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

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Endocrine 269

H¨urthle cell variant (i.e. >75% of the tumour cells are H¨urthle cells – old name = ‘H¨urthle cell

adenoma’) can show marked atypia and mitoses +/ haemorrhage and necrosis and papillae may be

present (but not nuclear changes of PTC)

Clear cell variants exist (but ! exclude d/dg metastatic RCC)

Immuno: +ve for thyroglobulin, TTF-1 (nuclear stain

)

! d/dg PTC (due to pseudopapillary areas occurring within degenerative changes) – but any nuclear

clearing in follicular adenoma is not accompanied by nuclear membrane accentuation and any CK19

+vity is focal (cf. diffuse in PTC)

d/dg follicular variant of PTC: diagnosis is made on unequivocal PTC nuclear changes. If these are

equivocal/focal some diagnose ‘well-differentiated tumour of uncertain malignant potential’ or, if there

is minimal capsular invasion, ‘well-differentiated carcinoma of uncertain malignant potential’

Follicular Carcinoma

Microfollicular, macrofollicular, solid, trabecular and pseudopapillary forms

H¨urthle cell variant

(i.e. >75% of the tumour are H¨urthle cells) is more likely to metastasise to LN

Immuno: thyroglobulin +ve, calcitonin −ve, galectin-3 +ve

, HBME1 ±ve

Ki-67 LI >5% is a poor prognostic

d/dg follicular variant of PTC: see ‘Follicular Adenoma’, above; and ‘Variants of PTC’, below

d/dg metastatic carcinoma esp. clear cell variant vs. RCC

Widely invasive type

EITHER:

◦

naked eye invasion OR

◦

extensive vasc. invasion by microscopy (e.g. >5 vessels)

Minimally invasive type

Microscopic evidence of either of the following two:

◦

capsular invasion:

 tumour cells must penetrate the entire original capsule (! a neocapsule may form around

an invasive tongue, ! epithelium trapped in the capsule [circumferentially disposed +/ not

connected to the main tumour mass] is not invasion)

 blunt-ended breaks in the capsule at invasion site (cf. sharp ends of d/dg FNA puncture artefact)

 a true invasive tongue is usu. mushroom-shaped

 some say that equivocal capsular invasion alone (with adequate sampling and without vascular

invasion) equates to ‘follicular tumour of uncertain malignant potential’ while others will

diagnose carcinoma on only partial invasion into the capsule

 d/dg FNA track artefact (pseudo capsular invasion):

 needle track: haemorrhage, granulation tissue, siderophages ± cholesterol crystals

 cells escape from capsule in linear fashion (not mushroom)

 breaks in capsule have sharp ends if caused by an FNA needle

◦

vascular invasion:

 requires intracapsular or extratumoural vessels only – not tumour cells in intratumoural vessels

 requires intralumenal tumour mass covered by endothelium (CD31/CD34) ± attached to wall

 d/dg endothelial hyperplasia in capsular vessels (pseudo vascular invasion) – ! but do levels

because this is assoc

with true vascular invasion elsewhere

Papillary Carcinoma (PTC)

Def

◦

evidence of follicular epithelial cell differentiation (incl. follicles and/or papillae)

◦

nuclear features:

(demonstration of

invasion is not necessary)

 enlargement

 irregular outline (usu. with thickened membrane)

 deep grooves, pseudoinclusions

 pallor, ‘ground glass’ chromatin (‘Orphan Annie eyes’)

Typical features also include:  nuclear overlapping/crowding

 nuclear elongation

 peripheral nucleoli

 squamous differentiation

. must block biotin well because thyroid cells are rich in endogenous biotin.

NB: it is outdated to diagnose an entity as ‘H¨urthle cell carcinoma’, instead we now speak of H¨urthle cell variants of other tumours

e.g. follicular adenoma, follicular

CA, PTC, poorly diff. CA, etc.

galectin-3 is not entirely speciﬁc for malignancy but if positivity is widespread and strong it may be taken as supportive evidence

of malignancy.

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Endocrine 270

The typical nuclear features may be (multi)focal but if only minor changes are seen in a non-invasive

follicular arch. tumour, some call it ‘follicular tumour of uncertain malignant potential’

Architecture:  usu. inﬁltrative/stellate but can be encapsulated

 both follicles (usu. elongated) and papillae (with ﬁbrovascular cores) are present

 inspissated colloid may be seen

 follicles blend into papillary areas

 multinucleated histiocytes in lumena of follicles – high speciﬁcity for PTC

 ± cribriform or trabecular areas

 trabeculae have elongated nuclei polarised perpendicular to their long axis

Stroma:  hyaline sclerotic/desmoplastic

 calciﬁcation ± psammoma bodies (proper lamellated bodies cf. d/dg the calciﬁed

concretions seen in the follicle lumena in some non-neoplastic conditions)

Immuno: +ve: CK19 (+ve in ≈ all cases so −vity is useful for exclusion but >50% of benign thyroids

are also +ve), HBME1, CK7, pan-CK and 34E12, RET, thyroglobulin (not squamoid areas), CD15,

galectin-3, [LP 34, CA-125 and CEA are +ve in ≈ 50% of cases], vide infra for EMA and AB

Immuno: −ve: Calcitonin, CgA, CK20

Prognostics ∝ age, size, stage

d/dg artefactual nuclear clearing occurring in follicular lesions due to poor ﬁxation:

 transition is gradual without clear demarcation and it is worst in the centre of the lesion

 other nuclear features (enlargement, crowding, irregular membrane, etc.) are not seen

d/dg true papillae of PTC vs. Sanderson polsters/hyperplastic papillae:

 ﬁbrovascular core favours PTC

 nuclear features of PTC favour PTC

 psammoma bodies favour PTC papillae (although polsters may rarely show calciﬁcation)

 strong +ve staining of the tips of the papillae with AB and EMA favour PTC papillae as

non-neoplastic ones give weak/negative staining

d/dg multifocal pap lesions without psammoma bodies: consider the tumour of Gardner’s syndrome

Variants of PTC

Typical follicular:  usu. encapsulated and often composed of small follicles .

