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Central Nervous System and Skeletal Muscle 189

Morphology

Type I ﬁbres are normally of similar size to type II ﬁbres

A motor unit = a single motor neuron (usu. an anterior horn neuron of the spinal cord) plus all the

muscle ﬁbres it supplies

All ﬁbres in a motor unit are of the same type

Fibres from different motor units are intermingled as a mosaic in any given muscle

Endomysial connective tissue is very sparse

<3% of ﬁbres should have central nuclei

Fibre type proportions in biceps brachii and quadriceps femoris

 adults = 33:33:33:1 (I:IIA:IIB:IIC)

 children = 50:50 (I:II)

Muscle ﬁbre diameter is deﬁned as the minor axis diameter (you ﬁrst ﬁnd the maximum diameter then

use the longest diameter which is at right angles to this) of the ﬁbre cut in transverse section. The mean

measurement of ≥200 ﬁbres is recommended (see Song et al., 1963)

Fibre diameter varies with age, gender, exercise and site: e.g. (all sizes are given in ) for adult

quadriceps femoris the mean diameter ranges from 62–65 (for Type 1 ﬁbres) and 63–66 (Type 2)

depending on the component e.g. superﬁcial vastus lateralis has means of 63.1 (Type 1) and 63.2 (Type

2) while for deep vastus lateralis these become 64.6 and 63.7; for sternocleidomastoideus the means

are 50.2 (Type 1) and 53.3 (Type 2); for psoas 54.5 and 51.7; for deep biceps brachii 49.8 and 52.1;

for deep triceps brachii 57.2 and 62.8; for the 1

dorsal interosseus 50 and 67; for medial head of

gastrocnemius 65 and 66 and for lateral head of gastrocnemius 48.4 and 50.5 (data from Polgar et al.,

1973)

In a Bx with a mixed population of small and large ﬁbres, perform the measurement on each population

separately (to see if the smallest ﬁbres are atrophic and the largest ﬁbres hypertrophic)

! Beware artefacts of sampling (e.g. Bx from near a tendinous insertion may normally show ﬁbrosis

and ﬁbre size variation)

Vacuolated Fibres

Slow freezing artefact: widespread vacuoles of irregular polygonal form that vary in size and may show

a gradation in size from one part of the section to another which was less affected

May be insigniﬁcant if only a few and contain glycogen (esp. if not convex and central)

If full of lipid (Sudan) they usu. connote a metabolic myopathy

Small vacuoles are also part of inclusion body myositis (q.v.)

Central multiloculated vacuoles (± Ca

) may be seen in the acute phase of periodic paralysis

Ragged Red Fibres

Fibres with scattered red blotches by Gomori stain (mitochondria)

Occur in some mitochondrial myopathies (± lipid vacuoles) and many other myopathies

Type I Fibre-selective Atrophy

Myotonic dystrophy and other dystrophies

In congenital myopathies Type I ﬁbres may be small/atrophic but they may predominate numerically

Type II Fibre-Selective Atrophy

Steroid (glucocorticoid) / thyroid hormone-assoc

myopathy

Disuse atrophy, paraneoplastic atrophy

MG: also focal lymphoid inﬁltrates, elongated endplates and (by EM) wide and shallow synaptic clefts

CTD, polymyalgia rheumatica, polymyositis / dermatomyositis

Some dystrophies (e.g. Type IIB ﬁbre atrophy in limb girdle dystrophy)

Regeneration

Central nuclei in small rounded ﬁbres (becoming angulated with time)

Cytoplasmic basophilia due to RNA (.

. will be pyroninophilic)

Large vesicular nuclei with prominent nucleoli

in the deltoid the proportions vary with depth of Bx

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Central Nervous System and Skeletal Muscle 190

Metabolic Myopathies

Diabetes mellitus

Thickening of vascular BM in a gastocnemius Bx is said to be diagnostic of diabetes

Others

Hypothyroidism, mitochondrial myopathies, glycogenoses (types 2, 5 and 7), lipid storage diseases,

malignant hyperpyrexia, periodic paralyses and other IEM.

Histology may be ‘suggestive of’ or ‘consistent with’ (e.g. ragged red ﬁbres +/ lipid vacuoles in

mitochondrial myopathies) but is usu. not diagnostic – the diagnosis being based on CPC (e.g. oph-

thalmoplegia, myoclonus, dementia, etc. in mitochondrial myopathies), biochemistry and genetics.

