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

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Cytopathology 359

 The supernatant can be used for molecular biological studies e.g. HPV subtype testing

with hybrid

capture/FISH

 Detection rate of squamous lesions is increased (and glandular rate is unchanged) cf. conventional

smears

 Can make repeat preps e.g. for immuno or if in need of further haemolysis, etc.

× Criteria for adequacy not yet deﬁned

× Endocervical glandular lesions look different and their criteria are not fully worked out

× SurePath



preps can give rolled edges to squames simulating koilocytes

× LBC makes high grade cells appear smaller and they can be dispersed and rare

× Solid microbiopsies are broken-up or not retrieved .

. important diagnostic material could be lost

× In non-gynae cytology, valuable background features are lost (.

. LBC may be useful as an adjunct to

conventional prep) and there is no advantage of LBC over cytospins w.r.t sputa and bronchial washes

× More expensive due to cost of ﬁlters

× Can’t make air-dried Giemsa preps (because all are OH-ﬁxed as part of the LBC procedure)

× Problems of de-skilling in conventional smears because:

◦

previous smears needing review are likely to be of conventional type

◦

if, after the 5 year assessment period, it is decided to go back to the conventional method

Advanced practitioners

Autonomous reporting of abnormal smears by specially trained screeners. Their autonomy is subject

to guidelines e.g. they must work in a department where at least two consultant cytopathologists are

available for showing difﬁcult cases to

BSCC review of guidelines for follow-up of CIN 2 or 3

The post-cone F/U period is now 10 years rather than the 5 years it was previously

New terminology (BSCC 2002 conference in Manchester, UK)

The ofﬁcial document is currently (2007) in press – it will be upto the NHSCSP to decide when or if

this terminology is to be recommended

‘Unsatisfactory’ – give reasons

‘BNC’ has 3 options:

◦

free text to conclude ‘favours reactive’ or ‘favours HPV’ or ‘favours low grade dyskaryosis’

◦

‘high grade abnormality cannot be excluded’

◦

‘in glandular cells’

‘Low grade squamous dyskaryosis’ (includes mild dyskaryosis and all koilocyte HPV changes but

non-koilocytic HPV is still BNC)

‘Ungraded dyskaryosis’ (equivalent to ‘dyskaryosis difﬁcult to grade’ and usu. refers to the distinction

between grades 1 and 2)

‘High grade squamous dyskaryosis’ ( = moderate and severe)

‘? Invasive carcinoma’

‘?Glandular neoplasia’ (endocervical, endometrial, other speciﬁc type or NOS)

Serous Cavities

Mesothelioma Features in Pleural Fluid (vs. Reactive Mesothelial Proliferations)

◦

Abundant cell aggregates

Tight and 3D aggregates (ﬂat sheets favour reactive)

Aggregates vary in size and incl. large clusters (uniform size and small clusters favour reactive)

! Abundant cells in non-pleural locations may be reactive (pericardial, peritoneal, hydrocoele)

! Papillary aggregates may be benign in hydrocoele

! Abundant cells may be seen in reactive pleura if chest drain in situ

◦

Nuclear atypia

A weak feature (only helpful in 50%) and best assessed on small groups cf. single cells

Reactive mesothelial cells may show hyperchromasia

Most signiﬁcant if widespread

may be useful in women >30ys old as many younger women have high risk HPV with low grade lesions. Cervical (not blood) HPV

testing is considered a possible 1

◦

screening test for these women with only those positive going on to have morphological assessment

of smears. Positivity predicts the presence of a dyskaryotic lesion but not its grade. HIV +ve women may also be screened in this

way due to their ↑ risk of CIN

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Cytopathology 360

Not present in well diff mesothelioma

Also seen in radioRx, dialysis, pancreatitis (all reactive)

◦

Cell enlargement

A useful feature, esp. if ‘gigantic’ forms are seen

NCR may be preserved

Not present in all cases

◦

Macronucleoli

A weak feature, but helpful if widespread

Seen particularly in well diff mesothelioma

May be seen in reactive mesothelial cells

If still in doubt, do immuno (preferably on cell blocks):

EMA: thick peripheral membranous staining in malig. vs. thin/weak/focal membranous in reactive