. d/dg fetal adenoma

 must be follicular throughout – if mixed follicular/PTC, call it usual type PTC

Diffuse follicular: variably-sized follicles incl. large ones, lacks a capsule .

. d/dg colloid goitre –

scrutinise for PTC features

Macrofollicular: >50% large follicles ± capsule .

. d/dg colloid goitre – scrutinise for PTC features

(best seen in the smaller follicles)

Solid: tight islands of cells with PTC nuclei separated by variable-thickness ﬁbrous bands ± focal

follicular/papillary areas

Encapsulated

PTC with lipomatous stroma

PTC with exuberant nodular fasciitis-like stroma (assoc

with breast phyllodes)

Diffuse sclerosing PTC:  clinical, serology and low power histology look like d/dg thyroiditis

 look for papillae, psammoma bodies, nuclear features of PTC

Tall cell PTC:

 >30% of tumour cells have a height:width ratio >2

 eosinophilic granular cytoplasm and PTC features

 immuno: CD15 +ve, EMA +ve

 d/dg Warthin’s tumour-like PTC: tall-cell PTC lacks a dense lymphoid stroma

 d/dg columnar cell variant of poorly diff thyroid carcinoma (which is not a PTC)

 columnar cells are often taller than PTC tall cells

 cytoplasm does not have the eosinophilic granular quality

 nuclei are pseudostratiﬁed and chromatin-rich (unlike PTC)

Warthin’s tumour-like: papillary H¨urthle cell tumour with PTC nuclei and lymphoid stroma

Oxyphilic (H¨urthle cell) – must see PTC nuclear changes, not just papillae

Cribriform morular PTC (similar to FAP-associated thyroid carcinoma q.v.)

Trabecular (d/dg HTT, vide infra)

De-differentiated PTC: deﬁnite PTC with areas of poorly diff/anaplastic carcinoma

Microcarcinoma: is deﬁned by the WHO as <1cm 

with encapsulated lesions it is best to err on the side of a follicular adenoma unless morphological criteria for PTC are very strong.

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Endocrine 271

Occult PTC: is one diagnosed as a result of tumour effects (usu. LN mets) where the 1

◦

is not clinically

apparent – usu. because they are small (but not necessarily microcarcinoma)

Latent PTC: is one that is discovered without it causing any clinical effects (e.g. in thyroidectomy for

goitre or at PM) – usu. small but not necessarily microcarcinoma. It needs no additional Rx

Hyalinising Trabecular Tumour (HTT/HTA/Paraganglioid Tumour/PLAT)

Encapsulated (malignancy deﬁned by capsular +/ vascular invasion as for follicular adenoma)

Nests and trabeculae of elongated cells with hyalinising matrix ± calciﬁcation/psammoma bodies

Lightly eosinophilic cytoplasm ± perinuclear halo and 5 perinuclear giant yellow lysosomes

Nuclear features: grooves, inclusions, ﬁne chromatin

Small cystic spaces +ve for thyroglobulin

Immuno: Ki-67 (granular cytoplasmic and membranous positivity), usu. −ve for 34E12 and CK7/19

d/dg MTC: the nuclear features and long trabeculae are unusual for MTC – but always do immuno

d/dg HTT-like foci: these occur in follicular adenomas and hyperplastic nodules

d/dg trabecular PTC: any focus of typical PTC should trump the diagnosis of HTT

Medullary Carcinoma (MTC)

Consider familial form if: multifocal/bilateral and background C-cell hyperplasia ± S100 +ve susten-

tacular cells

Well circumscribed ± capsule

Nuclei: NE nucleus (i.e. evenly-distributed ﬁne grainy chromatin and absent/inconspicuous nucleoli)

Few mitoses (>1/25hpf is a worse prognostic) – but can see more in some variants e.g. small cell MTC

Cytoplasm: ﬁne azurophilic granules (i.e. red on MGG, but the eosinophilia is not obvious on H&E)

Many cell forms/variants: round, spindle, polygonal, binucleate, oxyphilic, squamoid, clear, signet ring

(± mucin and +ve for CEA), small or large (anaplastic) ± isolated tumour giant cells

Tendency to cell dyscohesion

Stroma: amyloid (± Ca

, ± giant cells), ﬁbrous bands, prominent microvascularity

Arch.: lobular/‘zellballen’/solid/trabecular/cords ± central necrosis, follicular, papillary

Immuno/stains: granular cytoplasmic CgA and Grimelius +vity, calcitonin (strong, diffuse +vity is

a good prognostic), CEA +ve (unlike the calcitonin +ve strumal carcinoids of the ovary), S100 +ve

sustentacular cells in the paraganglioid variant, CK +ve (unlike paragangliomas)

d/dg: metastatic carcinoid or lobular breast carcinoma, any 1

◦

thyroid tumour, angiosarcoma: MTC

should be diagnosable by looking for the nuclear and stromal features and foci of more typical MTC

elsewhere ± immuno/stains

d/dg SmCC vs. small cell MTC: difﬁcult, small cell MTC is also aggressive and often calcitonin −ve.

