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

Подождите немного. Документ загружается.

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 219

TABLE 16.4 Nephrogenic adenoma or clear cell carcinoma?

Clear cell carcinoma Nephrogenic adenoma

>40 years, large size → clinical presentation younger, small, incidental (unless urethral)

No PMHx of GU surgery/trauma/calculi often PMHx of GU surgery/trauma/calculi

tubules, cysts, papillae and diffuse sheets ditto - but no big diffuse sheets

clear (glycogen) cells + ﬂat + hobnail cells ditto - but glycogen not as abundant

prom. nucleoli, nuc. pleomorphism + mitoses bland cytology - but some may have nuc. atypia

d/dg TCC has a prominent exophytic component, sig. atypia and mitoses, ± keratinisation, inﬁltration

(but beware TCC extending into von Brunn’s nests)

Small Cell Carcinoma of the Bladder

Polyp/nodule ± ulcerated, mitoses ++, NE nuclei, nests, necrosis, Azzopardi/crush effect ± rosettes

Usu. mixed with a conventional CA (usu. TCC) – this is good evidence of 1

◦

cf. metastatic SmCC

Synaptophysin and CD56 (NCAM) +ve, CgA ±ve, CAM5.2 +ve in

of cases (paranuclear dot-like)

Poor prognosis .

. must mention a SmCC component no matter how little is present

Transitional Cell Carcinoma (TCC)

Immuno: hCG +vity is a bad prognostic, p63 +vity suggests urothelium (see also p.18)

Features suggestive of stromal invasion: cytoplasmic eosinophilia, lack of basal palisading, ± desmo-

plasia, ± retraction clefts (! not d/dg vasc.) [NB: adipose may occur in normal lamina propria]

d/dg papillary nephrogenic adenoma (which, in turn, must be differentiated from nested carcinoma of

the bladder with tubular differentiation). NA is p63 −ve.

d/dg paragangliomas of the bladder are often misdiagnosed as invasive TCC on biopsy/curettings

d/dg poorly diff TCC vs. high grade prostatic adenocarcinoma

d/dg ‘transitional cell papilloma’: this has ﬁbrovascular cores but no cytol. atypia or urothelial disor-

ganisation/frond fusion (cf. TCC) and no increase in cell layers (although some say thickness is not

important); it is a small and isolated lesion and is rare; younger patients may be affected.

d/dg transitional cell hyperplasia: this has marked ↑ cell layers (e.g. >7) but not disorganisation/atypia

and is either ﬂat or tufted/undulating (= ‘papillary’ but lacks well-developed ﬁbrovascular cores)

Grading TCC by the 1973 WHO Scheme (currently recommended in the UK)

G1 ↑ cell layers (often > 7), mild atypia, mitoses rare solid areas are rare, ± papillary fusion

G2 focal moderate atypia, more than an occasional mitosis fusion of papillae may be seen

G3 focal high-grade nuclei (at least), mitoses easy to ﬁnd solid areas more common, ± necrosis

G4 undiff

CA (if total, can only call it ‘TCC’ by assumption, e.g. previous Bx showed G1–3 TCC)

Grade by worst area (not predominant grade) and avoid tangential cuts through basal urothelium

The 2004 WHO papillary TCC grades (‘PUNLMP’, ‘low grade’, ‘high grade’) are not quite the same

(‘low grade’ includes some G2 and those G1 cases that are not ‘PUNLMP’; ‘high grade’ includes G3

and some G2 cases)

Micropapillary TCC

High grade and usu. high stage with vascular invasion

Mets look similar to the primary

Prognosis is similar to poorly diff TCC

SCC Bladder

Exclude 2

◦

from cervix – esp. when it is in the trigone

Concurrent squamous metaplasia favours 1

◦

Adenocarcinoma

◦

tumours are just as common as 1

◦

(and either may be intestinal, clear cell or signet ring type)

◦

usu. arise in urachus or an exstrophic bladder

d/dg: endocervicosis, nephrogenic adenoma (vs. CCC)

Urachal carcinomas arise within the muscle hence there is controversy over signiﬁcance of depth

of invasion and the importance of establishing a urachal origin (dome location, intestinal histotype,

lack of mucosal involvement and exclusion of a colonic 1

◦

[CEA is nearly always +ve in colonic

adenocarcinoma but may be −ve in urachal so a −ve result helps but a +ve result means nothing])

Flat Carcinoma in situ of the Urothelium (CIS)

Types: small cell, large cell (with moderate cytoplasm), Pagetoid variant of large cell type

Dilapidated brick wall (dyscohesion) and disorganised orientation of cells (± extension into von Brunn

nests)

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 220

Proliferated microvasculature in the superﬁcial lamina propria

Full-thickness dysplasia and ↑ cell layers are NOT required for diagnosis

Nuclei: pleomorphism, hyperchromasia, coarse chromatin, prominent angulated nucleoli

Mitoses common and abnormal

Immuno:  CK20 (umbrella cells only in normal, full thickness staining in CIS)

 CEA +ve (−ve in normal)