Neurogenic Myopathies (Denervation and Reinnervation)

Causes: trauma, peripheral neuropathy (usu. with assoc

sensory Sx), CNS motor neuron damage (usu.

no sensory Sx – e.g. SMA, MND, etc.)

Early: +++ (dark) NSEst reaction

Intermediate: disseminated atrophy: small angulated

ﬁbres (that stain +++with NADH, this is useful

since non-neurogenicatrophic ﬁbres do not usu. showthis intense NADH reaction) are mixed in amongst

normal ﬁbres

Late:

 ﬁbre type grouping (due to re-innervation) – some deﬁne a ‘group’ as ≥15 ﬁbres of the same

type being adjacent to each other – ! distinguish from ﬁbre predominance (vide infra)

 groups of pyknotic nuclei

 target ﬁbres (central pale zone with accentuated dark rim in ﬁbres with NADH and succi-

nate dehydrogenase – without the rim they are ‘core ﬁbres’ that may also occur but are less

characteristic of neurogenic atrophy and may be seen in other things incl. central core disease)

d/dg non-neurogenic myopathies:

 re-innervation produces groups of type I and groups of type II ﬁbres whereas non-neurogenic

myopathies show selective atrophy or predominance of one ﬁbre-type that can give an impres-

sion of grouping. Some deﬁne ‘predominance’ as >50% of ﬁbres being type I or >80% Type

 similarly, neurogenic atrophy produces atrophic ﬁbres of both types

Necroinﬂammatory and Destructive Myopathies

Necrotic ﬁbres are pale (on H&E), lack nuclei and striations and are +ve for NADH

Phagocytosis

‘Moth-eaten’ ﬁbres (i.e. show irregular partial staining for NADH)

Variation in ﬁbre size and features of regeneration (q.v.)

Endomysial ﬁbrosis

Some examples:

 dermatomyositis:  perifascicular necrosis or atrophy

 B-cell-rich inﬁltrate with admixed T4 cells – predom. perivascular

 polymyositis:  endomysial patchy necrosis

 T8 predominant inﬁltrate – predom. within and around muscle ﬁbres

 d/dg facioscapulohumeral dystrophy – but this has hypertrophic ﬁbres

 d/dg HIV myopathy – may also show nemaline rods and giant cells

 in both dermatomyositis and polymyositis the only changes may be Type II ﬁbre atrophy or

late changes (ﬁbrosis and variable ﬁbre atrophy). If a CTD vasculitic process is also present

there may be superimposed changes of vascular damage (vide infra)

 vascular damage:  features of the vascular lesion (atheroma, arteritis, etc.)

 focal necrosis / infarction

 neurogenic damage (vide supra) due to vasc.compromise ofsupplying

nerves

 trauma:  if extensive may get scarring

 if repeated → continuous myoblast and myoﬁbroblast prolif

and granulation

tissue (= proliferative myositis) + ossiﬁcation (= myositis ossiﬁcans).

For details, see p. 309.

atrophic ﬁbres are rounded in Werdnig-Hoffman disease = infantile SMA (SMA type 1)

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Central Nervous System and Skeletal Muscle 191

 inclusion body myositis:

 proximal muscle wasting in middle-aged (clin. d/dg polymyositis unresponsive to

steroids)

 mixed abnormalities: ±lymphoid inﬁltrates, ± ﬁbre grouping, ﬁbre hypertrophy (±

splitting), ragged red ﬁbres

 nuclear inclusions and cytoplasmic vacuoles: best seen on FS and contain smudged

pale pink (H&E) material that may contain sparse -amyloid ﬁlaments (Congo red

is faint/−ve). Basophilic rimming of the vacuoles by Gomori is characteristic but

not speciﬁc

 some dystrophies (e.g. Duchenne) – but these usu. have ﬁbre hypertrophy and lack inﬂam

 viruses / drugs / toxins (e.g. inﬂuenza, Coxsakie B, HIV, alcohol, penicillamine, snake venom

[snake and scorpion venom can also cause an acute ischaemic colitis])

 parasitic infections (e.g. Trichinella spiralis, Echinococcus granulosus, etc.) – look for

eosinophils and parasite morphology (see Chapter 23: Infection and Immunity)

 sarcoidosis: granulomas may have prominent lymphoid inﬁltrate in early stages (d/dg TB)