CEA +vity may help (favours MTC)

d/dg anaplastic carcinoma thyroid: a relatively low mitotic count should suggest MTC, look for foci

with more typical features/immuno

d/dg medullary adenoma: bland encapsulated lesions lacking amyloid are called adenoma by some but

these may still metastasise and many do not accept the existence of a benign counterpart of MTC

d/dg C-cell hyperplasia: vide infra

d/dg mixed MTC and follicular or MTC and PTC: vide infra

C-Cell Hyperplasia

C-cell hyperplasia occurs in MEN 2 (± cytological atypia) and also adjacent to non-MTC neoplasms,

in Hashimoto’s thyroiditis, in hypergastrinaemic and hypercalcaemic states

Diffuse type: EITHER >50 cells per low power ﬁeld OR groups >20 cells across

Nodular type: the follicle is replaced by C-cells

Immuno: collagen IV may be useful to delineate the BM

d/dg MTC: hyperplasias are contained within the follicle BM (must show a single, complete, continuous

surrounding of BM without breaks or foci of reduplication – else = MTC)

d/dg nodular hyperplasia vs.:

 cross section of an MTC tumour embolus in thin-walled vessel or intrathyroid ‘metastasis’

 palpation thyroiditis (focal follicles are partly/ﬁlled with histiocytes ± lymphocytes/plasma

cells/giant cells)

 tangential shave of a normal follicle

 islands of squamous metaplasia, parathyroid tissue, ultimobranchial body/thymic rests

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Endocrine 272

Differentiated Carcinoma of Intermediate Type (Mixed Medullary and Follicular Carcinoma)

Follicular and cribriform areas are intermingled with C-cells or solid C-cell islands

WHO criteria: must have

◦

thyroglobulin +ve follicular areas; and

◦

calcitonin +ve MTC areas

d/dg entrapped benign follicles in an invasive MTC

d/dg collision tumour (follicular CA and MTC or PTC and MTC) – may be impossible to distinguish

d/dg aberrant calcitonin expression in an otherwise typical follicular carcinoma

d/dg thyroglobulin +ve MTC – may have a better prog. cf. usual-type MTC (? radio-iodine sensitive)

Poorly Differentiated Thyroid Carcinoma

Def

: CA with differentiation in between well diff (follicular CA, PTC, MTC) and undiff (anaplastic CA)

Insular carcinoma, columnar cell carcinoma and other (less-well characterised) types exist

Insular carcinoma

Arch.: large, tightly-packed solid islands ± extensive necrosis ± stromal sclerosis, islands are often

separated by loose vascular stroma (cf. dense ﬁbrous bands)

Cells: relatively uniform (cf. anaplastic carcinoma), ↑NCR, variable mitotic rate, vesicular hyperchro-

matic nuclei, small nucleoli

Foci of better diff areas (follicular, PTC, MTC) or worse (anaplastic CA – carries a worse prognosis)

Minor foci of insular CA in a PTC/follicular CA should be mentioned but does not alter the diagnosis

Immuno: +ve for thyroglobulin (focal) and Bcl-2 (most cases), −ve for calcitonin

d/dg anaplastic carcinoma: Bcl-2 +vity and lack of pleomorphism favour insular carcinoma

d/dg CASTLE but CASTLE has prominent nucleoli, CD5 +vity and ≈ no necrosis

Columnar cell carcinoma

Arch.: solid, glandular, cribriform, pap.; EITHER a) frankly invasive (worse prognosis);

OR b) encapsulated (± microinvasion of capsule or

vessels)

Columnar cells have hyperchromatic, elongated, pseudostratiﬁed nuclei ± cytoplasmic vacuoles

d/dg metastatic colorectal/endometrioid carcinoma: histologically very similar

d/dg PTC (tall cell and cribriform morular variants – q.v.)

Undifferentiated Thyroid Carcinoma (Anaplastic Carcinoma)

Usual type has epithelioid, spindle and giant cells with signiﬁcant nuclear pleomorphism, mitoses ++,

vascular invasion and inﬂam

cells (incl. PMN). d/dg sarcomas

◦

SCC (and ASC) are considered variants of anaplastic due to their aggressive course .

. exclude the

d/dg before making this diagnosis (i.e. 2

◦

SCC, benign squamous lesions, CASTLE)

Paucicellular variant has spindle cells with milder pleomorphism concentrated at the periphery with a

central paucicellular expanse of sclerosis-like necrosis containing ghost vessels

 d/dg Riedel’s thyroiditis: look for vascular invasion, necrosis, cellular periphery and mets

 d/dg myoﬁbroblastic lesions: because this anaplastic

CA variant may be +ve for MSA

Other variants incl.: ‘carcinosarcoma’ (= metaplastic CA with heterologous elements), angiomatoid

(see d/dg angiosarcoma on p. 321), lymphoepithelial (see d/dg CASTLE) and anaplastic

CA with

osteoclast-like giant cells

Small cell variant: outmoded – instead classify as SmCC, insular CA, MTC, lymphoma, HX, etc.

Immuno: ±ve (useful if +ve) for CK, CEA (esp. in SCC), vimentin, FVIIIRA (focal), EMA;

−ve for calcitonin and thyroglobulin

FAP-associated Thyroid Carcinoma

F  M, may be multifocal in FAP

Cribriform areas (empty follicles), trabeculae of columnar cells, squamoid morules, spindle elements

Nuclear features of PTC only focally, biotinylated nuclear inclusions

d/dg tall cell PTC, cribriform morular PTC (use CPC), columnar cell carcinoma, HTT, etc.