Desmin: +ve in reactive, but 10% of malig. are also +ve

p53: −ve in reactive but only 50% of malig. are +ve

CK20: −ve in reactive, +ve in malig. according to some reports (but not an absolute)

Sarcomatoid Mesothelioma

Effusionsare rare and showsparse malignant spindle cells: not speciﬁc – d/dg soft tissue tumours/spindle

carcinomas (esp. RCC)

FNA of Mesothelioma

‘Metaplastic’-like cells in ﬂat sheets and 3D clusters; cellular smear

Central nuclei, elongated cell processes, hyaluronic acid vacuoles (goblet cell-like)

Sarcomatoid:

◦

cohesive spindle cell clusters or

◦

sparse spindle cells with oval nuclei

d/dg: reactive mesothelium: low cellularity, ﬂat sheets with admixed inﬂammatory cells, no 3D arch.

d/dg: adenocarcinoma (esp. BAC) or spindle carcinoma (esp. RCC)

Mesothelial Cells

Angulated ﬂat sheets with regularly-spaced nuclei (esp. in washings)

Small groups (<10 cells) with scalloped border/small papillae (± rare psammoma bodies)

An oblong ‘window’ (clear space) may be seen between cells in an isolated pair or small group

Single cells (variable size, dense cytoplasm, fuzzy borders, low NCR, even chromatin)

 ± T-cell rosetting

 ± mitoses (esp. after chemoRx)

 small vacuoles that are perinuclear (cf. whole cell in adeno

CA) and contain lipid

 degenerate → large vacuoles (d/dg signet ring cells, but mucin −ve)

Not 3D clusters/true acini/epithelial mucin. Exception: can get 3D clusters in liver disease ascites

CK is perinuclear (cf. whole cell in carcinomas)

Immuno: +ve for thrombomodulin, nuclear calretinin (± cytoplasmic), CK5, CK7, CA-125, SM047

(SM047 is −ve in breast carcinoma cells whereas CK7 may be +ve)

Immuno: −ve for Ber-EP4, TTF-1, EMA and CEA

Eosinophils in Effusions

Pneumothorax

Recurrent aspirations/instrumentation

Rarer: HL, T-cell lymphomas, Churg-Strauss, parasites, etc.

Rheumatoid Arthritis

Proteinaceous ‘messy’ background with amorphous purple globules ( = immune complexes)

± Cholesterol crystals

Multinucleated M with elongated cytoplasmic extensions

PMN, lymphocytes, ± a few mesothelial cells

SLE

Variable inﬂammatory cell component

LE cells (PMN with engulfed light magenta globules = nuclear fragment-Ab complex)

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Cytopathology 361

Ruptured Oesophagus

Nucleated squames

Purulent background

Adenocarcinoma (General Features)

Large 3D clumps with smooth (‘hard’) outline (not ﬂat sheets)

Nuclei: crowded, unevenly distributed, overlapping, anisonucleosis, irregular nuclear membrane, ±

prominent nucleoli; NCR is high and variable

Cytoplasm: sharp borders, mucin (neutral or hyaluronidase resistant AB), lipid in RCC

Glandular differentiation: acini, papillae, proliferation spheres, solid cell clusters

d/dg endometriosis/endosalpingosis

Non-Cohesive Tumours

Lymphoma, melanoma, sarcoma

Some carcinomas (signet ring, RCC, breast ILC, poorly diff)

Some Features of Malignant Cells

Intranuclear cytoplasmic inclusions: melanoma, lung, paraganglioma, thyroid, Dutcher bodies

Round shape except: SCC, TCC, sarcomas, granulation tissue and cells with radiation effect

Big cells except: breast, stomach, pancreas, lung, SBRCTs, lymphomas

Mucin vacuoles: neutral/acidic (sialated/sulphated/highly sulphated)

Pigments: melanin/bile

Glycogen: mesothelial/mesothelioma, CCC, liver/HCC, RCC, seminoma, Ewing’s, RMS

Crystalloids: Reinke/alveolar soft part sarcoma

Psammoma bodies: esp. if many – but diagnosis must only be made on cells

Some Features Suggesting Primary Sites for Carcinomas in Effusions

Lung

Clusters (rarely acini, papillae or psammoma bodies)

Cytological atypia can vary from severe (adenocarcinoma) to bland (Clara cells)