Congenital Myopathies

General

Although muscular dystrophies may be inherited they are not usu. manifest at birth but they are progres-

sive with a poor prognosis. Congenital myopathies are usu. manifest as ‘ﬂoppy baby’ shortly after birth

but tend to plateaux or resolve with good prognosis – hence the importance of making the distinction

They have characteristic histological features but don’t show dystrophy-like destructive changes

Centronuclear myopathy (= myotubular myopathy)

Central nuclei in variably sized ﬁbres. Prognosis may be poor in some infants

Congenital ﬁbre type disproportion

Atrophy and size variability of Type I ﬁbres (usu. ≥12–15% smaller than Type II)

Hypertrophy (or normal) Type II ﬁbres

Nemaline rod myopathy

Should have many rods in most ﬁbres and an appropriate clin. Hx (because these rods are not speciﬁc)

Nemaline rods are clusters of thread-like structures that stain red with Gomori (not obvious on H&E)

Other congenital myopathies

These include central core disease, multicore disease (= minicore disease) and desmin myopathy

Muscular Dystrophies

General

Prominent regeneration myocytophagia

Fibre hypertrophy (± ﬁbre splitting)

> 3% ﬁbres with central nuclei

No inﬂam

(except in facioscapulohumeral dystrophy or in reaction to necrosis)

Duchenne muscular dystrophy

Endomysial ﬁbrosis ± adiposity

Greater variability in ﬁbre size (atrophic and rounded hypertrophic ﬁbres)

Scattered ‘pre-necrotic’ ﬁbres (rounded, hypereosinophilic, hyaline)

Loss of membranous +vity for dystrophin (may be focal)

Becker’s muscular dystrophy

Like Duchenne but less regeneration and necrosis

Myotonic dystrophy

Type I ﬁbre-selective atrophy

Features of regeneration

Ring ﬁbres (a peripheral ring of radial striations seen in a transversely cut ﬁbre) – these are also seen

(in smaller numbers) in limb girdle dystrophy and other conditions

Other muscular dystrophies

These include facioscapulohumeral, distal, scapuloperoneal and oculopharyngeal dystrophies and the

≈ 10 subtypes of limb girdle dystrophy

Tumours

See Chapter 21: Soft Tissues.

hypertrophy is useful because non-dystrophy necroinﬂammatory myositides do not usu. show this (except inclusion body myositis)

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Central Nervous System and Skeletal Muscle 192

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Eye and Ear 193

14. Eye and Ear

Normal Eye

fovea

lamina cribrosa

sclerae

RETINA

CORNEA

choroid

(vascular & pigmented)

KEY (Retina)

1. Bruch's (basement) membrane

2. Retinal pigment epithelium (RPE)

3. Layer of rods & cones (outer segment)

4. Layer of rods & cones (inner segment)

5. Outer nuclear layer

6. Outer plexiform layer

7. Inner nuclear layer

8. Inner plexiform layer

9. Ganglion cell layer (scant to many nuclei thick)

10. (Optic) Nerve fibre layer (with retinal vessels)

OLM = Outer limiting membrane

endothelium

epithelium (non-keratinised)

basement membrane (PAS +ve)

Bowman's layer/membrane (PAS -ve)

Descemet's (basement) membrane

stroma (avascular)

ora serrata

SCLERA

retinal vessels

OLM

FIGURE 14.1 Eye histology

Cysts and Developmental/Inﬂammatory Conditions

Pterygium

A ‘wing’ of vascular granulation tissue encroaching (usu. from the nasal side) on the cornea

Epithelial actinic changes (incl. upto marked dysplasia)

Stromal elastosis, basophilic degeneration and hyalinisation

Destroys Bowman’s layer

Hamartia and Hamartoma

A hamartia is a developmental lesion resulting in abnormal arrangements/proportions of tissues that

would otherwise have been normally formed at that site. [From the Greek    = sin]

When a hamartia takes the form of a mass it is called a hamartoma

Haemangioma and neuroma/neuroﬁbroma are common examples

Assoc

with the phakomatoses and various syndromes

Chorista, Choristoma, Dermoid and Teratoma

A chorista is a developmental lesion comprising tissue(s) not normally present at a site (i.e. ectopic)