Thyroid Tumours Resembling Thymic Tumours

SETTLE (Spindle and epithelioid tumour with thymus-like elements)

Youths, indolent but may metastasise (esp. to lung/kidney)

Arch. is lobular (cellular masses separated by thick sclerotic ﬁbrous septae)

generally, a single aberrant immuno result should never change the diagnosis if there are no other corroborating features.

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Endocrine 273

Bland cytology with rare mitoses (cf. d/dg synovial sarcoma where mitoses are more common)

Spindle cell elements (fascicles/storiform) predominate and merge with epithelial elements

Epithelial elements (papillary/tubular/trabeculae/sheets) may contain HC-like structures

Mucus/respiratory epithelium may form cysts (unlike in d/dg synovial sarcoma)

No immature lymphocytes (generally, lymphocytes are scant) unlike in d/dg intrathyroidal thymoma

Immuno:  CK +ve (both spindle and epithelioid cells)

 spindle cells are +ve for MSA, SMA and CD99

 CD5, calcitonin and thyroglobulin are all −ve

d/dg: anaplastic thyroid CA, immature teratoma, synovial sarcoma (esp. vs. extrathyroidal SETTLE)

CASTLE (Carcinoma showing thymus-like elements, Intrathyroidal thymic carcinoma)

Middle-aged, indolent, local complications, mets are rare

Arch: lobular/insular with ﬁbrous septae, extrathyroidal spread is common

Histology: squamoid thymic CA (see p. 96) ± adjacent thymic rests

Immuno: −ve for thyroid/C-cell markers, CD5 +ve, Bcl-2 +ve

d/dg: lymphoepithelial variant of anaplastic thyroid CA (but that is CD5 −ve and not lobular)

d/dg: 1

◦

thyroid SCC, FDC sarcoma, lymphoma and insular carcinoma of the thyroid (q.v.)

Mucin-containing Tumours

◦

adenosquamous carcinoma (has an aggressive course in the thyroid)

Mucinous carcinoma (! exclude d/dg metastatic origin)

Amphicrine variant of MTC may secrete mucin and have signet-ring-like cells

MEC: epidermoid component may contain pearls. Thyroglobulin +vity may be seen

Sclerosing MEC with eosinophilia:

 usu. arises in background of Hashimoto’s

 both mucoid and epidermoid components show nests and cords

 the background shows a diffuse sclerotic stroma containing eosinophils and other inﬂam

cells

 immuno: thyroglobulin is usu. −ve

 d/dg: NSHL, sclerosing Hashimoto’s, PTC with squamoid metaplasia, SCC

Lymphomas

± Background of thyroiditis and may also involve local LN or ‘home’ to the GIT

usu. DLBCL or MALToma (incl. plasma cell predominant variant). Histol. is similar to elsewhere

d/dg ﬂorid Hashimoto’s: CD43 +vity, conﬂuent sheets of B-cells and ﬂorid LEL favour lymphoma

Some Pitfalls in Thyroid Tumour Diagnosis

Don’t call PTC:  a cyst (cystic PTC)

 a colloid goitre (diffuse follicular PTC, macrofollicular PTC)

 a thyroiditis (diffuse sclerosing variant)

Don’t call anaplastic carcinoma Riedel’s thyroiditis (paucicellular variant)

Don’t call MTC a PTC or follicular carcinoma: NE nuclei, calcitonin, CgA +ve; thyroglobulin −ve

Frozen Section Histology and Per-operative Cytology in Thyroid Diagnosis

Concomitant imprint cytology can give complementary information (esp. in PTC and MTC)

Distinguish thyroid from parathyroid (thyroid has birefringent oxalate crystals ±C-cells and has larger,

more variably-sized follicles with denser colloid cf. parathyroid. Imprint cytology also helps)

! Beware separated nodules of thyroid that may be misidentiﬁed by the surgeon as ‘LN’ – such seques-

tration (= ‘lateral aberrant thyroid’) may occur in MNG or Hashimoto’s – do not misdiagnose as LN

metastasis.

Distinguish LN metastasis from ﬁbrous Hashimoto’s (look for a LN sinus architecture) – in ﬁbrous

Hashimoto’s the ﬁbrosis can mimic a LN capsule or desmoplasia, the lymphoid follicles can mimic LN

follicles and the atypical H¨urthle cells can mimic metastatic carcinoma deposits.

Distinguish Riedel’s thyroiditis from desmoplastic carcinomas

‘Orphan Annie eye’ nuclei/nuclear inclusions do not show on FS (.

. do imprint cytology)

Distinguish calciﬁed amyloid deposits of MTC from psammoma bodies of PTC

Defer to parafﬁn if ?lymphoma or ?metastatic carcinoma from elsewhere (e.g. colon, lung, breast)

FS should not be used on a 1

◦

tumour to distinguish follicular adenoma vs. follicular carcinoma

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Endocrine 274

Parathyroid

Normal Histology

Dark chief cells (functional, minority cell type, pale eosinophilic cytoplasm with tiny or absent lipid

droplets), transitional chief cells, light chief cells (resting, water clear cytoplasm and paranuclear lipid

droplets). The cytoplasm contains argyrophil granules and they may form follicles with colloid-like

material (+ve for PTH ± amyloid but no oxalate crystals – d/dg thyroid follicles)

Immuno: +ve for CgA and PTH; −ve for CEA, CgB and thyroglobulin (cf. thyroid follicle and C-cells)

Oxyphil cells (inactive oncocytes) ↑ with age and may form nodules in the elderly (if large, the only

difference to functional oxyphil adenoma may be EM evidence of protein synthesis in adenomas)

Adipocytes ↑ with age to 40’s and are ∝ to nutritional state. Fat constitutes 10–50% of gland volume

Normal plasma total [Ca

] = 2.1–2.6 mM/l with [PTH] = 0.1–0.9 ng/ml

Frozen Section

Record the position of the gland (left upper, left lower, etc.)

