Tadrous P.J. Diagnostic criteria handbook in histopathology: a surgical pathology vade mecum

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d/dg mets or testicular tumours extending to the paratesticular region: e.g. carcinoma of the rete testis

or epididymis

Penile Neoplasia

Squamous Dysplasia

Any grade can occur (low grade: ≤ basal

of epithelium affected, high grade: >

). Full-thickness

lesions (CIS) are termed Erythroplasia of Queyrat, Bowen’s disease or Bowenoid papulosis (vide infra)

Morphological subtypes: squamous, warty, basaloid

Deﬁnitive diagnosis should be by CPC since prognosis differs (upto 20% of Bowen’s disease and

Erythroplasia progress to SCC ± mets whereas Bowenoid papulosis rarely progresses, usu. responds

to local Rx and may spontaneously regress)

Erythroplasia of Queyrat

Typical age 50 years; well-deﬁned red velvety plaque on the glans; usu. single

Irregular acanthosis; high grade dysplasia ± dyskeratoses; (± parakeratotic hyperkeratosis)

Chronic inﬂam

and prominent capillarity in the underlying ﬁbrous tissue

Bowen’s disease

Typical age 40 years; usu. paler (cf. Queyrat’s erythroplasia) scaly lesion on the shaft; usu. single

CIS also extends down pilosebaceous epithelium, hyperkeratosis is common (cf. erythroplasia)

Bowenoid papulosis

Typical age 30 years; multiple papules on the shaft (± glans/prepuce)

Irregular acanthosis, ± warty features, ± more pigmented (melanin)

The dysplastic cells, although full-thickness, may be more spaced out cf. Bowen’s disease with some

surface maturation and pilosebaceous units are usu. spared.

Squamous Cell Carcinoma

Differentiate verrucous carcinoma from other types (see p. 285)

Grading is as for skin (Broders’ classiﬁcation – see p. 284)

Note local satellite nodules (discontinuous spread) – a poor prognostic feature

d/dg PEH (as elsewhere)

See also p. 42 and p. 51

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17. Gynaecological

Vulva

Kraurosis Vulvae (Lichen Sclerosus)

See p. 215 under ‘penile lesions’

Bartholin Gland Cyst

Lining may be squamous, mucinous or transitional (similar to other vestibular gland cysts)

d/dg the small (<2mm) apocrine gland retention cysts + hair follicle keratin plug of Fox-Fordyce

disease

Squamous Cell Carcinoma (the Two Clinicopathological Types)

◦

older women, well-diff, keratinising, arising on a background of dystrophies

◦

young, basaloid, arising on a background of VIN with HPV; risk of synchronous/metachronous CA

FIGO Stage 1A (≤2cm , ≤1mm stromal invasion – from adj. dermal papilla) → conservative Mx

Extramammary Paget’s Disease

Sites (rich in apocrine glands): male or female perineum, external auditory meatus, eyelid, axilla

! An accompanying atypical squamous proliferation may mask the underlying Paget’s

Stromal invasion limited to <1mm = ‘minimally invasive’ (local excision may be curative)

Immuno/stains: +ve for mucin (AB, DPAS), LMW CK (CAM5.2), CK7 (CK20 favours colonic/bladder

◦

); ±ve for EMA, CEA, GCDFP15, AR, HER2, CD5; −ve for ER, PgR, PSA, Melan-A, HMB45

d/dg Bowen’s (+ve for HMW CK, −ve for mucin, CK7, GCDFP15) vs. anaplastic Paget’s: Paget’s

spares the basal layer, may form small ducts and is +ve for mucin with a different immuno proﬁle

d/dg melanoma or metastasis from a visceral malignancy: use CPC, morphology and immuno

Vagina

Vaginal Intraepithelial Neoplasia (VAIN)

Grading criteria for VAIN are the same as for CIN

d/dg transitional cell metaplasia/epithelium

Effects of Diethylstilboesterol Exposure in utero

Fibrotic anomalies: bands, septae, fornix obliteration, etc.

