Benign lacrimal gland neoplasm consisting of a mixture of epithelial, myoepithelial, and mesenchymal-appearing components	Recurrent translocations of PLAG1 on 8q12 PLAG1 translocation t(5; 8) (p13; q12) is highly specific for PA HMGA2 translocation on 12q14 less frequent Diagnostic molecular pathology Usually not required	Epithelial cells: CK7+, CAM5.2+ Myoepithelial cells: p40+, p63+, SMA+, calponin+ Ki67 low PLAG1 (nuclear)+ GFAP +/−	Essential: admixture of bilayered ducts, myoepithelial cells, and chondromyxoid/fibrous stroma in the absence of invasion and malignant cytomorphological features Desirable:PLAG1 or HMGA2 alteration (by IHC or molecular methods) in select cases	[64–69, 73]
Carcinoma ex PA Malignant lacrimal gland neoplasm that shows presence of an epithelial and/or myoepithelial malignancy arising in association with primary or recurrent PA	PLAG1 and HMGA2 rearrangements identical to PA Sequential loss of heterozygosity of 8q, 12q, 17p Alterations in 12q genes (HMGIC, HMGA2, MDM2) Copy number alterations in 9p and 22q, resulting in activation of NFIB and PDGFB Activation of IL6/JAK/STAT3 Diagnostic molecular pathologyPLAG1 or HMGA2 rearrangements serve as markers of pre-existing PA, differentiating from de novo lacrimal gland carcinomas	Carcinoma areas: p53+, c-MYC+, Ki-67 high PA component: PLAG1+ and HMGA2+ Androgen receptor (AR)+ in carcinoma component may indicate lacrimal duct carcinoma differentiation	Essential: histological areas compatible with PA or history of previous PA in the same site; presence of an epithelial and/or myoepithelial malignant component	[70–74]
Adenoid cystic carcinoma Malignant lacrimal gland neoplasm composed of epithelial and myoepithelial cells (EMCs) arranged in tubular, cribriform, and solid patterns associated with a basophilic matrix and reduplicated basement membrane material, frequently accompanied by MYB::NFIB rearrangements	t(6; 9) (q22-23; p23-24) (up to 50%) results in MYB::NFIB fusion and activation of the MYB oncogene and associated target genes such as KIT and BCL2 which are involved in cell growth, apoptosis, transcription, and cell cycle regulation Loss of 6q, 12q, and 17p Gains of 19q, 8q, and 11q Aberrant NOTCH signaling KRAS, NRAS, Met mutations Diagnostic molecular pathology MYB rearrangement in select cases	MYB+ (although less sensitive, may be used as a surrogate for MYB rearrangement in select cases) KIT+ p53 overexpression Mean Ki67 index 30%	Essential: a malignant biphasic tumor composed of proliferating myoepithelial cells and luminal ductal cells Desirable: perineural invasion. Positive MYB, KIT IHC, or MYB rearrangement in challenging cases	[66, 75–79, 96]
Primary ductal adenocarcinoma of the lacrimal gland High-grade adenocarcinoma and a counterpart of salivary duct carcinoma, resembling invasive ductal carcinoma of the breast	Unknown, although at least a subset of cases show HER2 overexpression by IHC and/or HER2(ERBB2) gene amplification similar to salivary duct carcinoma Diagnostic molecular pathology HER2 amplification in select cases	AE1/AE3+, CK7+, CK19+, EMA+, AR+, GCDFP-15+, HER-2/neu+, p53+, cyclin D1+ Usually SMA−, p63−, calponin−, ER−, PR−, PSA− Ki-67 up to 70%	Essential: an invasive adenocarcinoma with ductal differentiation, arising de novo (not arising from a benign tumor such as PA) in the lacrimal gland Desirable: tumor comedonecrosis	[80–84, 96]
Secretory carcinoma Rare monophasic lacrimal gland carcinoma characterized by a rearrangement of the ETV6 gene resulting in ETV6::NTRK3 fusion in most cases	Lacrimal gland: ETV6 rearrangement resulting in ETV6::NTRK3 fusion Salivary glands: alternative ETV6 fusion partners include RET, MET, MAML3 Diagnostic molecular pathology ETV6 gene rearrangement can be demonstrated by breaking apart FISH. Detection of NTRK3 fusion by RT-PCR or RNA sequencing may be predictive of response to NTRK inhibitors for unresectable or metastatic cases	S100+, SOX10+, mammaglobin+, CK18+, Cam5.2+, GCDFP-15+, NTRK+ (or pan-TRK+) CK5−, p63−, DOG-1, AR− Ki-67 < 5%	Essential: monophasic tumor with vacuolated secretory material, lacking cytoplasmic granules; IHC positivity for S100 protein, mammaglobin, and NTRK (or Pan-TRK) and negativity for p40/p63, and CK5 Desirable:ETV6 and/or NTRK3 gene rearrangement	[85–96]
Mucoepidermoid carcinoma (MEC) Malignant lacrimal gland neoplasm characterized by squamous (epidermoid) cells, mucous cells, columnar cells, and intermediate cells	CTRC1::MAML2 gene fusion is present in majority lacrimal gland MEC and is considered a key oncogenic driver leading to EGFR upregulation RAS/PIK3 mutations in poorly differentiated tumors involved in EGFR upregulation Diagnostic molecular pathology MAML2 rearrangement/CTRC1::MAML2 fusion in select cases	P63+, p40+ S100−, SOX10−	Essential: squamous cells, intermediate cells, and mucous cells in varying proportions Lower grade tumors: cystic, mucous cell rich, and well circumscribed Higher grade tumors: solid, higher proportion of squamous and intermediate cells Desirable:MAML2 rearrangement/CRTC1::MAML2 fusion	[96–98]
EMC Low-grade malignant biphasic tumor of the lacrimal gland characterized by tubular structures, usually composed of tightly coupled inner ductal and prominent outer myoepithelial cells	HRAS mutations, most commonly at the codon 61 Diagnostic molecular pathology Assessment of HRAS mutations is useful for diagnosing EMC and excluding its mimics; MYB fusion by molecular methods/IHC might help in differentiation from adenoid cystic carcinoma and hybrid tumors	Inner cells: panCK+, CK7+ Outer myoepithelial cells: p63+, SMA+, calponin+, S100+ Diffuse membranous and cytoplasmic RAS Q61R expression, almost always restricted to myoepithelial cells in 65% of EMCs	Essential: usually multinodular invasive growth; at least partly with a dual arrangement of inner ductal cells and outer prominent, and usually clear, myoepithelial cells	[99–103]
Acinic cell carcinoma Rare malignant lacrimal gland neoplasm displaying predominantly serous acinar differentiation	Salivary gland tumors: recurrent rearrangement [t(4; 9) (q13; q31)] leads to NR4A3 upregulation Diagnostic molecular pathology NR4A subfamily rearrangements by molecular or IHC methods in challenging cases	NR4A3+ or NR4A2+ DOG1+, SOX10+ p63−, S100− Mammaglobin−, pan−TRK−	Essential: tumor cells with acinar differentiation; zymogen granules in focal areas Desirable: nuclear staining for NR4A3/NOR-1 or NR4A2/Nuur1 Molecular demonstration of NR4A3 rearrangement	[104–106]