When a chorista takes the form of a mass it is called a choristoma

Assoc

with the phakomatoses and various syndromes e.g. Goldenhar’s =limbal dermoids + auricular

appendages + vertebral anomalies (= oculoauriculovertebral dysplasia)

A dermoid cyst is lined by epidermis-like epithelium and contains (pilo)sebaceous units ±sweat glands

in its wall (unlike an epidermal cyst or an inclusion [= implantation] dermoid cyst) ± a foreign body

reaction to spilled contents/keratin

Diagnostic Criteria Handbook in Histopathology: A Surgical Pathology Vade Mecum. Paul J. Tadrous



2007 by John Wiley & Sons, Ltd. ISBN: 978-0-470-51903-5

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Eye and Ear 194

Dermoids are usu. situated in the orbit (e.g. external angular dermoid) but can be epibulbar (scleral)

Zimmerman’s tumour is a phakomatous choristoma of the lid (made up of lens epithelium) – rare

A simple choristoma contains a single tissue type (e.g. osteoma or the ﬁbroadipose dermolipoma)

A complex choristoma contains >1 tissue type (epidermal/dermal, smooth muscle, cartilage, neural,

lacrimal, bone, etc.)

Atrueteratoma is a choristoma containing representatives of all three germ layers (ectoderm, endoderm

and mesoderm) and are usu. benign in the eye

Hordeolum (= Stye)

Acute localised purulent inﬂammation (≈ ‘boil’ of the eyelid)

Centred on pilosebaceous glands of Zeiss (= external hordeolum)

Centred on a Meibomian gland of the tarsal plate (= internal hordeolum)

Chalazion

A lipogranuloma of the lid arising from a Meibomian or Zeiss gland or their ducts

Focal granulomas and abscess around fat

Giant cells (± Schaumann or asteroid bodies), lymphocytes, plasma cells

d/dg ! do not call it sarcoid or TB

d/dg juvenile xanthogranuloma – this may occur on the eyelid, conjunctiva, orbit, iris

Amyloid

Eyelid, conjunctiva, cornea, vitreous, perivascular (retina/choroid)

Usual features of amyloid (see p. 11)

May form an isolated amyloid tumour

± Foreign-body giant cell reaction & chronic inﬂammation

Cysts of the Eyelid

Sudoriferous (apocrine gland of Moll): columnar epithelial lining

Meibomium (sebaceous): epidermoid lining with sebaceous glands, ﬁlled with keratin. The sebaceous

glands are not seen all around the cyst wall (otherwise = dermoid)

Dermoid: epidermoid lining with sebaceous glands all around the cyst wall

Beh¸cet’s Disease

Def

◦

recurrent uveitis,

◦

oral aphthae,

◦

genital ulceration. [Also get arthritis ± Crohn’s-like

ileocaecal disease or colitis]

Retinal necroses 2

◦

to retinal vasculitis with thromboses

Vitreous haemorrhage

Acute and chronic non-granulomatous inﬂammation of the uveal tract

Reiter’s Disease

Non-speciﬁc anterior uveitis

Conjunctivitis (mixed PMN and lymphocytic with perivascular cufﬁng)

Juvenile Rheumatoid Arthritis (Still’s Disease / Juvenile Chronic Arthritis)

Granulomatous anterior uveitis (may be sarcoidal)

d/dg other causes of granulomatous uveitis (vide infra)

Rheumatoid Arthritis (Adult)

Granulomatous scleritis (rheumatoid nodules) ± perforation and PMN (scleromalacia perforans)

Corneal stromal thinning ± perforation

± Uveitis

Ankylosing Spondylitis

Acute iridocyclitis

Non-granulomatous uveitis

Sj¨ogren’s Syndrome (Sjøgren’s Syndrome)

MESA of the lacrimal glands, parotid (see pp. 132–133), other glands and RhA/CTD

d/dg Mikulicz syndrome =multigland enlargement due to any cause e.g. MESA, sarcoid (‘uveo-parotid

fever’), TB, lymphoma, lead poisoning, iodide excess, etc., and no CTD association

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Eye and Ear 195

Granulomatous Uveitis

Infection: Brucella, syphilis, TB, leprosy, Toxocariasis (incl. retinal involvement)

Immunological: cutaneous tattoo ophthalmitis (cobalt blue pigments), sympathetic ophthalmitis