↑risk of squamous VAIN

Vaginal adenosis (usu. affects the upper vagina):

 M¨ullerian glands (endocervical, tubal/endometrial) in submucosa (may extend to the surface)

 variable architectures including cystic (d/dg Nabothian follicles) and papillary (d/dg CCC, but

CCC contains glycogen rather than mucin)

 squamous metaplasia may occur (and may be the only feature if a superﬁcial section is cut .

. get

levels if you see squamous epithelium dipping down deeper than usual into the stroma of a

vaginal Bx)

 may undergo Arias-Stella reaction (!d/dg atypical adenosis or CCC)

 d/dg endometriosis (endometrial stroma and siderophages are absent in adenosis)

 d/dg Wolfﬁan remnants: occur deeper, no mucin (see Gartner’s duct remnants p. 236)

Atypical adenosis: adenosis with cytological atypia (prominent nucleoli, etc.) and no evidence of

invasive architecture. Seen adjacent to (and thought to be the precursor of) CCC

Carcinoma: CCC type, occurring in adolescent to young adult age group (always <40 years)

Other Mass Lesions

Fibroepithelial polyp ± atypical (‘bizarre’) stromal cells

‘Mesonephric’ papilloma (young girls) – slender papillae lined by bland cuboidal-to-columnar

non-mucous cells ± squamous metaplasia. Thought to be M¨ullerian rather than mesonephric

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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Rhabdomyoma (middle-aged): ﬁbromyxoid stroma, elongated (strap-like) cells with vesicular nuclei

& focal cross-striations by LM/EM. No cytol. atypia. Poorly circumscribed but usu. small (<3cm

)

RMS botryoides (see p. 58)

Many other very rare things incl. lymphoma, melanoma, leiomyosarcoma, ectopic rests, etc.

Cervix Uteri

FIGO Staging of Cervical Carcinoma (Old = 1988;New= 1995)

I conﬁned to the uterus (corpus extension does not change the stage but worsens the prognosis)

II extracervical but not to the pelvic walls/lower third vagina (IIB = parametrial involvement)

III conﬁned to pelvis but extends to walls/lower vagina or causes hydronephrosis/non-functioning kidney

IV mucosa of bladder/rectum involved or extrapelvic spread (IVB = distant mets)

Stage IA = detectable by microscopy only (‘microinvasive’)

AND ≤7mm  (i.e. ≤3 blocks)

 IA1 =≤3mm deep

 IA2 = 3–5mm deep

 old IA1 = depth unmeasurable = <1mm (‘early stromal invasion’), no

 limit

 old IA2 = depth measurable = 1–5mm deep, ≤7mm ∅

Stage IB: >1A or if clinically apparent (even if old IA1); Old IB: > old IA2

Retain and distinguish the ‘earlystromal invasion’ group as a subgroup of the newIA1 because treatment

may be conservative provided the diameter is ≤7mm (if >7mm

, Rx is individualised)

It is misleading to diagnose IA carcinoma if a lesion is incompletelyexcised. In such cases measurements

should be qualiﬁed ‘measuring at least ...’

Ulcerated lesions should not be staged as IA – their management should be individualised

Small cell carcinoma should not be called ‘microinvasive’ – even if they are stage IA

Vascular invasion does not affect the staging but should be mentioned

Cervical Squamous Intra-epithelial Neoplasia (CIN) and Early Invasive Squamous Carcinoma

BAUS = basal layer nuclear abnormalities without full-thickness changes

For CIN there must be nuclear abnormalities all the way to the surface epithelium for all grades 1–3

Grading CIN: grades 1–3 show nuclear atypia (=enlargement, pleom., ↑NCR, variablehyperchromasia,

irregular nuclear membranes, coarse chromatin and usu. lack of prominent nucleoli) & evidence of

maturation lack occupying no more than the 1

or 3

thirds of the epithelial thickness respectively.

