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

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Osteoarticular 329

22. Osteoarticular

Normal

Woven bone: closely packed and irregularly orientated large lacunae with plump osteoblasts. Matrix

collagen is haphazardly arranged (woven) so only faint criss-crossing lines are seen by polarisation (no

lamellae). Architecture is trabecular or spiculated

Lamellar bone: lacunae are smaller, spindle shaped, more regularly spaced out and have their long axes

parallel to the lamellae. The matrix collagen lies in parallel bundles giving lamellae (bright and dark

lines). Architecture is trabecular (= cancellous/spongy bone) [lamellae lie parallel to the long axis of

the trabeculae] or compact (cortical bone) [with circumferential lamellae]. If lamellar bone is thick

enough to be vascularised, concentric lamellae surround the vessels (Haversian systems)

Morphometry of mineralisation (requires undecalciﬁed tissue ± Goldner’s or von Kossa-stain):

 calciﬁcation front (= mineralisation front), the line of active mineralisation between osteoid

and mineralised bone, can be labelled by pulses of tetracyclines (→ crisp thin line of yellow

autoﬂuorescence) and occupies ≈ 40–60% – or more – of normal trabecular surface

 osteoid covers ≤20% of the trabecular surface (and is <5% of trabecular volume) at a thickness

of ≤4 bright lamellae by polarisation. Increased with any cause of ↑ turnover

Hyaline cartilage:

 chondrocytes occur in (artefactual) lacunae surrounded by a basophilic, MPS-rich zone of

matrix (the territorial zone) separated from each other by the eosinophilic interterritorial

matrix

 chondrocytes are round or angulated cells with a single small nucleus and are not mitotically

active in mature cartilage. Exceptions: articular cartilage of small tubular bones and children

 articular cartilage collagen and chondrocytes are parallel to the surface in the superﬁcial

lamina splendens (zone I), irregularly arranged in the transitional zone (II) and form vertical

columns in the deep zone (III) separated from the calciﬁed zone (IV) by the tide mark (wavey

calciﬁed line)

 epiphyseal growth plate (= physis) shows endochondral ossiﬁcation: small chondrocytes, in

vertical columns, have a prolif. zone towards the epiphyseal end of the plate and hypertrophy

towards the diaphysis as they mature. Mineralisation occurs in these hypertrophic foci

Non-neoplastic Bone Disease

Osteomalacia and Rickets

Causes: ↓ vitamin D

(dietary, solar) or hypophosphataemia (renal, parathyroid, paraneoplastic)

Osteoid: ↑ volume, ↑ thickness and ↑ surface coverage (usu. to > 35% of trabecular surface area)

Calciﬁcation front: ↓ coverage, irregular and blurred line by tetracycline labelling

↑ Osteoblastic activity

Thickened epiphyseal cartilage with defective mineralisation (extension of cartilage into underlying

bone)

± Changes of (2

◦

) hyperparathyroid bone disease (see OFC below)

d/dg non-lethal AD forms of hypophosphatasia: like osteomalacia but has ↓ n˜os of osteoblasts

d/dg aluminium toxicity: in this, the calciﬁcation front is sharp and stains red with aurinitricarboxylic

acid; there is also ↓ osteoblastic activity

Hyperparathyroidism: Osteitis Fibrosa Cystica (OFC)

Sites: widespread incl. tubular bones of hands/feet, clavicle, mandible, cranium and others

Dissecting resorption by ↑ n˜os of osteoclasts ±woven bone (osteoclasts have fewer nuclei and are not

limited to the trabecular surface cf. d/dg the early, lytic, phase of Paget’s disease)

↑ Osteoblastic activity

Fibrous replacement of bone marrow (usu. paratrabecular cf. d/dg myeloﬁbrosis)

± Crystal arthropathies (gout and pseudogout)

Multiple lytic lesions (these are the ‘cystica’ in OFC): degenerative cystic spaces and brown tumours

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



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

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Osteoarticular 330

Brown tumour of hyperparathyroidism

Lobular arch., active ﬁbrous tissue septa ± woven bone, vessels, haemorrhage and haemosiderin

Irregularly distributed multinucleated osteoclasts (may cluster around haemorrhage)

d/dg other giant cell-rich lesions in bone with ≈ identical histology (giant cell reparative granuloma,