Tumors of the Orbit (Table 14)

Table 14.

WHO Eye5: tumors of the orbit [2]

Teratomas, hamartomas, and choristomas

Choristomas and cysts

Orbital dermoid cysts and other orbital cysts

Vascular malformations

Cavernous vascular malformation

Combined lymphatic-venous malformation of the orbit

Orbital venous malformation

Arteriovenous malformation

Hamartomas

Orbital glial heterotopia

Mesenchymal hamartoma of the orbit

Germ cell tumors

Teratoma

Yolk sac tumor

Melanocytic tumors of the orbit

Primary orbital melanoma

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.

Hematolymphoid Tumors (Table 15)

Table 15.

WHO Eye5: hematolymphoid tumors [2]

Reactive lymphoid lesions

Reactive lymphoid lesions

Reactive lymphoid hyperplasia

IgG4-related disease

Intraocular hematolymphoid proliferations

Primary choroidal lymphoma (PCL)

Primary vitreoretinal large cell B-cell lymphoma (PVR-LCBL)

Ocular adnexal lymphomas

B-cell lymphomas

Extranodal marginal zone lymphoma

Follicular lymphoma

Mantle cell lymphoma

Chronic lymphocytic leukemia/small lymphocytic lymphoma

Diffuse large B-cell lymphoma

Plasmacytoma

T/NK cell lymphomas

CD30-positive lymphoproliferative disorders

T-cell lymphomas

Extranodal lymphoma of mature NK or T-cell lineage

Myeloid tumors

Extramedullary myeloid sarcoma

Histiocytic and dendritic cell tumors

Juvenile xanthogranuloma

Rosai-Dorfman disease

Erdheim-Chester disease

Langerhans cell tumors

Xanthelasma

Adult orbital xanthogranulomatous disease

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. 7–9; 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].