Full thickness atypia (± slight surface ﬂattening) is CIS (a subtype of CIN3)

Mitoses: high mitoses and abnormal ﬁgures are helpful (2-group and 3-group forms – i.e. strag-

gling/isolated chromosomes at the spindle poles – are more common than multipolar mitoses). For

CIN1 the presence of mitoses (unless abnormal) is not helpful but some degree of nuclear enlarge-

ment and pleom. are essential. CIN in immature squamous metaplasia may not be gradable (= ‘CIN

ungradeable’)

In high grade lesions the basal layers are often verticallyorientated (lateral crowding)and the epithelium,

in general, has a tendency to strip off. Nuclear and cytoplasmic p16 +vity is typical

Iodine artefact can result in under-grading CIN3 because it causes a pallor of staining in the superﬁcial

half of the epithelium with a sharp demarcation from the deeper half (nuclear morphology, apart from

staining intensity, is not affected)

Immuno: Ki67 +ve in the superﬁcial levels, strong cytopl. and nuclear p16

INK4a

+vity (but may be

−ve in low grade lesions)

ISH for high risk

HPV: nuclear dot +vity

◦

indicates integrated virus,

◦

is seen in ≈ all cases of

high grade CIN (i.e. CIN 2/3), and

◦

may identify those cases of CIN 1 at risk of progression

Features of impending invasion: extensive crypt involvement with distension, comedonecrosis and focal

eosinophilic squamoid maturation (→ do levels); ! d/dg CIN3-like invasive SCC (p. 234)

Features of early/microinvasion: irregular buds of cells (usu. arise from crypts cf.surface) with squamoid

maturation (± pearls), nucleoli, stromal reaction (incl. chronic inﬂam

± neovascularisation), bizarre

giant basal cells (upto 5× normal size) and lack of basal palisading

Both IA1 and IA2 are included in this category by the Working Party drawing up the UK National Dataset but some other authorities

exclude the new IA2 from the ‘microinvasive’ category

measured from the nearest stromal-epithelial junction – surface or crypt – from which the tumour arises

= subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 58, 59, 66, 68 (according to Kalof et al. 2005, all but 59 and 68 were used in their

study)

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Gynaecological 234

d/dg ! transitional cell metaplasia of the cervix can be misdiagnosed as CIN 3 but metaplasia:

 has vertically (perpendicular to the BM) orientated nuclei in the deeper layers becoming

transverse superﬁcially (! but this may also be seen in high grade CIN)

 smooth, oval nuclei with neat nuclear grooves cf. the nuclear atypia of CIN3 (vide supra)

 lacks mitoses

d/dg: ! do not mis-diagnose CIN3-like invasive SCC (irreg. islands of solid/comedo tumour) as CIN3

d/dg postmenopausal atrophy: some advocate ‘CIN ungradeable’ if there are <4 cell layers with all

horizontally orientated atypical cells; (mitoses or ↑Ki-67 LI help to conﬁrm CIN)

d/dg reactive/inﬂam

/immature metaplasia (look for nucleoli and mucus cells but ! see SMILE, below)

Grading and Variants of SCC

Large cell keratinising (well diff/G1): bridges and keratinising squamous pearls

Large cell non-keratinising (moderately diff/G2): no pearls but may have single cell keratinisation

Small cell non-keratinising (poorly diff/G3) and CIN3-like SCC: high grade cytology ± necrosis ±

large pleomorphic cells with giant bizarre nuclei ± surrounding invasive squamoid tongues

Squamotransitional cell CA (papillary SCC): the superﬁcial part looks like urothelial G1/G2 pTa TCC

but deeper it can be widely invasive (d/dg squamous papilloma which is rare esp. postmenopause)

d/dg CIN3-like SCC vs. SmCC:

 SCC has a solid pattern of inﬁltrative growth: ‘back-to-back’ islands showing comedonecrosis

 SmCC:  irregular loose/dyscohesive aggregates

 organoid +/rosettes/acini

 lack of a lymphoid response

 vascular invasion more common than with SCC

 immuno: 34E12, p63, CK14 +ve in SCC; CD56 +ve in SmCC; CgA ±ve in SmCC and

SCC

Adenoid Basal Carcinoma/Epithelioma

Elderly, not mass-forming, assoc

with surface CIN2-3 but on its own it has a good prognosis

Basaloid islands (BCC-like cells with palisading) ± columnar cell rosettes within them ± mucin