 Ki-67 +ve (not limited to basal layers in CIS; weak, patchy and basal in normal)

 p53 strong +ve in >30% of cells in CIS cf. weak and <20% (usu. 10%) in normal

d/dg chemo/radioRx atypia – these show:

 worse atypia than expected for CIS

 cytomegaly more than ↑ NCR

 smudged chromatin detail rather than crisp coarseness

 lack of mitoses (esp. given the degree of atypia)

 associated stromal changes (and appropriate Hx)

d/dg inﬂammatory atypia (apply criteria ± immuno above)

d/dg urothelial atypia/dysplasia not amounting to CIS – this is diagnosed by the following:

 urothelium still cohesive

 architectural distortion – clustering of nuclei

 some but not all cells are dysplastic

 chromatin is ﬁne, nucleoli small and mitoses rare

Secondary Tumours of the Bladder

Usu. by direct spread from cervix/colon, else blood-borne from melanoma/breast

Extensive vascular invasion favours a 2

◦

origin

Coexistence of usual-type 1

◦

tumour or preneoplastic metaplasia/dysplasia favours 1

◦

Prostatic Carcinoma and its Mimics

Prostatic Adenocarcinoma (of Conventional Acinar Type)

Inﬁltrative arch. (if > Gleason 2) between benign glands and esp. perineural/intravascular

Single layered glands (in lower grades) with absent basal cells ± glomeruloid tuftings ± mitoses

Nuclear enlargement, nucleolomegaly ± hyperchromasia

Intralumenal: collagenous micronodules (speciﬁc but rare), crystalloids, wispy blue mucin

Immuno: for AMACAR, PSA, PSAP and basal cell markers, see p. 18

Adenomatous Polyp of the Prostatic Urethra (Prostatic-Type Polyp)

Usu. young, at verumontanum, haematuria/haemospermia

Two architectures:

 prostatic glands covered by smooth urothelium

 slender villoglandular (or stubbier rounded) fronds lined by typical prostatic epithelium

A basal cell layer is present and the cytology is bland

d/dg prostatic duct carcinoma (q.v.)

Normal Seminal Vesicle/Ejaculatory Duct (vs. d/dg Prostate Carcinoma)

Closely packed glands (resembling low grade prostatic adenocarcinoma)

Lipofuscin and scattered ‘monster’ cells; nuclei may be apical; muscle may have hyaline globules

Monster cells have hyperchromatic degenerative-like pleomorphic nuclei adjacent to benign appearing

nuclei in well formed glands

Immuno: PSA and PSAP −ve; 34E12 +ve (i.e. the opposite to prostatic adenocarcinoma)

Atypical Adenomatous Hyperplasia (Adenosis)

Mostly occurs in the transitional zone



so AAH should be a rare diagnosis

Well-circumscribed ± minimal peripheral inﬁltration on core Bx (need to see whole lesion)

Closely packed small acini lacking epithelial infoldings

Acini may appear to bud from the adjacent benign glands/merge with a usual hyperplastic nodule

Cells: clear cytoplasm, lack malignant nuclear features (but prominent nucleoli occur in 20–30% of

cases)

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 221

A disrupted basal cell layer is present (by immuno)

d/dg adenocarcinoma:  basal layer present in AAH

 architectural features

 nucleoli usu. <1 (>3 is incompatible with AAH)

Cases that don’t fulﬁl AAH criteria and have some features suspicious for adenoCA = ASAP (q.v.)

AAH has uncertain malignant potential

Sclerosing Adenosis

Well formed glands and cellular spindled stroma

Limited foci on TURP chips (cf. d/dg high grade adenocarcinoma)

Inﬁltrative but still relatively circumscribed (cf. d/dg high grade adenocarcinoma)

Benign nuclei (although some may be moderately enlarged with prominent nucleoli)

Hyaline sheath-like structure around some of the glands

Basal cell layer present (discontinuous): SMA and S100 +ve (i.e. myoepithelial phenotype) unlike

prostate basal cells (for immuno proﬁles of basal vs. myoepithelial cells, see p. 18)

Spindle cells of the stroma show focal CK and SMA +vity (myoepithelial differentiation)

No association with carcinoma

Sclerotic Atrophy and Postatrophic Hyperplasia

Low power shows basophilia due to shrunken cytoplasm (gland-forming prostate carcinomas are not

so basophilic due to their more abundant cytoplasm); ± residual periglandular chronic inﬂam

Postatrophic hyperplasia shows arbitrarily more acini; they have variable shape and size (mostly small)

Hyperchromatic nuclei, occasional small nucleoli, ↑ nuclear size and minimal pleomorphism

Fibrosis imparts an inﬁltrative appearance but the glands appear inﬁltrative as a patch – not individual

glands inﬁltrating between larger benign glands (like carcinoma)

Immuno: partial atrophy can be AMACAR +ve with focal loss of basal cells (! d/dg adenoCA)

d/dg atrophic carcinoma (rare):  truly inﬁltrative

 presence of ordinary (less atrophic) carcinoma

 greater cytological atypia

Prostatic Intraepithelial Neoplasia (PIN)

Mostly occurs in the peripheral zone, high grade is usu. seen in association with peripheral cancers

The level of serum PSA does not correlate with the volume of PIN

↑ PSA and high grade PIN on Bx → re-Bx (or process rest of chips); close F/U with PSA and rectal

exam

Low power: basophilia; 4 main arch.: ﬂat (single layer), tufting, micropapillary, cribriform

Cytol. features are often abrupt (stratiﬁcat

, ↑ nuclear and nucleolar size, anisonucleosis, coarse chro-

matin)