Idiopathic: rheumatoid arthritis (adult/juvenile), sarcoidosis

HSV Keratitis

Corneal epithelial ulceration

Swelling and inclusions in corneal epithelium

Disciform keratopathy: oedema and thickening of the stroma with thickening and corrugation of

Descemet’s membrane

Chlamydial Keratoconjunctivitis (TRachoma and Inclusion Conjunctivitis – TRIC)

Follicular conjunctivitis

Papillary hyperplasia of the conjunctiva

Inclusions are ≈ nucleus-sized collections of Chlamydial elementary bodies in a glycogen matrix

(Giemsa and PAS +ve)

Trachoma:  predominantly affects the upper tarsal

 chronic inﬂam

goes deep (includes tarsal glands) → scarring, atrophy and distortion

 chronic follicular inﬂam

at the limbus → trachomatous pannus (pterygium)

Inclusion Conjunctivitis:  predominantly affects the lower tarsal

 superﬁcial inﬂam

and no scarring, limbic follicles or pannus

d/dg other causes of follicular conjunctivitis e.g. adenovirus (this has no papillary hyperplasia, etc.)

Hypertensive Retinopathy

Histological changes are recognisable in stage III & IV (IV = III + papilloedema)

Haemorrhage in the nerve ﬁbre layer (‘ﬂame’) or deeper e.g. inner nuclear layer (‘dot/blot’)

Microinfarcts of the nerve ﬁbre layer with vacuolated dilatation of axons (‘cytoid bodies’)

Hyaline protein and lipid (± foamy M) exudates in the outer plexiform layer

Diabetes Mellitus

Anterior Chamber and Ciliary Body

Diabetic iridopathy

Lacy vacuolation (glycogen accumulation, PAS +ve) of the iris pigment epithelium

Rubeosis iridis

Not conﬁned to diabetics and seen in association with severe microvasc. disease elsewhere

Leaky neovascularisation over the anterior iris

Contractures, synechiae and haemorrhage are accompanying features

Ciliary body

BM thickening (> expected for age) of the plicated part of the pigment epithelium

Stromal ﬁbrosis

Neovascularisation

Diabetic Retinopathy

Non-proliferative retinopathy

BM thickening ± hyaline arteriolosclerosis-like changes

Loss of capillary pericytes

Microaneurysms

Prominent collateral networks 2

◦

to local ischaemia (intraretinal microvascular anomalies – IRMA)

Tortuosity and dilatation of veins

Haemorrhage in the nerve ﬁbre layer (‘ﬂame’) or deeper e.g. inner nuclear layer (‘dot/blot’)

Microinfarcts of the nerve ﬁbre layer with vacuolated dilatation of axons (‘cytoid bodies’)

Macular changes: ﬂorid oedema or cystoid degeneration (p. 197)

Proliferative retinopathy

Also seen in oxygen toxicity (retrolental ﬁbroplasia) and ischaemic states (e.g. sickle cell anaemia)

Thin capillary glomeruloid loops and sheets start in the retina

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Eye and Ear 196

Progression involves extension into the vitreous together with ﬁbroblasts & glial cells

Haemorrhage, contraction and scarring → retinal detachment

Degenerative/Age-Related Changes

Xanthelasma

Lipid foamy M (as elsewhere)

Pinguecula

Grey-white conjunctival thickening in the horizontal plane of the palpebral ﬁssure

Epithelial atrophy with loss of goblet cells ± actinic dysplasia or even hyperplasia

Stromal elastosis ± granulomatous reaction

Accumulation of amorphous hyaline material ± Ca

d/dg incl. Gaucher’s disease (if the patient is young)

Keratoconus

Conical bulging of the cornea, begins in teens, FM, Down’s syndrome > sporadic, bilateral >

unilateral

Apex of cone shows stromal thinning, irregularity and scarring (hypercellularity) ± amyloid

Bowman’s (normally acellular hyaline) layer gets interrupted by cellular foci containing nuclei

± Breaks in Descemet’s membrane: occur later but may be associated with oedematous thickening of

the stroma (clinically presenting as acute keratoconus)

The base/rim of the cone shows Fe deposition in the epithelium (i.e. a Fleischer ring – ! do not confuse

with a Kayser-Fleischer ring which shows copper in Descemet’s membrane)

Cornea Guttata

F>M, bilateral, elderly; affects the central cornea; changes of Fuch’s occur later (q.v.)