Record the trimmed weight (≈ 30 – 40mg per normal gland; ≥60mg is abnormal provided ≥3 other

normal glands can be identiﬁed)

Weigh and examine any trimmings in case these too are parathyroid (or thymus – vide infra)

Conﬁrm that it is parathyroid tissue (d/dg thyroid, LN, thymus, adipose, brown fat)

State if any of the surrounding tissue is thymic (this indicates that the gland is a lower one)

Distinguishing adenoma vs. hyperplasia is not important at FS but missing a carcinoma is disastrous

A fat stain for intracytoplasmic lipid globules may be useful in d/dg normal vs. abnormal tissue:

 Sudan IV and oil red O stain lipid positively, toluidine blue/methylene blue are −ve stains

 normal/atrophic chief cells have large globules (upto ≈ size of nucleus)

 hyperplastic/neoplastic chief cells have absent lipid or sparse small globules

d/dg pure oxyphil parathyroid adenoma cf. thyroid H¨urthle cell neoplasm (may be impossible)

d/dg microfollicular parathyroid adenoma cf. thyroid follicular neoplasm (may be impossible)

Features Favouring Adenoma Over Hyperplasia

No single feature is absolute or present in every case (adenomas can mimic hyperplasia and vice versa)

One enlarged gland with ≥3 normal ones identiﬁed – strong evidence whatever the histology

(NB:in

hyperplasia the enlargement of all glands may be asymmetrical; double adenomas may rarely occur)

Excess weight: if 1g it’s more likely to be an adenoma

Thin capsule separating it from a rim of uninvolved gland (but a capsule may be incomplete/absent)

Rim of uninvolved gland (lipid stains may help): may be absent, atrophic, normal or hyperplastic

Absence of adipocytes (but occasional scattered adipocytes are often present in adenomas)

Single diffuse growth (cf. multinodularity typical of hyperplasia)

Other features of adenomas

Cell type: chief or oxyphil (may be elongated) or, rarely, spindle cells. Lymphocytes may be admixed

Degenerative changes: cystic, myxoid, Ca

, haemorrhage; subsequent ﬁbrosis may entrap tumour

cells, usu. with haemosiderin (! d/dg do not misdiagnose as capsular invasion implying parathyroid

CA)

Mitoses are sparse to absent (Ki-67 LI is usu. <3%)

‘Endocrine-type’ atypia foci occur (esp. adjacent to haemorrhage or in oxyphil cells) but are not mitotic

d/dg: rare papillary and follicular variants may cause confusion with thyroid neoplasia

Other features of hyperplasia

◦

hyperplasia may be chief cell (nodular/diffuse, ≈ 2

◦

hyperplasias) or water-clear cell (diffuse)

Chief cell type: may have other cell types sparsely admixed. May have a ‘dominant nodule’

Water-clear cell type: very rare variant, large clear cells (not the same as pale chief cells), looks like

low grade RCC (NB: RCC and pulm. SCC are the commonest causes of ectopic hyperparathyroidism)

Mitoses are usu. absent in 1

◦

hyperplasia but may be seen in 2

◦

hyperplasias (e.g. in CRF, etc.)

Parathyroid Carcinoma

Clin: usu. ↑↑PTH, ↑↑[Ca

] (common cause of death), pre-op tumour palpable, per-op ‘stuck down’

Thick hyaline ﬁbrous capsule and internal broad ﬁbrous bands enclosing nodules (may be expansile)

Arch.: sheets, trabeculae and rosettes are said to be typical (but any may occur in adenomas too)

the need to identify ≥3 normal glands is because some people have <4 glands in total so their normal total gland mass is concentrated

in fewer (but bigger) normal glands.

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Endocrine 275

Invasion of adjacent structures (e.g. thyroid) or distant mets are deﬁnitive evidence of malignancy

Invasion of vessels or capsule (! d/dg scarring in an adenoma – use follicular thyroid CA criteria)

Cells are monotonous but may have frequent prominent nucleoli +/ ↑NCR or be spindled

Pleomorphism may be generalised or focal (with mitoses, unlike d/dg ‘endocrine-type’ atypia)

± Coagulative tumour cell necrosis

Mitoses and Ki-67 LI may be very low but if high (>5/10hpf and >5%) or abnormal favour carcinoma

over adenoma

If absolute criteria are lacking (local invasion and mets) and other criteria are equivocal the terms

atypical adenoma or parathyroid tumour of uncertain malignant potential may be used

Immuno: nuclear +vity for p105 (pRb) favours carcinoma over adenoma (−vity means nothing)

d/dg pseudoinﬁltrative pattern of parathyroid tissue implants from previous surgery (use CPC)

d/dg pseudoinﬁltrative pattern of clear cells in the wall of a benign parathyroid cyst

d/dg metastatic tumours (esp. clear cell types)

Adrenal

Normal Histology

Capsule varies in thickness and may be focally absent (→ fusion of adrenal with kidney/liver)

Fetal cortex is an ≈homogeneous mass of eosinophilic hepatocyte-like cells, a more basophilic rim of

developing deﬁnitive cortex appears after birth and the adult form is established by late teens

The outer zona glomerulosa (ZG) is only focally present (if continuous it is considered hyperplasia)

Zona fasciculata (ZF): large cells with abundant lipidised cytoplasm (? a storage zone)

Zona reticularis (ZR): smaller, lipid poor, eosinophilic, compact cells, the inner ones showing lipofuscin

± apoptoses

An invaginated sheath of cortex invests the central vein and may develop pathology (nodules, etc.)