Grade 1: ↑ nuclear size and anisonucleosis are the main features} = Low grade

Grade 2: hyperchromasia, chromatin margination, ↑ nucleolar size} = High grade

Grade 3: many large nucleoli, nuclear crowding, less anisonucleosis} = High grade

Some diagnose high grade PIN without prominent nucleoli provided there is: marked pleomorphism,

hyperchromasia, mitotic activity and a cribriform or micropapillary architecture

A basal cell layer (even discontinuous) must be identiﬁed to exclude invasive carcinoma (! but small

cribriform foci of PIN on Bx may lack a basal layer due to unrepresentative sampling)

d/dg  invasive cribriform carcinoma (Gleason 3–4): but in PIN the lobular architecture is retained

 primary duct (endometrioid)

CA may mimic micropapillary PIN: but PIN is usu. peripheral,

shows a central maturation effect and lacks endometrioid columnar cells or true papillae

 TCC is usu. PSA −ve

 post radiotherapy changes: main d/dg with this is invasive

CA but a basal layer will remain

 cribriform hyperplasia will lack the nuclear atypia of PIN

 basal cell hyperplasia (q.v.) has oval regular nuclei with (usu.) small nucleoli and is LP34

+ve

 reactive epithelium (post trauma/inﬂam

) is hyperchromatic but lacks other nuclear features

 ‘intraduct carcinoma’: basal layer +ve but has necrosis and pleom.  that of high grade

PIN. This may actually be cancerisation associated with an aggressive invasive

CA nearby

rather than CIS

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 222

Other Mimics of Prostatic Adenocarcinoma

Normal structures (esp. if adjacent to nerves) e.g. small prostatic glands, Cowper’s glands (mucinous

acini) and paraganglia (have their own internal capillary network – unlike cancer)

Hyperplasias: basal cell (q.v.), clear cell cribriform, transitional cell, verumontanum mucosal gland

Stromal hyperplasia with atypical giant cells

Inﬂammatory: malakoplakia, granulomatous prostatitis

Other tumours: TCC (e.g. micropapillary pattern), nephrogenic adenoma (rare, but can be AMACAR

+ve and is basal cell –ve; PSA/PSAP is either –ve or only focal and weakly +ve)

Gleason Grading and Scoring of Prostatic Adenocarcinoma

Gleason Score =predominant grade +next most abundant grade (provided the latter constitutes >5%

of the tumour – otherwise just double the predominant grade)

WHO (1999): also record the % of tumour that is high grade (= Gleason 4 or 5)

1) Closely packed uniform glands without intervening normal glands. Well-circumscribed. Glands tend to

have even lumenal surface and more crystalloids. These tumours are small and occur in transition zone

(periurethral area) .

. rare on needle Bx. A few small malig. glands on needle biopsy with intervening

normal glands may be mistaken for low grade (1–2) cancer but this is obviously wrong as low grade

does not have intervening normal glands.

2) More separation, more variation and irregular outline to the group of pale glands but still no intervening

normal glands. Same comments re needle biopsy as above.

3) The malignant glands, while single and separate, are smaller than the glands in 1 and 2. They inﬁltrate

between normal glands. A few small (i.e. size of a normal gland) well-circumscribed cribriform glands

may be present which are difﬁcult to distinguish from cribriform PIN. Ragged cribriform areas indicate

grade 4 as does fusion of cribriform acini (= acinus elongated to ≥4:1 length:width).

4) The glands are no longer single and separate. In cribriform carcinoma the cribriform areas are larger

than the size of a normal gland, have a more ragged edge and less well developed composite gland

spaces (cf. the punched out holes of the small cribriform foci seen in some grade 3 cases). The lack of

stroma within the cribriform unit means that they tend to fragment on Bx. Another pattern is that of

loss of individual gland formation with only focal lumenal differentiation. ± Clear cell change.

5) Individual cells lacking glandular lumenal differentiation. Solid sheets of cells ± focal rosetting (poor

attempts at gland formation). Cords of cells. Comedo necrosis in solid nests of cells. ± Clear cell

change (= hypernephroid variant).

d/dg for grades 2 and 3 with dilated gland architecture: benign prostatic hyperplasia

d/dg for grades 4 and 5 includes: NEC, TCC, (xantho)granulomatous prostatitis and malakoplakia

Criteria for Extraprostatic Extension of Prostatic Carcinoma

Extraprostatic spread up-stages the tumour; intra-capsular inﬁltration is not sufﬁcient

Tumour must inﬁltrate periprostatic fat OR seminal vesicle muscle or glands

! Some intraprostatic skeletal muscle (of the urogenital diaphragm) may be seen at the apex

Atypical Small Acinar Proliferations (ASAP and ASAPUS)

A small (i.e. <24 acini and usu. <12) atypical lesion which, after levels, immuno, etc., cannot be

diagnosed as adeno

CA with sufﬁcient conﬁdence to form the basis of deﬁnitive cancer Rx

Report level of suspicion for CA (‘suspicious’ or ‘highly suspicious’) and advise re-Bx

The term ASAPUS suggests a lower suspicion of CA cf. ASAP (it is of ‘uncertain signiﬁcance’)

d/dg ‘minimal cancer’ = deﬁnite CA involving <5% of the tissue

Prostatic Duct Carcinoma (includes Endometrioid/‘Endometrial’ Carcinoma of the Utricle)