Few mitoses and no desmoplastic stromal reaction

Islands with abrupt keratinisation

Immuno: basaloid cells +ve for reserve cell CK (14, 17 and 19); columnar cells +ve for CEA, EMA

d/dg CIN3-like SCC, adenoid cystic carcinoma, ASC with adenoid basal-like areas

d/dg postmenopausal basaloid reserve cell change: buds, nests and interconnecting cords of basaloid

reserve cells around endocervical glands without a stromal reaction (! do not call it cancer)

Cervical Glandular Intra-epithelial Neoplasia (CGIN) and Invasive Adenocarcinoma

Classiﬁed into: low grade (CGIN I) and high grade (CGIN II and III = ACIS)

CGIN often co-exists with CIN (but a cervical smear is not sensitive for detecting CGIN)

High grade CGIN (but not low grade) is assoc

with HPV 18

Histology of dysplasia

Abrupt change from normal to abnormal areas in a gland is a feature of dysplasia (! or metaplasia)

Hyperchromasia, pleomorphism, (abnormal) mitoses, aberrant (gastric neutral) mucin, apoptoses

Goblet cells (not seen in non-neoplastic conditions)

Low grade: nuclear abnormalities limited to the lower

of the epithelium; apical mucin persists

High grade: abnormal mitoses and apoptoses are common, arch. anomalies more usual cf. low grade

(gland clustering, outpouchings, papillary formations, cellular bridging, etc.)

d/dg: if ?dysplasia but can’t tell whether squamous/glandular consider ‘atypical reservecell hyperplasia’

d/dg: stratiﬁcation is normal (cyclical) in endocervical cells so is insufﬁcient for diagnosis in the absence

of nuclear abnormalities; likewise cribriform change per se is not speciﬁc to neoplasia

Features of stromal invasion

Oedema, ﬁbrosis, inﬂammation and squamoid change are indicative of invasion

Extension beyond the normal glandular ﬁeld (presence of medium-sized arteries or >7.8mm deep)

Large irregular ‘crab-like’ glands/dysplastic glands with ‘stretched’ areas and stromal oedema/inﬂam

Solid growth patterns (see Figure 17.1 on p. 245) and adenosquamoid areas

Variants

Endocervical, endometrioid, enteric, clear cell, adenosquamous, ciliated, microcystic adenoCA

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Gynaecological 235

Immuno

CEA +ve (−ve in non-dysplastic structures in d/dg)

EMA and CA-125 cytoplasmic staining (lumenal staining in non-dysplastic glands)

CA-19.9 +ve in 50% of CGIN/adenocarcinoma (negative in non-dysplastic glands)

p16 is diffusely +ve (nuclear and cytoplasmic) in high grade CGIN and some adenocarcinomas but

usu. negative in non-neoplastic glands

Bcl-2 −ve

Ki-67 LI > 67% (some use a MIB1 of <10% and >50% as cut-off points for reactive vs. dysplasia)

Minimal Deviation Adenocarcinoma (Endocervical Type MDA = Adenoma Malignum)

Clin: worse prognosis cf. other adenocarcinomas and is assoc

with Peutz-Jeghers and mucinous ovarian

tumours (even in the absence of Peutz-Jeghers multifocal SCTAT)

Deep inﬁltration (beyond the middle third/>7.8mm/presence of medium-sized arteries)

‘Finger-in-glove’/‘crab-like’ complex outlines with pointy angles to glands

Columnar mucinous cells with minimal/focal atypia

Desmoplastic response focally (± vascular invasion): periglandular stromal cells become SMA +ve,

ER −ve (the opposite of periglandular stromal cells in benign glandular conditions)

Immuno: −ve for ER, PgR and diffuse CA-125 and +ve for CEA (focal) and EMA (cytoplasmic)

Contains pyloric-type mucin (neutral sialomucin) cf. normal glands (sulphomucins – mixed pur-

ple/violet on ABDPAS) – but ! exclude d/dg simple pyloric metaplasia using morphology

d/dg: endometrioid variant MDA (good prognosis, pseudostratiﬁed glands) ! d/dg CGIN/TEM

d/dg Fluhman Type A tunnel clusters (undilated, branched/budded hyperplastic glands). Type B tunnel

clusters are like deep Nabothian polyfollicles (can also get deep Nabothian follicles proper)

d/dg lobular glandular hyperplasia/deep crypts (rounded glands, lobular, no desmoplasia, immuno)

d/dg mesonephric remnant hyperplasia (p. 236)

d/dg endocervicosis (in the cervix there must be a gland-free zone between superﬁcial and deep glands)

d/dg ﬂorid cystic endosalpingiosis lacks atypia or stromal response

Other Tumours

AdCC: S100 −ve (unlike other sites), may co-exist with adenocarcinoma or SCC, poor prognosis