Medulla is only present in the head and body and consists in ill-deﬁned nests of polygonal/elongated

chromafﬁn +ve NE phaeochromocytes, (larger, more basophilic and less-well deﬁned cf. cortex cells)

with coarse and marginating chromatin and focal ‘endocrine-type’ atypia. Sustentacular and ganglion

cells are also present. Eosinophilic globules may be seen in the phaeochromocytes and ganglion cells

Normal plasma ACTH = 3–15 pM/l with peak cortisol of 700 (a.m.) and 280 (p.m.) nmol/l

Cortical Hyperplasia due to ACTH

ACTH source may be pituitary (Cushing’s/stress) or ectopic (usu. NET of bronchus, thyroid, thymus,

pancreas or adrenal medulla)

Bilateral ↑ cortical thickness with relative ↓ZF and ↑ZR

Diffuse hyperplasia is more common than multi-nodular hyperplasia

d/dg multi-nodular diseases of the cortex with ↓/normal plasma ACTH levels:

 incidental nodules: unencapsulated, multiple, tiny/upto few cm, ZF-like or ZR-like cells

 macronodular hyperplasia without ACTH secretion: distorting nodules of ZF-like cells

 PPNAD: familial Cushing’s ± Carney complex, pigmented nodules with small clear cells

Cortical Neoplasia – Adrenocortical Adenoma and Adrenocortical Carcinoma (ACC)

Well-circ. with pseudocapsule, usu. single, orange/yellow/mottled cut surface, may be pigmented

Adjacent cortex may be normal, atrophic or hyperplastic

±Spironolactone bodies in tumour/adjacent cortical cells (if Rx with aldosterone inhibitors for Conn’s):

 large eosinophilic round inclusions in ZG or peripheral ZF cells

 whorled/spiral/‘scroll-like’ with surrounding clear halo

Cells: usu. ZF-like but ZG-like (esp. in Conn’s) and oncocytic or ZR-like foci occur with focal

‘endocrine-type’ atypia. Pure oncocytomas may be very large even though benign

Arch.: alveolar and trabecular architectures are more common in benign tumours (cf. solid/diffuse)

Features favouring malignancy

Clin. risk factors: childhood, large size (esp. if > 1 kg or non-functioning), sex hormone production

In the absence of mets or gross local invasion (e.g. of the IVC), must use a multiparameter approach

and CPC to give an estimate of malignancy risk (i.e. metastatic potential)

Some diagnose malignancy if there is the simultaneous ﬁnding of:

◦

↑ mitotic count (>5/50hpf with

a 0.47 mm ﬁeld

)

◦

abnormal mitoses, and

◦

venous invasion. Other risk factors are:

 locally recurrent tumours (these all eventually metastasised in Hough’s series)

 tumour divided into lobules by broad ﬁbrous bands (‘broad’ means >1 hpf wide)

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 conﬂuent areas of tumour necrosis, esp. if extensive (‘extensive’ means ≥ 2 contiguous hpf)

 a solid/diffuse cell architecture (= patternless sheets in >33% of the tumour; non-diffuse is

deﬁned as >67% showing patterned architectures e.g. alveolar, broad trabecular, etc.)

 vascular/sinusoidal invasion (deﬁned as tumour cells in vessel lumen)

 ↑ proliferation (mitotic count of >20/50 hpf or >10/100 hpf or >10/10 hpf or Ki-67 LI >3%

have all been quoted with a 20/50 hpf mitotic count used as the cut-off between low grade and

high grade carcinomas in one system)

 nuclear grade III or IV (by Fuhrman grading) – although some claim pleom. is unhelpful

 capsular invasion (deﬁned as cell nests/cords into or through the capsule, some also require a

stromal reaction): on its own this is unhelpful unless there is invasion of adjacent organs

 a low proportion (Weiss suggests ≤25%) of clear (lipidised ZF-like) cells

 immuno +vity for MMP-2 favours malignancy (and worse prog. if >20% of cells are +ve)

If a spindle/sarcomatoid component is prominent some diagnose adrenocortical carcinosarcoma

Some diagnose ‘adrenocortical tumour of uncertain malignant potential’ if the above features are

equivocal or sparse (e.g. only 2 or 3 features present)

d/dg ACC vs. RCC vs. HCC is decided on CPC, EM and immuno (see table 19.1)

d/dg phaeochromocytoma: ACC may have a few lipidised cells, an alveolar pattern and be +ve for NSE,

synaptophysin and CD56 (±↑catecholamines clinically) but is −ve for CgA. Phaeochromocytoma

may be +ve for ACTH and have some lipidised cells but is −ve for the D11 cortical Ab by immuno.