Fig. 7.

Primary choroidal lymphoma (PCL), clinical and imaging findings. a Creamy choroidal infiltrates. b Optical coherence tomography demonstrates thickened choroid with an undulating hyperreflective anterior border (arrow) and obscuration of underlying choroidal vasculature from an infiltrative process.

Fig. 9.

Primary vitreoretinal large B-cell lymphoma (PVR-LCBL), clinical and cytopathologic findings (subretinal fine needle aspiration biopsy and vitrectomy). a Punctate and nodular subretinal pigment epithelial (RPE) deposits (arrow), geographic placoid gray subretinal deposits focally associated with hemorrhage (black arrowhead), and areas of RPE atrophy. b Optical coherence tomography highlights subretinal (arrowhead) and sub-RPE (arrow) deposits. c Large cells with irregular nuclear contours, prominent nucleoli, and scant to moderate amounts of cytoplasm. d Foci of granulomatous inflammation (paraneoplastic granulomatous vitritis). e The large atypical cells and the apoptotic debris are positive for CD20 (e) and co-express bcl6 (f) and interferon regulatory factor 4 (IRF4/MUM1) (g). CD10 is negative (h). Ki-67 proliferative index is brisk (i). Targeted MYD88 mutation studies detected MYD88 p.L265P mutation [hematoxylin-eosin (c, d), CD20 (e), bcl6 (f), MUM1 (g), CD10 (h), Ki-67 (i), ×630 (c), ×400 (d–i)].

Table 16.

WHO Eye5: intraocular hematolymphoid proliferations [2]

	Primary choroidal lymphoma (PCL)	Primary vitreoretinal large cell B-cell lymphoma (PVR-LCBL)	Ref
Definition	PCL is an extranodal marginal zone B-cell lymphoma (EMZL) of the uveal tract without evidence of systemic lymphoma	PVR-LCBL is the most common high-grade lymphoma that arises in the eye and is frequently accompanied by involvement of the central nervous system (CNS)	[2]
Pathogenesis	Morphological, immunohistological, and genetic alterations are similar to those of EMZL at other locations Clonal expansion of post-germinal center (GC) B cells t(11; 18) (q21; q21) MYD88 mutations Dysregulation of the NF-κB, BCR, and PI3K signaling pathways	PVR-LCBL cells demonstrate similarity to LCBL of immunoprivileged sites (IP-LCBL) Genetic alterations that enable immune escape and downregulation of specific immune reactions Features corresponding to mature GC-exit B cells, which have undergone a prolonged GC reaction with evidence of ongoing somatic hypermutation in their rearranged immunoglobulin (IG) genes Rearrangement in the IGHV4-34 gene (55%) Concordant MYD88 (L265P) and CD79B mutations (likely early events) The genomic signature resembles the C5/MCD/MYD88 signature found in diffuse large B-cell lymphoma NOS Other mutations: PIM1 (71%), IGLL5 (52%), TBL1XR1 (48%), and ETV6 (45%) Translocations in IG and BCL6 genes Frequent genetic imbalances, particularly 9p21/CDKN2A deletions (75%)	[107–122, 126, 127, 129]
Histopathology (enucleation, tissue biopsy)	Diffuse infiltration of choroid by small-to-medium lymphocytes with mildly irregular nuclear contours, small-to-inconspicuous nucleoli, typically with expansion of small centrocyte-like lymphocytes, and varying numbers of plasmacytoid and monocytoid B cells Lymphoid follicles with GCs variably colonized by neoplastic cells The infiltrate may extend to ciliary body, iris and/or sub-conjunctival tissue, or even through Bruch’s membrane	Large lymphocytes with irregular nuclear contours and prominent nucleoli, with brisk apoptosis/necrosis in the vitreous, neural retina, and/or beneath the RPE The highly characteristic sub-RPE infiltrates (of variable thickness) consist of neoplastic B cells accumulating anterior to the Bruch membrane There is perivascular accumulation of atypical lymphocytes, often associated with occlusion of retinal vessels	[107, 108, 123–125, 127]
Diagnostic cytopathology	Monomorphous population of small atypical B cells	Large atypical B cells in a background of apoptosis, necrosis, small T cells, and macrophages	[125, 127]
Immunohistochemistry (IHC) and flow cytometry	Neoplastic cells are CD20+, CD79a+, PAX5+, BCL2+, IgM+, CD43+/−, MUM1+, CD5−, CD23−, CCND1−, CD10−, frequent light chain restriction, with a low Ki67 index	Neoplastic cells are CD20+, CD79a+, PAX5+, BCL2+, BCL6+, MUM1/IRF4+, IgM+, CD10− and have a high Ki67 index	[107] [121]
Diagnostic molecular pathology	Clonality analysis (IGH and/or IGK PCR) demonstrates clonal B-cell population	Clonality analysis of IGH genes demonstrates clonal B-cell population In rare cases where a PVR T-cell lymphoma is suspected, clonality analysis of the T-cell receptor (TCR) gene Mutational analysis: MYD88 and CD79B hotspot mutations (particularly useful in low cellularity cases)	[108, 111, 116–119, 123, 125, 128]
Essential diagnostic criteria	Diffuse infiltrate of small- to medium-sized lymphoid cells in the uveal tissue Expression of B lineage markers Exclusion of systemic lymphoma with secondary ocular involvement	Large B-cell lymphoma primarily confined to the vitreous or retina at presentation, with or without concurrent CNS lymphoma Exclusion of secondary involvement by a systemic DBCL (after clinicopathological correlation)	[2]
Desirable diagnostic criteria	Demonstration of light chain restriction or clonal IG gene rearrangement	Post-GC B-cell phenotype (CD20+; CD79a+; MUM1+; BCL6+; CD10−) Demonstration of a high Ki67 growth fraction Absence of Epstein-Barr virus Demonstration of clonal B-cell population or a MYD88 and/or CD79B hotspot mutations in cases in which histology is not definitive (e.g., corticosteroid-mitigated PVR-LCBL) and paucicellular cytology)	[2]