Usu. >60 years, haematuria/BOO, PSA may be normal, poor prognosis

Columnar cells ± glycogen clearing (not mucin)

Endometrioid subtype has dark cytoplasm ± subnuclear vacuoles +/cilia

High grade nuclei with prominent nucleoli (except some type A cases), mitoses ++, loss of nuclear

polarity (nuclei may be elongated/stratiﬁed)

Two architectures (may be a mixture):

 A(1

◦

duct type – less common): tall, complex papillae

 B(2

◦

duct/endometrioid type): cribriform, comedo, low papillae

Immuno: PSA and AMACAR +ve, CEA ±ve, 34E12 basal cells mostly absent

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 223

d/dg:  adenomatous polyp (low grade simple epithelium, basal layer ++, architecture, age)

 verumontanum hyperplasia (as for adenomatous polyp, above, also AMACAR is −ve)

 TCC (does not usu. have glands, has different immuno)

 high grade PIN (basal layer ++ but ! ductal adeno

CA can spread intraductally – see Pickup

and Van der Kwast, 2007)

Basal Cell Hyperplasia (BCH), Basal Cell Adenoma and Basal Cell Adenomatosis

Associations: BPH of the transitional zone, anti-androgen Rx, edge of infarcts

Basaloid cells (little cytoplasm, bland oval non-grooved nuclei, small nucleoli), sparse mitoses

Well-circumscribed at low power with lobular architecture ± some intermingling with normal glands

at the periphery in ﬂorid forms (‘pseudoinﬁltrative’), may merge into normal glands

Con/eccentric prolif

around lumenal cells or solid nests ± cribriform areas ± peripheral palisading

± Central Ca

+/ intracytoplasmic (

AT/AFP +ve) globules (useful if present)

Stroma: cellular but otherwise normal prostatic type

Variants:

 ‘sclerosing BCH’ has sclerotic stroma (d/dg sclerosing adenosis – SMA/S100 may help)

 ‘BCH with prominent nucleoli’ = ‘atypical BCH’: larger nucleoli and focal chronic inﬂam

 ‘ﬂorid BCH’:

◦

mostly solid nests with little intervening stroma, pseudoinﬁltration, nuclear

and nucleolar enlargement and ↑ mitoses or

◦

BCH forming a nodule of >100 acini in one slide

 ‘basal cell adenoma’ = BCH forming an expansile nodule (= ‘adenoid basal tumour’ if

cribriform areas ++ or ‘adenomatosis’ if multifocal)

Immuno: +ve for LP34, 34E12, CK7; −ve for CK20, AMACAR; ±ve for PSA, SMA, S100

d/dg: PIN, adenocarcinoma, sclerosing adenosis (q.v.)

d/dg urothelium (more cytoplasm, grooved nuclei, CK20 +ve), TCC (as for urothelium plus more

pleomorphic and ↑ mitoses cf. BCH)

d/dg BCC: invasion (incl. perineural and extraprostatic), necrosis and higher Ki-67 LI

Basal Cell (Basaloid/Adenoid Cystic) Carcinoma

Inﬁltration (outside prostate/around nerves/around retained glands)

Foci of necrosis ± desmoplastic reaction

No metastases reported to date

d/dg basal cell hyperplasia/basal cell adenoma (vide supra), TCC

Other Types of Prostatic Carcinoma

Neuroendocrine tumours (carcinoid and SmCC subtypes): have eosinophilic granules:

 NE differentiation in any tumour may be mis-interpreted as poorly diff adenocarcinoma

 Gleason 5 adenocarcinoma may be misinterpreted as an NET (.

. do immuno)

SmCC may be 1

◦

or 2

◦

(usu. from lung):

 co-existing usual-type adenocarcinoma favours 1

◦

, extensive vascular invasion favours 2

◦

 immuno for TTF-1 is not helpful as 1

◦

prostatic SmCC may be +ve

Mucinous carcinoma/signet ring carcinoma

SCC/ASC

Lymphoepithelioma-like carcinoma (‘like’ because EBV cannot be demonstrated)

Sarcomatoid carcinoma

Carcinoma with oncocytic features

Secondary Tumours of the Prostate

Usu. by direct spread from bladder/rectum

Extensive vascular invasion favours a 2

◦

origin

Coexistence of usual-type 1

◦

tumour or preneoplastic metaplasia favours 1

◦

Effects of Radiotherapy

Benign prostatic tissue

Cytologicalatypia: nucleolar enlargement,nuclear enlargementand vacuolated/hazychromatin, nuclear

pyknosis, cytoplasmic eosinophilia ± vacuolisation

Lumenal haematoxyphil mucin

Glandular atrophy

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 224

Metaplasias: mucinous, squamous and Paneth-like

Atypical basal cell hyperplasia (nuclear vacuoles, powder-like chromatin and cytoplasmic vacuolation

help identify radioRx as the likely cause)

Xanthogranulomatous foamy M

Immuno: basal layer strongly +ve for 34E12, lumenal cells weak/−ve for PSA

Prostatic adenocarcinoma

Poorly-formed glands with single cells and haphazard arrangement (!Gleason grade inﬂation – but

post-radioRx Bx grade still correlates with subsequent prostatectomy ﬁndings)