GC reaction of hands +feet, GC epulis and solid variant ABC) requires CPC (incl. serum PTH levels)

d/dg GC tumour of bone: multiple lesions favour brown tumour. For histological differences see p. 335

Renal Osteodystrophy

◦

OFC

◦

Osteomalacia

◦

Osteosclerosis (due to woven bone ++): radiologically may be seen as a ‘rugger jersey spine’

Osteoporosis

Def

: osteopaenia (difﬁcult to diagnose by histology) of sufﬁcient severity to cause pathological fracture

The cortex and weight-bearing trabeculae are least affected

Trabeculae appear thinned and separated ±↑surface osteoclasts (subtle)

Transient, juxta-articular, osteoporosis may show ↑ marrow vascularity ± fat necrosis

Osteonecrosis (Avascular Necrosis, Bone Infarct)

Days: necrotic marrow → granulomas (reaction to dead marrow/bone fragments), pyknosis and coag-

ulative necrosis, dystrophic calciﬁcation and dissolution/saponiﬁcation of the adipose tissue

Weeks–months: empty lacunae, bone matrix shows paucity of staining or ↑ basophilia

Periphery:  viable new bone is laid down around necrotic fragments

 ﬁbrous and granulation tissue (eventually calciﬁes → well-deﬁned rim on radiol)

Osteomyelitis

Clin., radiol. and macro.: may simulate d/dg Ewing’s sarcoma or HX

Reactive woven bone and ﬁbrosis ↑ with time to form a chronic (Brodie’s) abscess

Osteonecrosis is most abundant in the earliest/acute phases

PMN pus may be found at any stage + other inﬂam

cells

Paget’s Disease of Bone (Osteitis Deformans)

A myxovirus infection of osteoclasts in (usu. Anglo-Saxon) people of late middle-age

Affects single or multiple bones (axial skeleton > peripheral)

Radiol: early lesions are lytic (ﬂame-shaped in long bones, osteoporosis circumscripta in cranium)

Early:

 large osteoclasts ++ with ↑ n˜o of nuclei resorption is not dissecting

 ↑ osteoblast activity → woven bone

⎫

⎬

⎭

and osteoclasts are more nucleated

 marrow is hypervascular and ﬁbrotic cf. d/dg OFC

Late:

 jigsaw mosaic of lamellar bone with crenated cement lines replaces trabeculae and cortex

 both cortex and trabeculae are thicker and irregular with loss of corticomedullary differenti-

ation (also seen on radiology)

 marrow is ﬁbrosed; osteoblastic and osteoclastic activity subsides

Paget’s sarcoma: a sarcoma developing 2

◦

to Paget’s – usu. osteosarcoma (or ﬁbrosarcoma/MFH/

chondrosarcoma/other) usu. in long bones, pelvis or skull

Achondroplasia

The normal columns of chondrocytes in the epiphyseal growth plate are disrupted and shortened

Mineralisation occurs in the vicinity of hypertrophic chondrocytes but very few of these are formed

Osteopetrosis (Marble Bone Disease of Albers-Sch¨onberg)

Severe forms result in cytopenic immunodeﬁciency, anaemia and leukoerythroblastic PB

≈ Solid, heavy bones with expanded diaphyses criss-crossed with vertical and transverse streaks

Dense meshwork of irregular trabeculae composed of bone and cartilage

Osteoclasts may be numerous (though functionally ineffective)

Marrow space is reduced and ﬁbrotic

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Osteoarticular 331

Osteogenesis Imperfecta (Brittle Bone Disease)

Growth plate fragmentation → bone ends ﬁlled with cartilage nodules (radiol: ‘bag of popcorn’)

Woven bone +/ thin lamellae (lamellae occur in the less severe forms)

Crowding of osteocytes and osteoblasts

± Osteoporosis

Multinucleated Giant Cell Rich Lesions (in General – not just osteoarticular)

Any anaplastic carcinoma, sarcoma, melanoma, etc. may have giant cells (to be distinguished from the

osteoclast-like giant cells present in variants of certain tumours e.g. IDC of breast, pancreas, anaplastic

carcinoma of thyroid and peripherally in clear cell chondrosarcoma)

Inﬂammatory and granulomatous conditions with multinucleated giant cells derived from macrophages

(e.g. xanthogranuloma of the ovary, foreign body reactions, etc.)