SmCC: moulding in single cell columns, angulated nuclei, sparse cytoplasm

Upper GIT

Dispersed cells ± signet ring forms; can be bland (d/dg M)

Breast

Proliferation spheres, dispersed, single ﬁles (but nuclei are not angulated/hyperchromatic as in SmCC)

Targetoid private acini: single vacuole (true signet ring cells are said to have multiple microvacuoles)

Monotonous cell size and nuclear morphology (CK pattern may distinguish them from mesothelium)

Lobular carcinoma is more likely to involve the peritoneum cf. IDC

Ovary

Very cellular with large clusters or dispersed cells with prominent vacuolation

Serous:  cells are pleomorphic to bland, papillae (but, rarely, a dispersed cell pattern is seen)

 psammoma bodies: brownish on Pap, only its outer rim stains with MGG (d/dg ‘vacuole’)

Mucinous

:  large cohesive groups of vacuolated atypical cells

 conﬁrm mucin with stains (because endometrioid can look similar but has glycogen)

Endometrioid: similar to carcinoma lung/colon, squamous metaplasia helps if present

Clear cell (CCC): small groups and single cells:

 Pap: cytoplasmic border accentuation (‘vegetable cells’), irregular nuclei and ↑nucleolus

 MGG: RCC-like vacuolation

 PAS: glycogen ++

RCC

Like CCC of the ovary but without vegetable accentuation and the vacuoles also contain lipid

Immuno: CD15 +ve (for more information, see p. 217)

Other carcinomas

Colonic carcinoma: ± columnar cells and palisades

PTC: typical cytology ± psammoma bodies (may also occur in M¨ullerian metaplasias/malignancy)

see ‘Pseudomyxoma peritonei’, p. 375 – but note that most people currently believe the 1

◦

site of epithelial neoplasia in PMP is the

GIT (usu. the appendix) rather than the ovary

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Cytopathology 362

TCC:  clusters of mesothelial-sized cells ±cercaria-like cells (i.e. tadpole with big head and short

fat tail)

 immuno: +ve for Ber-EP4, CK20 and LP34, −ve for CA-125

Well-diff SCC: ! beware anucleate squames – these may be: contaminants, from a ruptured teratoma,

squamous metaplasia of the serosa or from a pleural ﬁstula to the bronchi/oesophagus

Curschmann’s spirals: may be assoc

with adenoCA (but are more common in the sputum of COPD)

Lymphoma/Leukaemia

Highly cellular – macroscopically the ﬂuid may be chylous (i.e. milky)

Dispersed cell pattern ± aggregates but no cohesive clumps

Low grade: reactive effusions are mainly T-cell .

. B-cell predominance suggests lymphoma (do :)

High grade: may show many apoptoses (d/dg poorly diff carcinoma/melanoma – do immuno)

Low grade lymphomas

CLL: monomorphic, coarse clumping of chromatin

LPL: Dutcher bodies

FCL: centroblast morphology

Rarely MALT or myeloma (usu. the high grade plasmablastic myelomas cause effusions)

T-cell: polylobated nuclei, aberrant T-cell phenotype (to distinguish from reactive)

High grade lymphomas

Burkitt: cytoplasmic lipid vacuoles

ALCL (d/dg carcinoma)

DLBCL incl. 1

◦

effusion lymphoma (PEL) and pyothorax-assoc

lymphoma (PAL)

PEL: B markers −ve; +ve for CD45, CD38, CD138, EMA, CD30, HHV8, AIDS, KS, clonal EBV

PAL: +ve for pan-B markers, pleural/thoracic mass; −ve for CD30, HHV8, EBV

Hodgkin lymphoma

Rare in effusions; see typical H/RS cells; eosinophils are scant

Leukaemias

The effusion may be infective (leukaemic cells get into any serous ﬂuid .

. you need to see many

leukaemic cells to diagnose a leukaemic effusion)

Chromatin is not as vesicular or clumped as lymphomas

Cytoplasmic granules may be positive for: MGG, MPO, lysozyme, CD68 (KP1), CAE

Melanoma

Dispersed, ± multinucleate, prominent nucleoli, vacuolated cytoplasm

– d/dg meso, adenoCA, RCC

Pigment = dust-like melanin: meso has lipofuscin, HCC has bile .