Hyperchromatic nuclei with less visible nucleoli (! d/dg benign/atrophy)

Cytoplasmic vacuoles (d/dg signet ring)/reticulated texture

Immuno: PSA +ve, 34E12 −ve

. Rely on architecture, invasion (e.g. perineural) and immuno rather than cytology to identify CA

Effects of Androgen Blockade Therapy

Benign glands: simpliﬁcation of gland architecture (loss of hyperplastic papillations), basal cell hyper-

plasia, squamous metaplasia

Malignant: ↓extent of PIN and CA, loss of gland lumens and ↓crystalloids, ↓ intensity of PSA staining

Both: cytoplasmic vacuolation; nuclear shrinkage, hyperchromasia, pyknosis and apoptosis with ↓

mitoses and loss of nucleolar prominence

Stroma: focal hypercellularity and chronic inﬂam

± foamy M

Testicular Tumours

Histological Classiﬁcation in Practice

Germ cell tumour: 1. Seminoma (must be 100% pure

± syncytiotrophoblastic cells)

2. NSGCT (list the histological components present)

3. Combined (give % of seminoma and NSGCT)

4. Spermatocytic seminoma

Non-germ cell tumours: sex cord/stromal, lymphoma, sarcomas, etc.

Germ Cell Tumours

Immunocytochemistry and tumour markers

Serum AFP and hCG must both be measured because they are produced by different cell types, ﬂuctuate

independently of each other and frequently only one is elevated

A patient with an apparently pure seminoma but a raised AFP must be treated as though he had an

undiagnosed teratoma in addition (because tumours in these circumstances behave aggressively)

AFP: YST (see also p. 19)

hCG: trophoblastic elements (may also be +ve in MTU)

NSE (serum and immuno), PLAP (membranous +vity), c-kit: seminomas (not spermatocytic),

ITGCNU, (PLAP may also be +ve in borderline seminoma/teratoma)

CD30: MTU (esp. if membranous +vity; may become −ve after chemoRx .

. Hx is important) and

non-neoplastic cells (e.g. activated lymphocytes/M) in any tumour/lesion

CAM5.2: MTU, YST but not seminoma unless aggressive (anaplastic/borderline) types

OCT4 (an octamer-binding transcription factor showing nuclear +vity by immuno in germ cells and

stem cells): +ve in ITGCNU, non-spermatocytic seminoma, germinomas and MTU but −ve in better

differentiated tumours such as YST, ChC and MTD. Positivity occurs at all 1

◦

sites (pineal, ovary,

retroperitoneum, mediastinum, etc.)

Podoplanin: +ve (membrane) in germinomas but −ve in NSGCT (incl. YST, MTU and ChC) in the

CNS

Intratubular germ cell neoplasia unclassiﬁed (ITGCNU)

Is the precursor of all germ cell tumours except spermatocytic seminoma

A single Bx is usu. sufﬁcient since ITGCNU is usu. diffuse .

. a −ve Bx is a sign of very low risk

Tumour patients should have a contralateral Bx if the testis is of poor quality (soft/small)

some accept rare foci of MTU (with just a few cells per focus, max.) in a seminoma but report that ﬁnding

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 225

Cells: large, vacuolated cytoplasm with irregular nuclei and nucleoli (some say you must see these

contiguously around at least 1 whole tubule cross-section to make the diagnosis)

Partially involved tubules may show residual spermatogenesis

Immuno/stains: glycogen, PLAP, c-kit, OCT4, NSE +ve (rarely: CAM5.2 +ve, also in Sertoli cells)

‘Unclassiﬁed’ distinguishes ITGCNU from intratubular embryonal CA/spermatocytic seminoma

Classical seminoma

Macro: homogeneous, grey-white, no haemorrhage/necrosis

Poorly-deﬁned solid lobules of seminoma cells (± focal tubular arch./Pagetoid spread in rete testis)

Delicate septa/dense scarring, T-cell inﬁltrates, granulomas

Cells: uniform, large, polygonal-round, clear cytoplasm, well-deﬁned cell borders, central large round

nucleus with delicate hyperchromatic chromatin strands and multiple (usu. 1–2) prom. nucleoli

Immuno/stains: contain glycogen ±lipid. PLAP, c-kit, OCT4 and NSE +ve; AFP −ve; CK (AE1/AE3)

−ve in

cases; some tumours have hCG +ve syncytiotrophoblastic cells; CD68 −ve; [i(12p)] +ve

d/dg: spermatocytic seminoma, MTU (which may be focally PLAP +ve), Sertoli cell tumour (esp. if

the seminoma has tubular areas), lymphoma, granulomatous orchitis – q.v.

d/dg vascular invasion vs. tumour smearing artefacts or intravascular histiocytes

d/dg ChC may have sheets of cytotrophoblast that mimic seminoma – look for more typical areas

Anaplastic seminoma

Variant of classical seminoma deﬁned as seminoma with ≥3/hpf mitoses

More pleomorphic and less lymphoid cf. classical seminoma

Stage for stage it has the same prognosis as classical but presents at a later stage more often

Spermatocytic seminoma

Older patients (but rare, so classical seminoma is still more common), mets are rare, excision is curative