Thickening of Descemet’s membrane (with typical EM) in a linear, corrugated and knobbly pattern

d/dg Hassall-Henle warts (a normal ﬁnding after age 20) are identical but are only found at the extreme

periphery of the cornea so should not be present on surgically excised corneal specimens

d/dg ageing results in a non-speciﬁc purely linear thickening of Descemet’s membrane

Fuch’s Combined Corneal Dystrophy

Refers to the epithelial and subepithelial changes that occur in combination with cornea guttata (q.v.)

Superﬁcial stromal cells insinuate through Bowman’s layer to lie horizontally in between that layer and

the epithelial basement membrane – this can form a multicellular thick stromal pannus with time

The overlying epithelial cells show variability in staining intensity

Late changes: oedema of stroma and epithelium ± bullae (that may rupture)

d/dg non-speciﬁc reactions to injury, oedema or inﬂam

can cause a pannus +/ bullae

Corneal Stromal Deposits

(called bland keratopathy it esp. affects the superﬁcial stroma incl. Bowman’s layer)

Amyloid: may be familial (incl. TGF or gelsolin amyloid in lattice corneal dystrophy) or sporadic in

many chronic eye diseases e.g. uveitis, sympathetic ophthalmitis, keratoconus, retrolental ﬁbroplasia,

glaucoma, trachoma and trauma

Others: MPS (macular corneal dystrophy), actinic eosinophilic change (climatic droplet keratopathy)

Cataract

Similar changes are seen in senile, diabetic and congenital forms but speciﬁc subtypes also exist

Clefts (spaces) ﬁlled with the following:

Eosinophilic globules of Morgagni

± Epithelial cells proliferate posteriorly (beyond the equator of the lens)

± Ca

deposition (= hypermature cataract)

Age-related Macular Degeneration (AMD)

Similar changes are seen in rare genetic conditions

Atrophy of the macular retina

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± Fibrous plaque (organised previous haemorrhage from choroidal vessels that perforated up through

Bruch’s membrane) in the disciform degeneration variant

Disruption of the retinal pigment epithelium ± some epithelial cell clusters remaining

Accumulations of BM material on Bruch’s membrane

Cystoid Degeneration of the Retina

Similar changes are seen in ageing, diabetes, myopia, neoplasia and inﬂammatory conditions

Is considered ‘normal’ in adults if restricted to foci at the ora serrata without complications

Most prominent at the periphery/macula regions

Mucopolysaccharide-ﬁled cysts in the outer plexiform layer of the retina

Cysts coalesce ±→clefting/retinal detachment/retinal perforation

Melanocytic Lesions

Melanocytic Naevi

Rarely involve the corneal or tarsal conjunctiva (common at the limbus)

Pigmentation and size may ↑ after puberty (does not imply malignancy)

50% have cyst-like spaces lined by conjunctival epithelium – rare in melanoma or acquired melanosis

cf. skin, they have more chronic inﬂam

and epithelial hyperplasias (! do not misdiagnose as SCC)

Junctional:  the cords and nests may reach the surface (unlike most skin naevi)

 naevocytes may be large

 d/dg melanoma: occurrence in childhood and Hx of pre-existing naevus help

Compound:  junctional activity and apparent atypia may lead to misdiagnosis of melanoma

 Spitz/Reed naevi equivalent:

 spindle and epithelioid cells (which can be multinucleated)

 mitoses more common than in skin

 occur in children – !d/dg melanoma

 d/dg melanoma: youth and downward maturation help (i.e. favour benignity)

Subepithelial:  occur in elderly patients

 in the substantia propria (≈ lamina propria) – usu. with a Grenz zone

 may be heavily pigmented

Balloon cell:  very large pale naevocytes with central small hyperchromatic nuclei

 balloon cells may also be seen in blue naevi and malignant melanoma

Blue:  well-circumscribed area in conjunctival stroma

 spindle/dendritic melanocytes in the episclera (i.e. the loose connective tissue external to

the sclera)

 = naevus of Ota if the surrounding skin is also involved (oculodermal melanocytosis)

Melanosis Oculi

Without atypia: ↑ basal layer pigmentation or basal layer hyperplasia of non-atypical melanocytes

With mild atypia: polygonal melanocytes with round nuclei and scant cytoplasm

With moderate/severe atypia: epithelioid, dendritic or spindle melanocytes ± suprabasal extension

Congenital

Unilateral, darker races, part of Ota’s naevus

Diffuse increase in melanocytes in uvea (incl. heterochromia iridis), sclera and episclera

The conjunctiva is not involved (.