. do Masson-Fontana or bleach

Amelanotic vs. RCC vs. meso (all can be S100 +ve and melanoma can be CK +ve, vimentin +ve)

Sarcoma

Rare – consider sarcomatoid tumours ﬁrst (mesothelioma, melanoma, carcinoma)

Low yield of cells: small round, pleomorphic epithelioid, spindle (pleomorphic/monomorphic)

Germ Cell Tumours

Seminoma/dysgerminoma: small clusters, pale nuclei, multiple nucleoli, vacuolated cytoplasm, T-cells

Embryonal carcinoma (MTU): large pleomorphic cells with prominent nucleoli

YST:eosinophilic hyalinecytoplasmic globules: ! maybe confused with adenocarcinoma; AFP immuno

is weakly +ve (ﬂuid AFP level may be better)

Ancillary Techniques

Neutrophil granules are a useful internal control to check adequacy of diastase digestion in DPAS

CD15 (Lewis

) is speciﬁc but not as sensitive as CEA for adenoCA (BG8 – Lewis

– is also good)

B72.3 is not generally useful but is positive in serous ovarian carcinoma

CEA: −ve in meso, RCC, breast, ovarian serous CA; +ve in GI and most other adenocarcinomas

Ber-EP4:more sensitivefor pulmonary cf.non-pulmonary epithelia. Most speciﬁc if basolateral staining

(only) is accepted as +ve

Adenocarcinoma vs. meso panel: CEA, CD15, Ber-EP4, TTF-1, CAM5.2, EMA, CK5/6, calretinin

esp. ‘balloon cell’ melanomas. In melanoma the vacuoles contain glycogen not mucin

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Cytopathology 363

Poorly diff. large cell (carcinoma vs. lymphoma vs. melanoma) panel: CAM5.2, MNF116, EMA, LCA,

S100, HMB45, T-cell markers, B-cell markers, CD30

Poorly diff. small cell (SmCC vs. SCC vs. lymphoid vs. neuro/nephroblastoma vs. sarcoma) panel: CK,

desmin, LCA, T-cell markers, B-cell markers, Tdt, CD10, CD99, CD56, NSE, S100

Spindle cell (sarcoma vs. carcinoma vs. mesothelioma) panel: CK, vimentin, desmin, EMA, S100,

SMA ± myogenin/MyoD1, CD34, CD31, HMB45, c-kit

CK is occ. +ve in: synovial sarcoma, epithelioid sarcoma, myeloma, ALCL, leiomyosarcoma, epithe-

lioid angiosarcoma, RMS, chondrosarcoma, melanoma

S100 is occ. +ve in: RCC, breast carcinoma, mesothelioma. Only 50% of MPNST are S100 +ve

Site Selective Antibodies

PSA, TTF-1, surfactant, thyroglobulin, GCDFP15, uroplakin III

CK7 and CK20: if both are negative consider gastric, renal, prostate, HCC

ER/PgR:  Strong: breast (but a weak or −ve reaction could also occur with breast CA)

 Weak: sweat gland, endometrium, cervix, ovary

 Negative: colorectal, lung, HCC

Lymph Nodes

See also ‘HIV and Opportunistic Disease’, below.

Some General Pointers

With cohesive cellular clumps on low power, consider: granulomas, histiocytic lesions, carcinomas

Clumps of histiocytes: check to see if epithelioid else it could be Kikuchi’s (look for apoptotic debris)

Large horrible cells: consider ALCL, HL and metastatic malignancy

Neck LN: before diagnosing SCC consider squamous metaplasia in a branchial cyst or in metastatic

PTC

Epithelioid Granulomas

Epithelioid M with admixed lymphocytes

The typical epithelioid M nucleus is slipper-shaped, vesicular, pale-staining ± nucleoli

Hodgkin Lymphoma (HL)

The background may be relatively hypocellular due to sclerosis

Features favouring H/RS cells over mimics (e.g. immunoblasts/carcinoma) are:

 the atypical cells are few and scattered

 mitoses are rare

 nucleoli are large and red on Pap (pale blue on MGG)

 paler, less basophilic cytoplasm

 reticular chromatin (→ paler nucleoplasm)

Need to see classic RS cells to make a 1

diagnosis but mononuclear Hodgkin cells sufﬁce for recurrence

Features Favouring Lymphoma over Reactive Lymph Node

Monomorphic population (or dimorphic in FCL with comma-shaped Cc), but can be mixture in TCL/HL