Macro: large, grey, gelatinous and cystic

Sheets of mitotic, cells with moderate-abundant cytoplasm (plasmacytoid if Bouin’s ﬁxed) with ≈

round nuclei showing ‘nemaline’/‘spireme’ chromatin (i.e. evenly-dispersed large elongated clumps)

These cells vary in size (more than shape) from large (± multinucleated) to small (lymphocyte-like)

and textbooks describe this as an admixture of ‘3-cell types: large, intermediate and small’

‘Anaplastic spermatocytic seminoma’ has areas where the large cells predominate (but is otherwise

typical)

Stromal oedema/myxoid change (there is a lack of true lymphocytes, sclerosis and granulomas)

May spread along tubules (= intratubular spermatocytic seminoma) thereby mimicking ITGCNU

No trophoblastic elements but may develop spindle sarcomatous transformation ± RMS

d/dg anaplastic seminoma: spermatocytic has sparse lymphocytes and is −ve for PLAP, c-kit, ITGCNU

and [i(12p)]

Only occurs in the testis (cf. seminoma/germinoma arising in mediastinum, pineal, etc.)

Borderline seminoma/teratoma (anaplastic germ cell tumour)

Features favouring undiff teratoma: overlapping nuclei, multiple nucleoli

Features favouring seminoma: lack of the above and lymphocytes in the stroma

Highly aggressive

Immuno: CD30 +ve (EMA −ve); CK (AE1/AE3 or CAM5.2), PLAP and NSE +ve (> 80%); c-kit

+ve in 40% of cases; AFP +ve cells and hCG +ve syncytial cells may be present

Differentiated teratoma (MTD)

Teratomas are germ cell tumours with differentiation towards all 3 somatic germ layers (ectoderm,

mesoderm, endoderm) or predominantly 1 (= ‘monodermal teratoma’) or 2 of them

MTD is a BTTP term that encompasses both mature and immature teratomas and any admixture of the

two because prog. ∝ age, not the presence of immature elements (cf. ovarian teratomas):

 pre puberty: these are benign (do not metastasise) even if there are immature elements. They

are usu. pure teratomas without associated ITGCNU. [.

. best omit the ‘malignant’ bit of

‘MTD’ in a report]

 post puberty: these are malignant (may metastasise), often have accompanying ITGCNU and

are rarely pure teratomas (they tend to occur with MTU +/other germ cell tumour elements)

Some elements may show cytological atypia or glandular complexity (.

. do not diagnose somatic

carcinoma arising in a MTD without good evidence of invasion)

A ‘dermoid cyst’ is a subset of MTD containing skin and adnexa only (some authors allow carti-

lage/bone and ciliated/GI epithelium in the wall provided that there is no cytological atypia, abnormal

spermatogenesis or ITGCNU elsewhere) – it is benign (in all age groups). d/dg epidermoid cyst (does

not show adnexa or surrounding ITGCNU – see ‘Frozen Section’ p. 228 for details)

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 226

◦

malignancy arising in MTD = overgrowth of a single component to ﬁll >50% of a low power ﬁeld

(×4 objective) or forming an expansile mass (of ≥1cm

 for neuroectodermal tumours). Unlike in the

ovary, sarcomas (esp. RMS) and PNET are more common than carcinomas

d/dg monodermal (or predominantly monodermal) MTU vs. metastatic tumour of that type (e.g. car-

cinoid): presence of ITCGNU or other differentiated tissues favour MTU; multiple/bilateral lesions,

vascular invasion ++ and clin. evidence of possible 1

◦

lesion(s) elsewhere favour a metastasis

Undifferentiated teratoma (MTU = embryonal carcinoma)

Rare alone but occurs in 45% of composite tumours. Macro: haemorrhage and necrosis

Sheets, alveolar, glandular patterns ± papillary projections

Cells are pleomorphic and epithelial-like (basophil to amphophil non-clear cytoplasm) with ill-deﬁned

cell borders ± overlapping nuclei; (d/dg seminomas can be pleomorphic, so use all these features)

Separate tumour nodules in the tunica or hilum suggest vascular invasion (which should be sought)

Malignant teratoma intermediate (MTI)

A mixture (any proportions) of MTU and MTD. It is the commonest subtype of teratoma in adults

Trophoblastic differentiation and Malignant teratoma trophoblastic (MTT)

For morphology of trophoblasts and ChC, see pp. 65–66

Isolated syncytiotrophoblastic elements are assoc

with hCG +vity in tissue and serum but does

NOT inﬂuence tumour behaviour. This may line degenerate cysts post chemoRx in retroperitoneal

Syncytio and cytotrophoblast = ‘choriocarcinomatous elements’

Syncytio and cytotrophoblast forming a villous or papillary pattern is required to diagnose MTT (thus,

MTT is just a villo/papillary architectural subtype of ChC [there are no stromal cores])

ChC/MTT/high serum hCG are assoc

with haematogenous mets, aggressive behaviour and good

response to chemoRx

Yolk sac tumour (YST) / yolk sac elements

Children: usu. pure YST; adults: usu. YST with other germ cell elements

Variable patterns: reticular (= microcystic), solid, glandular (alveolar, intestinal and endometrioid-

like), macrocystic, polyvesicular vitelline (= irregular vesicles [with constrictions] partly lined by