Fig. 8.

Primary choroidal lymphoma (PCL), cytopathologic findings, fine needle aspiration biopsy. a Monomorphic small blue cells in a background of hemorrhage. Neoplastic cells express CD20 (b), bcl2 (c), and interferon regulatory factor 4 (IRF4/MUM1) (d). Neoplastic cells are negative for CD5, which highlights T cells (e) and CD10 (f). Overexpression of kappa light chain (g) over lambda (h). The Ki-67 labels rare nuclei (i) [hematoxylin-eosin (a), CD20 (b), bcl2 (c), MUM1 (d), CD5 (e), CD10 (f), kappa (g), lambda (h), ki-67 (i); all figures. ×400].

Soft Tissue and Bone Tumors (Table 17)

Table 17.

WHO Eye5: soft tissue and bone tumors [2]

Soft tissue tumors

Fibrous, fibroblastic tumors

Conjunctival stromal tumor and ocular surface fibroma

Fibrous histiocytoma

Nodular and proliferative fasciitis, proliferative myositis

Solitary fibrous tumor

Inflammatory myofibroblastic tumor

Dermatofibrosarcoma protuberans

Angiomyxoma

Adipocytic tumors

Benign lipomatous lesions

Malignant adipocytic tumors

Skeletal muscle tumors

Rhabdomyosarcoma family

Smooth muscle tumors

Leiomyoma

Mesectodermal leiomyoma

Leiomyosarcoma

Peripheral nerve sheath tumors

Schwannoma

Neurofibroma

Solitary circumscribed neuroma

Granular cell tumor

Malignant peripheral nerve sheath tumor

Vascular tumors

Masson tumor

Infantile hemangioma

Lobular capillary hemangioma

Lymphangiectasia

Epithelioid hemangioma

Hemangioblastoma

Angiosarcoma

Perivascular tumors

Glomus tumor

Myopericytoma, including myofibroma

Tumors of uncertain derivation

PEComa

Epithelioid sarcoma

Synovial sarcoma

Alveolar soft part sarcoma

Tumors of orbital bone

Osteogenic tumors of orbital bone

Osteoma

Osteoblastoma

Osteosarcoma

Chondrogenic tumors of orbital bone

Soft tissue chondroma

Mesenchymal chondrosarcoma

Fibrous, fibroblastic tumors of orbital bone

Fibrous dysplasia

Vascular tumors of orbital bone

Hemangioma of bone

Epithelioid hemangioendothelioma

Angiosarcoma of bone

Osteoclast-rich giant cell tumors of orbital bone

Aneurysmal bone cyst

Giant cell tumor of bone

Other tumors of orbital bone

Ewing sarcoma

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].

Metastases to the Eye and Surrounding Structures

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].

Genetic Tumor Predisposition Syndromes

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.

Conclusion

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.

Acknowledgments

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.

Statement of Ethics

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

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding received.

Author Contributions

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.

Funding Statement

No funding received.