Lack of: ‘germinal centre structures’, tingible body M and admixed plasma cells (germinal centre

structures are loose aggregates of a mixture of cells of the types expected in a normal germinal centre)

Predominance of large cells ±↑mitoses and apoptotic debris (tingible body M may be seen, e.g. in

Burkitt’s)

Although some mixed populations may be present, these are not in ‘logical proportions’ – i.e. those

expected in a benign lymph node including any reactive pattern

HIV and Opportunistic Disease

Indications for FNA of LN in HIV Lymphadenopathy

LN size >2 cm in any peripheral site or

Tenderness or

Recent ↑size or

Deep-seated (mediastinal, retroperitoneal/peri-pancreatic, etc.)

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Cytopathology 364

Common Diagnoses

Reactive HIV-type LNp (clinical correlate is PGL) – ! d/dg blast-rich reactive LNp vs. lymphoma

Infections (usu. mycobacterial) – ! may only show non-speciﬁc inﬂam

. take samples for culture:

 MAI usu. shows foamy M and long, beaded, numerous, intracellular AAFB while TB usu.

has granulomas, PMN, necrosis and scant, short, less beaded AAFB but the converse (and

M. bovis) may also occur – so take samples for culture +/ PCR. For more information, see

p. 344

 ﬁnding Aspergillus spp. in respiratory samples does not imply clinically signiﬁcant disease

Neoplasia (usu. KS or lymphomas)

Inadequates (NB: acellular samples may still culture bugs) and multipathologies (e.g. infection + KS)

Folliculolysis (as part of PGL)

May see aggregates of epithelioid-like cells with a few admixed lymphocytes but these are the residual

FDC of germinal centres and not granulomas. FDC nuclei are round/ovoid (not slipper-shaped) with

denser chromatin (not vesicular) cf. true epithelioid histiocytes

Lymphoid cellularity in the background may be low

Cystic Lymphoid Hyperplasia (Cystic MESA)

Painless ﬂuctuant swelling ± bilateral – usu. restricted to the parotid

Intermediate or anucleate squames

Lymphocytes ± lymphoblasts} !/d/dg FCL

FDC and M

Similar lesions occur elsewhere (multilocular thymic cyst and multicystic autoimmune thyroiditis)

Kaposi Sarcoma

Overlapping spindle cell tissue fragments

Spindle cells (individual or in loosely cohesive clusters) with elongated cytoplasm ± vacuoles

Nuclei are oval with ﬁne chromatin ± prominent nucleoli (± bare nuclei)

MGG shows metachromatic stroma

d/dg granulation tissue, mycobacterial pseudotumour or vascular transformation of LN sinuses

CSF Cytology in HIV

↑Lymphocyte count is non-speciﬁc – it could be infective (viral, TB, other) or lymphocytic leptomenin-

gitis (if marked)

Cryptococcus (do Grocott/ABDPAS) – in IRDS you may not see the fungi (just lymphocytosis)

Lymphoma may be conﬁrmed in the appropriate clinical context

CSF cytology can’t diagnose the following ADI: PML (JC polyoma virus), HSV, Toxoplasma

AIDS-Deﬁning Illnesses (ADI) Likely to be Diagnosed Cytologically

SCC cervix (NB: SCC of the anus is not an ADI)

NHL incl. extranodal high grade BCL, EBV +ve, plasmablastic and PEL (see p. 362)

CMV – most likely seen in respiratory samples (esp. BAL) but is uncommon – (unlike in Tx patients)

PCP – see p. 370 (the granulomatous variant is most difﬁcult to diagnose)

Cryptococcus

Urinary Tract

Cells that may be Present

Seminal vesicle (lipofuscin), renal tubular, columnar ±cilia (seen in cystitis cystica glandularis or ileal

conduit samples), endometrial, corpora amylacea

Inﬂammation

Reactive single cells ± degeneration (vacuolation, ragged cytoplasm), anucleate squames

Infection

Trichomonas, Candida, Enterobius, schistosome ova, viruses (CMV, BK polyoma, HSV, HPV)