. clin. the pigmentation does not move with it when pulled)

Acquired (epithelial)

Bilateral: age-related ↑ in conjunctival basal layer pigmentation (≈ ephelis in skin)

Unilateral:  age >40, pre-malignant

, poorly-circumscribed irreg. pigmentation in conjunctiva

 the melanosis ﬂuctuates (due to variable inﬂam

and pigmentary incontinence)

 ↑ pigmentation of conjunctival epithelium (most basally)

 variable chronic inﬂammatory response in the stroma

 lesion progression involves progressive lentiginous proliferation of junctional

melanocytes with increasing pigmentation, nesting and invasion into the underlying

stroma and may be classiﬁed by the Zimmerman stage

ocular counterpart of lentigo maligna

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Zimmerman Stage: I (benign)

A. minimal lentiginous/junctional activity

B. excessive lentiginous/junctional activity

II (cancerous – i.e. invasive melanoma, often shows junctional

nesting)

A. with minimal invasion e.g. <1.5 mm deep (or pT2 i.e.

≤0.8mm deep)

B. with extensive invasive growth

Differential Diagnosis (Naevi vs. Melanoma vs. Melanosis)

Naevi: intra/subepithelial, clinically stationary, cystoids

+ve, inﬂammation ±ve

Melanoma: intra/subepithelial, clinically progressive, no cystoids, inﬂammation ++

Melanosis:

 acquired: intraepithelial, ‘waxes and wanes’, no cystoids, inﬂammation +

 congenital: scleral/episcleral, stationary, heterochromia iridis, no cystoids, no inﬂammation

Also, naevi can show any degree of pigmentation but acquired melanosis is heavily pigmented

Conjunctival Melanoma

50% arise de novo, and 50% from naevi/acquired melanosis

Suspect melanoma developing in a naevus if there is a size increase not assoc

with:

1. ↑ pigmentation at puberty/pregnancy ± UV/sun exposure

2. enlargement of cyst-like spaces lined by conjunctival epithelium

3. inﬂammation

Similar histology to skin melanoma – usu. pleomorphic epithelioid cell type

Depth is measured from the top of the conjunctival epithelium (Jakobiec-Breslow thickness)

d/dg extension of a uveal melanoma through the sclera

Uveal Melanoma

Origin in choroid, ciliary body, iris

There are four main histological types (the modiﬁed Callender classiﬁcation):

1. Spindle A: thin spindle cells, small elongated nuclei + longitudinal groove, no/inconspicuous

nucleoli, ill-deﬁned cell borders, few mitoses

2. Spindle B: plump spindle cells, ovoid nuclei with coarser chromatin and prominent nucleoli, well-

deﬁned borders, mitoses ++

3. Epithelioid: polygonal cells with pleomorphic nuclei, prominent nucleoli, multinucleate cells, mi-

toses ++

4. Mixed (spindle and epithelioid): state % proportions of each type

Prognostics: spindle types have a better prognosis than epithelioid; melanoma conﬁned to the iris has

a very good prognosis regardless of histological type; growth pattern (focal mass, diffuse or ring),

trabecular meshwork involvement (for iris lesions), extracellular matrix pattern on PAS (heterogenous,

rings or loop networks)

Conjunctival Tumours

Squamous papilloma

Squamous carcinoma: usu. exophytic, can be pigmented

MEC

Lymphomas: usu. MALTomas, d/dg follicular conjunctivitis, chronic dacroadenitis, chloroma, CLL

Melanocytic tumours (vide supra)

Sarcomas incl. RMS, leiomyosarcoma and KS

Myxoma: stellate ± multinucleate myxoma cells (+ve for SMA and vimentin, −ve for S100 &

desmin) ± pale nuclear inclusions, mast cells & AB +ve hypovascular background

i.e. cyst-like spaces lined by conjunctival epithelium

conjunctival melanoma is rare cf. uveal which is the commonest adult intraocular malignancy