ﬂattened and partly by columnar epithelium in a cellular or loose mesenchyme), hepatoid, papillary,

myxoid, adenoﬁbromatous, parietal (= abundant extracellular eosinophilic conﬂuent BM material),

mesenchyme-like, YST with 2

◦

neoplasia (e.g. RMS or NET)

Those in bold constitute special variants if they occupy >50% of the tumour (have Mx implications)

± Schiller-Duval bodies (= cuboidal/columnar epithelial papilla with a single vessel in the core and

projecting into a space lined by ﬂattened cells). If numerous or predominant the term endodermal sinus

pattern/tumour is used. It also has labyrinthine spaces amid branching loose ﬁbrous cores festooned

with epithelium

Variable cytology (∝ arch.): ﬂat to columnar, clear to hepatoid, blastematous, ± basal vacuoles, ±

intestinal differentiation, ± mucin glands, ± EMH foci (!d/dg syncytiotrophoblast which is rare in

YST)

Variable stroma (∝ arch.): primitive spindle, mesenchymal, heterologous elements, luteinisation

Intra and extracellular DPAS +ve hyaline globules are common but non-speciﬁc (AFP/

+ve)

Nuclei: bland or large, hyperchromatic and irreg. with prominent nucleoli; ± vacuoles, ±mitoses ++

Immuno: −ve for EMA and OCT4; +ve for CK, AFP, 

AT, PLAP [and canalicular CD10/pCEA in

hepatoid]

AFP is +ve in: YST, teratoma (liver/skin/nerve/tubular epithelial structures), hepatoblastoma/HCC

d/dg ChC may have sheets of cytotrophoblast that mimic YST – look for more typical areas

d/dg hyperplasia of the rete testis with hyaline globules and MTU [for other d/dg, see p. 252]

Prognostic indicators and response to therapy

Pure seminoma: radioRx/carboplatin

Non-seminomatous and mixed germ cell tumours:

ChC elements/high serum hCG: risk of haematogenous spread

vascular invasion +ve: → chemoRx

vascular invasion −ve: → F/U

—–

1: presence of MTU

1: absence of YST elements

1: presence of blood vasc. invasion

1: presence of lymphatic invasion

YST elements: more likely to present at stage I (conﬁned to testis)

MRC Prognostic Score for Stage I Teratoma (see box on the

right – add to give score out of 4):

Gonadoblastoma, polyembryoma, diffuse embryoma, malignant mixed germ cell tumour

See p. 252.

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 227

Sex Cord/Stromal Tumours

Immunocytochemistry

(Also see ‘Normal Testis’ section and table 16.1 on p. 211)

Melan A (A103) may be +ve in Sertoli/Leydig tumours (and, to a lesser extent, stromal tumours)

Leydig cell tumour

No familial tendency; liberate testosterone, oestrogens or other hormones

Intracellular lipofuscin and Reinke’s crystalloids are typically present

May be calcifying

Immuno: S100 +ve in some cases

Features of malignancy (never occurs in children):  >5cm 

 inﬁltrating margins

 prominent foci of necrosis

 3/10 hpf mitoses (not sufﬁcient on its own)

 vascular invasion

 metastases

 do not respond to chemo/radioRx

d/dg: large cell calcifying variant of Sertoli cell tumour

d/dg Leydig cell hyperplasia (microscopic, multifocal and preserves underlying architecture)

Sertoli cell nodule (= Pick’s adenoma/tubular adenoma/Sertoli cell adenoma)

Usu. microscopic in maldescended testis but may be upto a few mm  and in a descended testis

Not neoplastic and no malignant potential .

. terms using ‘adenoma’ are inappropriate

Unencapsulated nodule of well-formed tubules of Sertoli cells with an immature phenotype (i.e. focal

CK18 +vity with vimentin, cells usu. tall and thin with indistinct cytoplasm and bland dark round/oval

nuclei)

Simple tubules or ‘cribriform’-like aggregates

May have hyaline eosinophil blob in lumens (= ‘Call-Exner-like bodies’) may anastomose ± lamellar

Usu. have interstitial Leydig cell aggregates (if not, some call it Sertoli cell adenoma)

± Intratubular spermatogonia or ITGCNU (! d/dg gonadoblastoma)

d/dg Sertoli cell tumour: features that favour nodule over tumour are:

 small and may be multifocal (! but a rare ‘giant’ variant, 1cm

, has been described)

 tubules well-formed throughout (even if some do not show a lumenal space)

 immature Sertoli cells with occ. spermatogonia throughout the lesion (cf. focal/peripheral)

 not encapsulated / pseudoencapsulated or expansile in nature

 presence of Call-Exner-like hyaline blobs and interposed Leydig cells (if present)

 lack of typical Sertoli cell tumour stroma/stromal changes

Sertoli cell tumour and Sertoli-Leydig cell tumour

Adult, present with mass (endocrine effects only if there is a Leydig component)

Well-circumscribed and usu. 3–4cm 

Tubular differentiation (at least focally):

 a lumen is not always present (i.e. solid tubules, cords and strands)

 simple lining or pseudostratiﬁed (endometrioid)

 architecture: simple, irregular or complex (reteform)

± Solid areas (may look like Leydig cell islands or, if poorly diff., like a spindle sarcoma)

± Heterologous elements: mucinous cysts (may dominate the tumour), muscle, fat, bone, cartilage.