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Cytopathology 365

Casts and Crystals

Red cell casts and dysmorphic RBC are mostly indicative of renal disease

The term ‘granular cast’ traditionally refers to a cellular cast not made of RBC (e.g. PMN or tubular

epithelial cells that may be seen in pyelonephritis or ATN respectively)

Hyaline casts are composed predominantly of Tamm-Horsfall protein and are usu. insigniﬁcant

Casts of wide diameter suggest dilated tubules (as occur e.g. in end stage renal disease)

Oxalate crystals are octahedral (‘folded envelopes’) and may indicate Ca

urinary calculi if plentiful

Urate crystals are fusiform and may be seen in normal urine as well as gout

Cystine crystals are hexagonal/ﬂower-shaped (seen in cystinuria)

Instrumentation and Calculi

Instrumented urines / bladder washings: cohesive groups with smooth outline, (normal NCR and

chromatin)

Instrumented/stones: cells often look columnar

Calculi:

 papillaroid clusters of atypical cells: smooth outline ± mixture (smooth and ragged groups)

 background of inﬂammation, RBC, crystals

 lack of atypical single cells (cf. d/dg TCC)

Carcinoma (TCC)

G1: clusters (ragged outline) of and single mildly atypical cells in clean background

G2: clusters with more atypia, less cohesion, clean background

G3: more atypia with prominent nucleoli, less cohesion, cannibalism, malig. diathesis background

CIS: high grade cells, many single cells, no nucleoli, clean background (50% are diagnosed as G3)

generally look for the malignant cell:

 dense cyanophil cytoplasm

 intensely hyperchromatic nucleus (helpful criterion but may be relaxed if other features

present)

 enlarged nucleus with irregular outline and chromatin.

 NCR should be ≥1:2

Malignant cells may be sparse and partly degenerate but can still result in a positive report once

the pitfalls are excluded. Repeatedly positive cytology (esp. CIS) should result in close F/U even

if cystoscopy and Bx are negative as it may precede a clinically detectable cancer by some time

and cystoscopy has >10% false negative rate. May advise retrograde studies to detect ureteric/renal

pelvis/renal parenchymal tumours

Pitfalls (Reasons for False Positive Interpretation)

Over-interpreting cells with low NCR

Considering papillary clusters to be a reliable sign of low grade neoplasia

Calculi/inﬂammatory/regenerative/degenerative and instrumented changes

Ileal conduit samples – p. 366

BK polyoma virus ( = ‘decoy cells’, a term also applied to some degenerative changes) – vide infra

Effects of cytotoxic chemoRx (esp. cyclophosphamide and alkylating agents) or radioRx – vide infra

Seminal vesicle cells

BK Polyoma (Papova) Virus

Dark homogeneous inclusion, does not replace all the chromatin (some internal strands still present)

Nuclear outline smooth, ± clear rim between nuclear membrane and inclusion

Post-infective ‘spireme’ lacy chromatin

Chemotherapy and Radiation Changes

Similar to that seen in cervical epithelial cells (p. 358)

3D Clusters

Endometrial cells: small cells with high NCR and dark nuclei. Consider menstrual contamination or

endometriosis if outside the expected range of the menstrual cycle

Renal tubular cells: more cytoplasm cf. endometrial cells, often degenerate, delicate chromatin, slightly

bulging peripheral nuclei

Other causes: instrumentation/calculi/infection/crypts in trabeculated bladder/neoplasia

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Cytopathology 366

Ileal Conduit Urine

Cellularity decreases with time since conduit formation

± Bacteria

Degenerate columnar cells which may shrink into rounded cells with eosinophilic cytoplasmic inclu-

sions (‘pseudoeosinophils’)

± Goblet cell clusters (! don’t misdiagnose as adenocarcinoma)

Degenerate Urothelial Cells

Nucleus becomes darker but also smaller and NCR is preserved

Nucleus may begin to break up with discontinuous nuclear membrane

Cytoplasmic changes: ﬁne vacuolation/disintegration ± coarse red granules

Ureteric Brushings

More cellular (cf. voided urine) often with aggregates or sheets of better-preserved urothelial cells

The cytological principles are similar to effusions: look for a dual population of cells