Glassy cell carcinoma: ASC variant with vesicular nuclei and prominent nucleoli, poor prognosis

Clear cell ASC: like glassy cell but no prominent nucleoli, poor prognosis

SmCC: occurs with adenocarcinoma or SCC–!DONOTmisdiagnose as ASC. Aggressive

Benign: M¨ullerian papilloma of childhood, adenomas (tubular, villous, TV, villoglandular)

Metaplasias and Other Lesions in the Differential Diagnosis of CGIN

Tuboendometrioid metaplasia (TEM)

Assoc

with trauma (cone, birth, prolapse)

Mixture of cell types: intraepithelial lymphocytes and tubal epithelium (alternating ciliated/secretory)

Cilia (favour a metaplastic rather than neoplastic process, esp. if well-formed)

Apoptoses are rare (likewise mitoses – and there should be no abnormal mitoses)

Immuno: p16 −ve/focal +vity; Bcl-2 +ve (diffuse cytoplasmic) } opposite to high grade CGIN

Pseudostratiﬁcation (cf. true stratiﬁcation in CGIN – requires EM to distinguish)

Atypical: variation in nuclear size (after accounting for the 3 cell types)

d/dg ciliated CGIN: CGIN lacks multiple cell types, has more complex arch., ↑Ki-67 LI, etc.

Microglandular endocervical hyperplasia (MGH)

Usu. (but not necessarily) assoc

with pregnancy or pill – can occur postmenopausally

PMN

Vacuolated cells, not stratiﬁed

Lacy columnar reserve cells present (MGH may coexist with reserve cell hyperplasia)

Normal mitoses and lack of apoptoses (cf. CGIN)

Immuno: p16 −ve (and Bcl-2 −ve)

Hyalinised stroma (pseudoinﬁltrative), solid sheets, hobnail/signet cells →d/dg clear cell CA (but CCC

has nuclear atypia, ↑ mitoses and intracellular glycogen predominantly [± a little mucin])

d/dg microglandular endometrial adenoCA – this lacks lacy reserve cells and has endometrial stroma

Stratiﬁed mucinous intraepithelial lesion (SMILE)

This is considered a form of unstable reserve cell hyperplasia

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Mucous vacuoles in stratiﬁed epithelium showing nuclear atypia and a high proliferation index

Assoc

with CIN, CGIN, adenoCA or SCC .

. do levels/embed more tissue if only SMILE is seen

Oxyphil metaplasia (OMEE)

Large nuclei with nucleoli but normochromatic, normal mitoses and inﬂammation in lumena

Florid cystic endosalpingiosis

Lacks atypia or stromal response

Papillary endocervicitis

Blunt-tipped papillae, not dysplastic or proliferative (cf. d/dg: villoglandular/papillary carcinoma)

Gartner’s duct remnants

(Gartner’s duct is the intra-cervical part of the Mesonephric [Wolfﬁan] system)

Acinar/lobular architecture

Eosinophil secretions (DPAS and AB +ve) but no intracellular mucin

Large vesicular nuclei (not hyperchromatic)

Immuno: CD10 +ve

d/dg SCC (CIN may extend into mesonephric remnants, esp. after conisation d/dg invasive SCC), MDA

(but this has columnar mucous cells and complex glands), metastatic breast carcinoma (but this is usu.

diffusely inﬁltrative–!maybeoverlooked as ‘stromal hypercellularity’)

Lobular glandular hyperplasia/deep crypts

Bland glands ± foreign body granulomatous reaction to spilled mucin

Arias-Stella reaction

May affect endometriotic or native cervical glands (see section on Arias-Stella, p. 237, for details)