ACC is further favoured by +vity for inhibin- and Melan-A

TABLE 19.1 Immuno of adrenocortical vs conventional renal cell and hepatocellular carcinomas

Antibody ACC RCC HCC

D11 +ve −ve −ve

Melan-A (A103) +ve −ve −ve

inhibin- +ve (focal) −ve −ve

EMA −ve +ve −ve (in ≈ 75%)

vimentin ±ve +ve usu.−ve

CK (AE1/3 or CAM 5.2) −ve +ve ±ve



AT −ve ±ve ±ve

AFP −ve −ve ±ve

pCEA usu. −ve −ve +ve (canalicular)

CD10 −ve +ve +ve (canalicular)

Hep Par 1 −ve −ve +ve

Phaeochromocytoma (Adrenal Medullary Chromafﬁn Paraganglioma, Chromafﬁnoma)

Macro: well-circ. (not encapsulated) and brown (hence ‘phaeo’) ± degenerative changes. Multiple,

bilateral tumours occur as a continuum of the background multinodular medullary hyperplasia in MEN 2

Arch.: zellballen/trabecular/solid with peripheral S100 (+/ GFAP) +ve sustentacular cells

Cells: polygonal/spindle, granular eosinophilic cytoplasm (± focal lipidisation) with basophilic gran-

ules, NE nuclei and ‘endocrine-type’ atypia, ± intranuclear cytoplasmic inclusions, ± cytoplasmic

DPAS +ve globules (the latter are also rarely seen in adrenocortical neoplasms)

Mitoses are usu. sparse (≤1/20 hpf)

Stroma: delicate rich vascularity, alveolar reticulin pattern, hyalinisation, (± amyloid in a minority)

Immuno/stains: chromafﬁn +ve (diffuse and granular cytoplasmic browning), +ve for CgA and other

NE markers ± various NE peptides (incl. ACTH, PP or VIP [→ WDHA]), CK −ve

Variants:

◦

composite phaeochromocytoma is one with a neural tumour component (neuroblastoma,

ganglioneuroblastoma, MPNST, etc.)

◦

pigmented phaeochromocytoma is black with melanin-like

pigment granules in cells

◦

extra-adrenal phaeochromocytoma (1

◦

sites include bladder, peri-renal,

coeliac axis, heart)

Malignancy (= mets via blood or LN) risk factors: conﬂuent necrosis, local invasion ++, ↑ prolif

(≥ 3 mitoses/20 hpf) and lack of globules or sustentacular cells. [Note: no phaeo is deﬁnitely benign]

d/dg: metastatic tumour, adrenocortical neoplasia (vide supra)

d/dg nodular hyperplasia in MEN 2 (some use an arbitrary size threshold of >1cm  = neoplastic)

Some Other Tumours

Lipoma and Myelolipoma: mature adipose ± haemopoietic marrow may form a benign mass lesion or

occur as ‘heterologous’ foci in adrenocortical tumours

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Malignant melanoma can arise as a 1

◦

adrenal tumour (as well as mets)

Metastases: esp. from lung or kidney, because these may be confused for 1

◦

adrenal tumours

For neural tumours of the adrenal medulla (neuroblastoma, etc.), see p. 59

Pituitary

Normal Histology

The anterior pituitary has a paraganglioid architecture with cell balls of trophs surrounded by S100

+ve folliculostellate cells. Occasional small thyroid-like follicles may form

Reticulin is packeted

Lateral wings are rich in somatotroph acidophils (! simulate the pure cell population of an adenoma)

Transdifferentiation and single cells expressing >1 hormone occur (as do plurihormonal adenomas)

The pars intermedia may show small columnar-lined clefts ± cystic change and squamous metaplasia

(! d/dg craniopharyngioma or Rathke’s cleft cyst)

The border of anterior and posterior hypophysis is blurred (! the basophil trophs appear to invade it)

Pituitary stalk axons have eosinophilic swellings (Herring bodies) ±granular cell islands (tumourlets)

The neurohypophysis contains axons and altered spindly glial cells (pituicytes) ± salivary acini rests

Normal upper limit of prolactin = 600 mIU/l in serum (25 ng/ml in plasma) for non-pregnant females

and 450 mIU/l (20 ng/ml) in males; can be around 5000 mIU/l (210 ng/ml) near term in pregnancy

tailing off with lactation

Stains and Interpretation of Staining Patterns

H&E (PAS Orange G for acidophil/basophil/chromophobe is outdated, capricious and not useful)

Retic: shows expanded packets in hyperplasia and is typically weak/absent (vascular only) in neoplasia

Immuno:  1

◦

panel: CK, PRL, GH, ACTH, -subunit (of the glycoprotein hormones)

 2

◦

panel if -subunit is +ve: -subunits (of TSH, FSH and LH)

 SF-1 (nuclear stain: +ve in gonadotroph adenomas incl. silent ones)

 Pit-1 (nuclear stain: +ve in somatotroph, lactotroph and thyrotroph adenomas)

 hCG (for craniopharyngioma)

 GFAP (for granular cell tumour and gliomas)

Problems with immuno interpretation can occur due to:

 trapped normal cells (! do not misdiagnose as a plurihormonal adenoma)

 overstaining by ACTH (high background – d/dg adenoma) and the normal grouping of ACTH

+ve cells (d/dg hyperplasia)

 pure populations of GH cells (in the lateral wings of the pituitary) simulating adenoma

 cross-reactivity between FSH and LH -subunits

 secretory exhaustion: patients with ↑↑serum hormone levels may show −ve immuno because

little hormone is left in the cells (but ISH for hormone mRNA should be +ve)

 over-interpretation of PRL due to PRL cell hyperplasia and Hx of hyperprolactinaemia that

may be due to pituitary stalk compression from any tumour/lesion.