Secondary Malignancy

Rare – example primary sites include cervix, colon, melanoma, breast

The cytological principles are similar to effusions:

 palisaded columnar cells: consider colorectal

 signet ring cells: consider upper GI (but may also be 1

◦

to the urinary tract)

 proliferation spheres: consider breast

 squames: consider TCC with squamous differentiation (i.e. 1

◦

) or cervix/lung

 small cell morphology: consider SmCC bladder (1

◦

) or lung

Miscellany

◦

melanoma is rare but urinary melanin pigment may be seen with widespread metastatic disease

Spindle cells in urine:  inﬂammatory pseudotumour (commoner than sarcoma)

 post laser/diathermy spindling

 low grade papillary TCC

Columnar cells in urine: instrumented/bladder stones, cystitis cystica, ileal conduit, adenoCA (1

◦

)

Non-cytological detection of cancer (urine immunoassays) for CK20, BTA, NMP22 and a cocktail of

Abs against tumour cell surface proteins/sugars (ImmunoCyt

test)

MSU (good for microbiology) is not ideal for cytology – a full voided sample is better (because it

contains sedimented cells) and this should be a mid-morning sample (to avoid the degenerative effects

of overnight stagnation in EMUs)

Biliary Tract (Brushings)

Normal/Reactive

En face: ﬂat sheets of regularly arranged cells, may have cellular projections at edge or spaces

On edge: cells are thin columnar with terminal ovoid nucleus (‘matchstick’) without prom. nucleoli

Some overlapping of cells and small nucleoli can be seen in reactive states (NCR is still low)

Dysplastic and Malignant

Dysplasia shows moderate cell crowding with overlapping, small nucleoli, moderately ↑NCR

AdenoCA may show the usual features (3D groups, nuclear irregularity, ↑nucleoli, etc.) but special

types (mucinous and papillary lesions) can have bland cytology – look for irregular cell arrangement,

3D clustering, pointy oval nuclei (in papillary lesions) or NE cells (in mucinous lesions) and advise

further Ix if present

Thyroid

Adequacy Criteria

Need at least six groups, of ≥10 epithelial cells per group, on at least two slides

if colloid ++but no cells call it ‘suggestive of colloid nodule but not diagnostic due to lack of epithelial

cells’

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Cytopathology 367

Thyroid FNA Grading/Scoring System

Thy1: non-diagnostic/inadequate

Thy2: non-neoplastic

Thy3: follicular lesions

Thy4: suspicious of malignancy

Thy5: diagnostic of malignancy

Intranuclear Cytoplasmic Inclusions

Sharp edged and ﬁlled with cytoplasm-coloured material (i.e. not empty vacuoles)

Thyroid carcinomas: PTC, medullary, follicular, anaplastic

Malignant melanoma

Paraganglioma

Metastatic renal cell carcinoma

Non-neoplastic conditions

Radiation effect

Hashimoto’s Thyroiditis

Lymphoid cells assoc

with Askanazy cells

± Multinucleated histiocytes and epithelioid M

With age: lymphoid ↓ and Askanazy↑

May present as a localised nodule

de Quervain’s Thyroiditis

Mixed inﬂam

inﬁltrate with lots of giant cells ± epithelioid M

d/dg Hashimoto’s disease with occ. giant cells: de Quervain’s lacks an intense lymphocytic inﬁltrate

d/dg giant cells vs. pseudogiant cells (i.e. intact follicles – but these are round with a crisp border)

Graves’ Disease

Moderately cellular, scant colloid, lack of inﬂammation

‘Normal’ and hypertrophic (Askanazyoid) two-dimensional groups ± intact follicles

Non-speciﬁc signs of hyperfunction: colloid at the periphery of cell groups shows smudged out-

pouchings (‘ﬁre ﬂares’) or bubbles (‘colloid suds’ and ‘marginal vacuoles’)

Features Favouring Colloid/Multi-nodular Goitre

Colloid in abundance

Flat sheets of cells (but relatively few sheets cf. neoplasia/hyperplasia)

Cell uniformity (regular honeycomb pattern)

Assoc

features: haemosiderin, foamy M, giant cells, stromal fragments, degenerate RBC

Dominant nodule: more cellular with follicular aggregates of varying size (+ features of MNG)

‘Cellular Lesion, Advise Excision’

If not sure whether papillary or follicular – but exclude a hyperplastic focus in a colloid goitre if possible

Features Favouring a Follicular Neoplasm

Scant colloid

(Micro) follicle formations, relatively abundant

Cell crowding and anisonucleosis

H¨urthle Cell Lesion or Variant (of some Lesion)