! do not confuse the stromal decidualisation for d/dg SCC

Radiation atypia

Nuclear hyperchromasia is rare

Stromal radiation changes are also present

Lack of mitoses – esp. in relation to the degree of atypia

! cytoplasmic CEA may be +ve

Corpus Uteri

Normal Endometrium

Simple glands i.e. no branching or budding (complexity)

The deep stratum basalis does not cycle:  weakly prolif. & minimally tortuous glands

 dense stroma intermingled with myometrium

The stratum functionalis (= mid stratum spongiosum and superﬁcial stratum compactum) undergo

morphological changes with the hormonal status/menstrual cycle

There is synchronous proliferation of blood vessels, glands and stroma – except that:

 glands predominate in late secretory/early menstrual

 stroma predominates in decidua/atrophy

The changes are uniformly developed across the uterine cavity (except the isthmus)

The lower uterine segment/isthmus has:

◦

spindled stromal cells with collagen ﬁbres in between,

◦

hybrid endometrial/endocervical glands,

◦

less marked hormonal effects

Typical immunoproﬁle: epithelial cells are +ve for CK, EMA, vimentin; CEA −ve; S100 −ve unless

in early pregnancy (i.e. <12 weeks); stromal cells are CD10 +ve

Dating Secretory Endometrium – see table 17.1

Diagnosing Pregnancy

Only a placental site reaction is diagnostic of intrauterine gestation:

 layer of (Nitabuch’s) ﬁbrinoid and intermediate (esp. multinucleate) trophoblasts in the en-

dometrium

 ± trophoblastic invasion of vessels (replace endothelium) and ﬁbrinoid vascular change

 ± villi or any of the other features described below

Coincidence of gestational endometrium with ↑hCG suggests a gestation (at any site)

Gestational endometrium (= ‘gestational hyperplasia’)

Hypersecretory glands: vacuolated cytoplasm, prominent pap. infolds (‘ferning’), secretions ++

Arias-Stella reaction (vide infra) ± nuclear clearing (! not d/dg HSV inclusions)

Prominent oedema (mid-secretory-like)

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TABLE 17.1 Dating Secretory Endometrium

Early features Mid. features Late features

POD Vacuoles Mitoses Secret

s Oedema Pre-decidual change Other

1 uniform & subnuclear

<50% of glands

++ − − −

2 uniform & subnuclear

>50% of glands

(ovulation conﬁrmed)

++ − − −

3 well-aligned

(↓pseudostratiﬁcation)

±−− −

4 move to lumenal aspect rare ±− −

5 sparse −+− −

6 − − +++ − −

7 − − +++ ++ −

8 − − +++ +++ −

9 − stromal +++ ++ ﬁrst appears spiral arteries

+ become

prominent

10 − stromal +++ + thick cuffs around

++ arteries

11 − stromal +++ + superﬁcial islands

12 −+++islands start to merge

13 −+++maximal conﬂuence granulocytes

become

prominent

14 −+±+RBC

extravasation

mens. −+exhaust

± halos crumbling

Decidual reaction of pregnancy (decidua vera)

 thick-walled spiral arteries (± atherosis/necrosis/inﬂam

– all suggest intra-uterine gestation)

 abundant, well deﬁned eosinophilic to clear cytoplasm (glycogen and lipid)

 large ovoid vesicular pale bland nuclei and well-deﬁned nucleoli

 ↑stromal granulocytes (K-cells) in early gestation (but these are ≈ absent by term)

 d/dg mononuclear intermediate trophoblasts (these are hPL, CD146 and CK +ve)

Decidual glands and Fallopian tube epithelium become S100 +ve in early pregnancy (i.e. <12/40)

Arias-Stella Reaction (= focal polyploid change)

Affects endometrium, cervix, Fallopian tube or endometriosis and may be 2

◦

to any cause of ↑hCG

(gestation, mole, tumours, etc) or hormone therapy or a corpus luteum (cyst or persistent)

Cytoplasm: clear, eosinophil or vacuolated ++ (NB: there is cytomegaly such that NCR is preserved)

Nuclei (active phase): ↑size, irregular outline, granular chromatin ± prominent nucleoli