. Use the pattern of hormone staining (see Figure 19.1) and H&E, retic and CPC:

Non-Neoplastic Conditions

ACTH PRL OTHERS

lysosome Crooke's hyalin golgi diffuse NE granules

FIGURE 19.1 Immuno of some pituitary hor-

mones

Radiation-induced changes

Hypophysitis: lymphocytic (usu. autoimmune),

CMV and granulomatous (incl. sarcoid)

Infarction/apoplexy (haemorrhagic necrosis) post

pregnancy (Sheehan) or within a tumour (is one cause

of the empty sella syndrome; hydrocephalic pressure-

induced pituitary atrophy being another)

Pituitary Adenomas and Carcinoma

Nomenclature

Aggressive adenoma = invasive adenoma: adenoma with local invasion

Carcinoma requires distant mets to the leptomeninges, spinal cord, vertebrae, liver, etc., is very rare

and is usu. +ve for PRL, ACTH or GH. They may over-express p53 (unlike non-atypical adenomas)

Atypical adenoma: adenomas with ↑ proliferation (e.g. Ki-67 LI >4%) – not universally accepted

Microadenoma: adenoma <10mm in maximum dimension (macroadenoma ≥ 10mm) by radiology

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Plurihormonal adenoma: the same cells (or separate neoplastic populations) express >1 hormone.

There is no minimum % criteria as long as all populations are neoplastic (not entrapped cells)

Silent adenoma: does not produce hormonal effects but may contain hormone products by immuno

Null cell adenoma: a silent adenoma which is not immunoreactive for hormonal peptides and lacks EM

features of speciﬁc trophs

Grading

This is actually a form of radiological staging and not performed by the pathologist

1. non-invasive microadenoma conﬁned below the sella diaphragm

2. non-invasive microadenoma all or partly above the sella diaphragm

3. invasion of (but conﬁned to) the bony sella turcica

4. invasion of other local structures

General histology

The acinar pattern of reticulin is diminished or lost (but retic is retained around the blood vessels)

Arch.: large irregular cell nests, trabeculae, solid, papillary and rosette formations may all occur

Cells are usu. larger than normal (but may be smaller) ± variable pleomorphism/hyperchromasia,

mitoses may be abundant – none of these features are predictive of malignancy

Tumour necrosis (d/dg apoplexy which may also occur) is a bad sign but does not imply malignancy

Bromocriptine Rx → ﬁbrosis, small cell size ± haemorrhage; somatostatin Rx → ﬁbrosis

Subtypes

Corticotroph (ACTH): Tumour cells are typically PAS +ve even when not basophilic. Functioning ade-

nomas cause Crooke’s hyalin (perinuclear CK, CAM5.2 +ve) to deposit in surrounding non-neoplastic

ACTH cells (takes 6 months of hypercortisolaemia to develop and upto 1 year to clear) – if absent con-

sider hyperplasia (cf. adenoma) or silent corticotroph adenoma (which is more likely to be aggressive).

Crooke’s adenoma is a rare variant where the tumour cells have Crooke’s hyalin

Somatotroph (GH)/Mammosomatotroph (GH + PRL): Pit-1 +ve. Rarely -TSH +ve. Paranuclear

rounded CAM5.2 +ve blobs (= eosinophilic ‘ﬁbrous bodies’ which may indent the nucleus) are said to

be pathognomonic. Sparsely granulated forms have chromophobic cells with weak/−ve GH staining

(± Golgi pattern) and well-formed ﬁbrous bodies. Densely granulated forms have eosinophilic cells,

dense diffuse cytoplasmic GH staining ± weak perinuclear CK ± -subunit +vity.

Lactotroph/Mammotroph (PRL): Pit-1 +ve. May show psammoma bodies or amyloid. Sparsely gran-

ulated: chromophobes with paranuclear PRL staining only. Densely granulated: eosinophilic cells with

diffuse cytoplasmic PRL. Always exclude 2

◦

↑ PRL due to hypophysitis/other tumour

Gonadotroph (LH/FSH): solid nests with peripheral palisades of polarised cells; nuclear SF-1 +ve

Rarer adenomas (all Pit-1 +ve): Thyrotroph; Acidophil stem cell (oncocytes, PRL, GH, ﬁbrous bodies);

Silent subtype 3 (ﬁbrosis, vascularity, plurihormonal: GH, -TSH, PRL, etc., local bone invasion, EM

helps)

Oncocytoma: null-type, +ve for PTAH and synaptophysin, −ve for DPAS, CD68, S100 and GFAP;

d/dg granular cell tumour (shows the opposite staining reactions) or acidophil stem cell adenoma

Differential diagnoses

Hyperplasia is reticulin +ve (expanded packets) and has a mixed (albeit skewed) cell population

Metastatic carcinoma

Craniopharyngioma and Rathke’s cleft cysts (see p. 184)

Granular cell tumour (see oncocytoma in list above) – also d/dg HX or (normal) granular cell tumourlets

Normal anatomical/physiological variants and artefacts of staining (vide supra)

Mixed adenoma with gangliocytoma (of the neurohypophysis) – very rare

Other Tumours

Pituicytoma: astrocytoma of the neurohypophysis with elongated cells and fasciculation: GFAP +ve

Meningioma and rare local tumours: germ cell tumours, chordoma, etc.

Metastatic carcinoma, granular cell tumour, HX and Rathke’s pouch lesions are discussed above

Frozen Section / Per-Operative Assessment

FS is best avoided (the small amount of tissue can be damaged by freezing) – use imprint cytology

Decide if it is pituitary tissue: adenomas showa monomorphous population of small cells ±2

◦

structures

(papillae, psammoma bodies, etc.) but it may not be possible (or necessary) to make this diagnosis at

this time