Lack colloid

Well-deﬁned eosinophil granular cytoplasm

Nuclear pleomorphism (usu. less than Hashimoto’s)

Papillary Carcinoma (PTC)

! Inclusions (and grooves) can be seen in other lesions (they are more helpful if plenty)

Papillaroid/3D groups/ﬂat sheets of ‘metaplastic’ cells (can be confused with Askanazy cells)

Single cells with dense cytoplasm (usu. bare in follicular lesions or ﬁnely granular in medullary)

Squamous metaplasia can be widespread (esp. diffuse sclerosing variant) (d/dg thyroglossal cyst)

Psammoma bodies may be seen in other conditions (e.g. Hashimoto’s) but always advise histology

because more likely to be from a PTC

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Cytopathology 368

Multinucleated giant cells, microfollicles and thin colloid (with PTC nuclei) favour follicular variant

Cystic change can lead to false −ve because there are many foamy cells but few diagnostic PTC cells

‘Chewing gum’ colloid (small dense irregular colloid fragments – not speciﬁc)

‘Cellular swirls’ deﬁned as ‘concentrically organised aggregates of tumour cells in which many of the

most peripherally situated cells have ovoid rather than round nuclei that are oriented perpendicular to

the radius of the swirl’ (Szporn et al., 2006)

Medullary Carcinoma

Dispersed cell pattern

Plasmacytoid or spindled with occasional bizarre cells with big nuclei

NE nucleus (see p. 271), may be elongated in spindle cell forms, ± inclusions

Fine red granularity to cytoplasm (esp. on MGG)

Follicular formations can be present (! do not misdiagnose as a follicular lesion)

Amyloid (irregular globules)

Anaplastic Carcinoma

Typical Hx: >50ys, M>F, recent rapid enlargement of a prior nodule/goitre

Large pleomorphic cells

PMN inﬁltrate ± necrosis

Cellularity may be scanty due to ﬁbrosclerosis

Metastatic Carcinoma

RCC may look like follicular neoplasms and may have nuclear cytoplasmic inclusions

Other 1

◦

sites: breast, lung, melanoma, colon, lymphoma, etc.

Radiation Atypia (e.g. from Radio-Iodine)

Cell enlargement with bizarre shapes ± cytoplasmic vacuoles

Nuclear changes may include hyperchromasia, coarse chromatin, big nucleoli, vacuoles, folds and

cytoplasmic inclusions

H¨urthle cell change ± lymphocytes (d/dg Hashimoto’s thyroiditis)

Background features may be consistent with colloid goitre (colloid ++, foamy cells)

d/dg anaplastic carcinoma (architectural and background features remain benign + Hx of radiation)

d/dg PTC: cells are too large and bizarre for a PTC that is differentiated enough to show good grooves

and inclusions. Cytoplasmic vacuolation, architecture and Hx also help

Salivary Glands

Pleomorphic Salivary Adenoma

Metachromatic ﬁbrillary background substance

Dispersed plasmacytoid cells with well-deﬁned cytoplasm

The epithelial groups may show some atypia/anisocytosis: ! do not mis-call as malignant

Malignancy: marked pleomorphism, necrosis, Hx of rapid enlargement

Adenoid cystic-like areas may be present in pleomorphic adenoma

Mucoepidermoid Carcinoma (MEC)

‘Dirty’ background with mucin

‘Goblet’ cells/mucin vacuoles in cytoplasm

⎫

⎬

⎭

low grade

Intermediate cells: smaller, dark oval nucleus ± vacuoles

Squames



⎫

⎬

⎭

high grade

Malignant squames can’t tell if 1

◦

SCC or high grade MEC

Warthin’s Tumour (and Oncocytoma)

Mucoid material, ﬂuid, debris, lymphoid cells (absent in oncocytoma)

Flat sheets of polygonal cells with regular nuclei (3D groups in oncocytoma)

± Atypical squames with degenerate/regenerative hyperchromatic nuclei but never the true refractile

orangeophilia of SCC

d/dg: ! common misdiagnoses are SCC or MEC

if it initially looks like a Warthin’s tumour but lacks true oncocytoid features, consider mucoepidermoid carcinoma and look for

cells with mucin vacuoles