These may be the source of sarcomatous overgrowth in some tumours

The cells have moderate eosinophil cytoplasm (± lipid foam/globules)

Mild nuclear pleomorphism and few mitoses unless poorly differentiated

Poorly diff. tumours have (at least focal) solid spindle-sarcoma-like areas with mitoses ++

Stroma: ﬁbrous/hyaline with dilated vessels (and Leydig cells in Sertoli-Leydig cell tumours)

Sclerosing variant: sclerotic stroma without the vessels, small atrophic tubules or solid areas

Large cell calcifying variant: younger, smaller (1–2cm), ± multifocal, larger eosinophil cells with

nucleoli, stromal Ca

, myxoid ± PMN, assoc

with Carney syndrome, (d/dg Leydig cell tumour)

Prognostics: size (esp. ≥5cm), mitoses (esp. >5/10hpf), necrosis, vascular invasion

d/dg: Leydig cell tumour, adenomatoid tumour (but this is usu. paratesticular not intratesticular), Sertoli

cell nodule (vide supra), tubular seminoma (look for lymphocytic stroma, granulomas ITGCNU and

more classical seminoma morphology elsewhere), carcinoid (morphology and immuno)

For more d/dg, see p. 249.

PIC

JWBK208-16 December 8, 2007 15:51 Char Count= 0

Urological 228

Testicular Lymphoma

Usu. painless and in older patients with other organ involvement (e.g. CNS, MALT)

Macro: homogeneous/nodular (d/dg seminoma)

Interstitial inﬁltrate with relative tubular sparing

DLBCL is the most common but others occur (e.g. HL, Burkitt’s and T-cell in younger people)

± Vascular invasion

d/dg: granulomatous orchitis (p. 215), leukaemia (late stage, usu. bilateral, PB ﬁndings)

Metastases from Testicular Tumours

◦

tumours with YST elements have a worse prognosis if metastatic disease is present (stages II–IV)

NSGCT: prior to cisplatin the mets looked like the 1

◦

, but now they mature (mature elements are

resistant) – MTD may be seen in the metastasis even if this was not seen in the 1

◦

In a retroperitoneal LN dissection state:

1) whether identiﬁable LN or surrounding tissues are present

2) the presence and type of any residual tumour incl. if any somatic malignancies have de-

veloped (carcinoma [must be invasive, dysplasia only = teratoma or d/dg chemoradioRx

atypia]/sarcoma/leukaemia/lymphoma/Wilms’/PNET/NB) – these may need different Rx.

d/dg sarcoma vs. immature teratoma mesenchyme (look for destructive invasion, lack of

organoid structure and the presence of abnormal mitoses)

d/dg carcinoma (very rare) vs. YST glandular elements.

3) completeness of excision

d/dg met from a somatic malignancy (non-testicular): use CPC (incl. serum markers and testicular USS),

EMA and mucin +vity is unlikely to be seen in an MTU, [i(12p)] favours seminoma and NSGCT

Metastases to the Testis

Sources: prostatic adenoCA, relapse of ALL after (testicle-sparing) radioRx, RCC, melanoma

There may be interstitial inﬁltration with tubular sparing

Extensive vascular invasion favours a 2

◦

origin

Coexistence of usual-type 1

◦

tumour or preneoplastic metaplasia favours 1

◦

Frozen Section of the Testis

The usu. problem is d/dg epidermoid cyst cf. well diff. teratoma (→ radical orchidectomy and LN

dissection)

Also, distinguish Sertoli cell nodule (→ no action) from Sertoli cell tumour (→ radical orchidectomy)

Epidermoid cyst of the testis

Benign but uncommon; usu. unilocular; should have all of the following Price criteria for diagnosis:

 intraparenchymal and without surrounding ITGCNU

 keratin contents and squamous lining (may be incomplete)

 ﬁbrous (dermis-like) wall/capsule but no testicular parenchymal scarring

 no other elements (adnexa, endodermal tissues, mesodermal tissues, etc.)

d/dg dermoid cyst: has adnexa (pilosebaceous) structures in the wall in normal skin-like orientation

d/dg teratoma: macro is irregular ± multiloculated; micro has other tissues and not so well organised,

± cytological atypia/ITGCNU/testicular atrophy/scar; serum tumour markers may be elevated

Paratesticular Tumours

Malignant:  mesothelioma (! d/dg ﬂorid mesothelial hyperplasia of tunica vaginalis)

 RMS: usu. spindle/embryonal subtypes

 leiomyosarcoma: usu. well-diff; look for necrosis and mitoses

 liposarcoma: usu. well-diff (lipoma-like) – may need many blocks

 ﬁbrosarcoma: usu. well-diff (! d/dg ﬁbromatosis)

 others: extra-abdominal Wilms’, ovarian/M¨ullerian-type carcinoma, KS, etc.

Benign:  adenomatoid tumour and (benign) papillary mesothelioma

 Brenner tumour

 most myxoid lesions are benign (myxoid variants of sarcomas are very rare here)

 developmental (adrenal rests, splenic-testicular fusion)

 inﬂammatory (ﬁbrous pseudotumour, sperm granuloma, sclerosing lipogranuloma)

 any benign soft tissue tumour (lipoma, proliferative fasciitis, etc.)