Nuclei (degenerate phase): smudged nuclear hyperchromasia and pleomorphism ± hobnailing

d/dg CCC: focality, background of gestational changes, normal NCR and lack of mitoses all favour

benignity

Menstrual Endometrium

Stromal ﬁbrin and ﬁbrin thrombi

Stromal crumbling forming balls with surrounding halos of pre-decidual cells

Glands showing ‘secretory exhaustion’ (dilated, ﬂattened cells with frayed borders)

Glandular apoptotic bodies and PMN inﬁltrates in glands

The stratum basalis is normal

Variants of Secretory

Under-developed secretory (Luteal phase defect = LPD)

Clin.: infertility/recurrent miscarriage (= habitual abortion i.e. ≥3 consecutive pregnancy losses)

Morphologically abnormal:  inadequate gland coiling (proliferative phase deﬁciency)

 inadequate secretions/decidualisation (luteal phase deﬁciency)

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Normal but delayed development (i.e. Out Of Phase = OOP)

 ≥3 days OOP occurring more than sporadically

 asynchronous development of glands vs. stroma (e.g. due to some drugs)

Normal morphology but luteal phase lasts ≤ 11 days

Causes of LPD:  hyperprolactinaemia, weight-loss and exercise-induced endocrinopathies

 ovarian (age extremes)

 endometrial (steroid receptor deﬁciency overlying leiomyoma)

 ovulation-inducing drugs

Mixed secretory pattern

Def

: >2 days discrepancy between fragments

Secretory changes in other conditions

For example, in hyperplasia/carcinoma

Variants of Proliferative

Atrophic/inactive/weakly proliferative

Clin: occurs pre-puberty/postmenopause/due to drugs

Epithelial mitoses: absent (atrophy/inactive) or scant (weakly proliferative)

Cuboidal/ﬂattened nuclei (atrophy) or elongated/pseudostratiﬁed (weakly proliferative)

±Cystic glands (± budding)

Variably collagenised stroma: d/dg normal lower uterine segment endometrium (p. 236)

Persistent proliferative

Def

: proliferative endometrium in postmenopausal women

Disordered proliferative

Clinical: anovulatory cycles/exogenous oestrogens; Mx is as for simple non-atypical hyperplasia

Poorly developed thin-walled vessels

Fibrin thrombi and stromal haemorrhage if shedding

Asynchronous growth: normal/cystic glands with shallow buds

Metaplasias (esp. ciliated) but no cytological atypia

Volume occupied by glands cf. stroma is < 3:1 (this glands:stroma ratio is a subjective evaluation)

d/dg simple hyperplasia: this is a continuum, diagnose hyperplasia if there are lots of dilated glands

Endometrial Hyperplasia

Glands:stroma ratio usu. ≥ 3:1 (may be very high in complex hyperplasia or ≈ normal is simple)

Gland architecture: simple (dilated glands ±occ. buds/infolds); complex (more crowding and irregular

shapes with branches, ‘hand-in-glove’, etc. but still with stroma between glands)

Nuclear cytology: non-atypical/atypical (↑size, rounding, vesicular, irregular membrane, prominent

nucleoli, coarse chromatin, normal mitoses, ± marked stratiﬁcat

) – compared to uninvolved glands

d/dg adeno

CA is favoured by: non-squamous solid/cribriform arch., central necrosis/PMN, desmoplasia

Endometrial Polyps

Glands orientated parallel to the surface endometrium are a useful sign of polyp (any type)

Functional polyps

Composed of cycling endometrioid glands (but often OOP cf. the background endometrium)

Fibrotic spindled stroma

Large thick-walled vessels

±Irregularly distributed and mis-shapen glands ± metaplasias ± prolif

(even postmenopausally)

Some consider features of simple non-atypical hyperplasia to be ‘normal’ in functional polyps so should

not be reported as hyperplasia unless they involve the background endometrium as well

Tamoxifen polyps

Usu. long ﬁbrous talk

Complex and cystic glands

Glandular metaplasias (squamous, mucinous, papillary, clear cell, apocrine, tubal, etc.)

Fibrous/ﬁbromyxoid stroma with focal stromal condensation around glands

±Infarction/ulceration/polyp-cancers

d/dg adenosarcoma: polyp has only focal periglandular stromal condensates and stromal mitoses are

sparse and not atypical