Reaction to intraosseous haemorrhage (incl. haemophiliac pseudotumour)

Stromal giant cells may occur in: the testis (? age-related), the lower female genital tract (e.g. in

ﬁbroepithelial polyps), ﬁbroadenoma (can be bizarre), other breast lesions or interlobular breast stroma,

the anus, bladder and nose

Surrounding stromal emphysematous spaces (e.g. pneumatosis intestinalis, emphysematous colpi-

tis/emphysematous vaginitis)

Syncytiotrophoblastic differentiation

HX (esp. Hand-Sch¨uller-Christian disease)

Juvenile xanthogranuloma (classically Touton-type giant cells)

Alveolar RMS (typically ‘wreath-like’ giant cells) and pleomorphic RMS

Giant cell arteritis

Giant cell myocarditis

Giant cell carcinoma of the lung

Giant cell interstitial pneumonitis

Anaplastic large cell lymphoma

Multinucleated FDC (Warthin-Finkeldey type) in reactive (esp. viral) lymphoid proliferations

Giant cell hepatitis

Giant cell hepatocellular carcinoma

Giant cell glioblastoma (grade IV)

Sub-ependymal giant cell astrocytoma (grade II)

Uterine carcinosarcoma (epithelial giant cells)

Giant cell pseudosarcomatous mural nodule in ovarian mucinous cystadenoma

Phyllodes tumour of the breast

Metaplastic carcinoma of the breast

Annular elastolytic giant cell granuloma (skin)

Lymphomatoid papulosis (LyP)

Melanocytic naevi (‘mulberry cells’ – a sign of benignity)

Atypical ﬁbroxanthoma (AFX)

Giant cell (de Quervain’s) thyroiditis

ABC and ABC-like lesions/lesions with ABC-like foci within them e.g.:

 osteoblastoma, chondroblastoma and chondromyxoid ﬁbroma

 giant cell tumours of bone/tendon sheath/PVNS

 ﬁbrous dysplasia

 mesenchymal hamartoma

 giant cell reparative granuloma (is ≈ identical to solid variant ABC) – p. 333

 rarely, malignant tumours (e.g. clear cell chondrosarcoma)

Giant cell epulis (= peripheral giant cell reparative granuloma) – occurs in gums, not jaw bones

Giant cell reaction of the hands and feet

Brown tumour of hyperparathyroidism (see p. 330)

Giant cell reparative granuloma (central): jaw bones (‘soap bubble’ lucency without periosteal

breach/reaction and with tooth displacement but not resorption), irregular distribution of GC (esp.

around haemorrhage), vascular stroma with ﬁbrous mononuclear cells producing collagen, metaplastic

bone or woven bone with osteoblast rimming, focal haemorrhage (ABC-like) ± Jaffe-Campanacci

syndrome: For d/dg see the section on ‘Brown tumour of hyperparathyroidism’, p. 330

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Osteoarticular 332

Chondroblastoma

Chondromyxoid ﬁbroma

Metaphyseal ﬁbrous defect and non-ossifying ﬁbroma

Solitary bone cyst (simple/unicameral/multicameral/latent bone cyst)

Osteoblastoma

Osteoclast-rich leiomyosarcoma: like osteoclast-rich osteosarcoma but lacks osteoid/bone

Osteoclast-rich osteosarcoma: cytological atypia, atypical mitoses, osteoid/bone

Giant cell tumour of bone (and GCT of soft tissues)

Giant cell tumour of tendon sheath/PVNS: lipid foamy M ± sparse GC. Like NOF but in synovium

Benign ﬁbrous histiocytoma (BFH)

Giant cell ﬁbroblastoma (DFSP variant with pseudovascular spaces lined by multinucleated cells)

Giant cell MFH

Giant cell reticulohistiocytoma/reticulohistiocytosis (typically ‘ground glass’ type giant cells)

Giant cell angioﬁbroma (≈ a cross between SFT and giant cell ﬁbroblastoma)

Pleomorphic lipoma/liposarcoma (typically ‘ﬂoret-like’ giant cells)

Proliferative fasciitis/myositis and ischaemic fasciitis: ganglion-like multinucleated cells

Very many other things

Bone Tumours and Tumour-Like Lesions

General Features in the Differential Diagnosis

OSTEOID COLLAGEN

FIGURE 22.1 Osteoid and collagen

Is the tumour producing osteoid or collagen? Os-

teoid forms branching microtrabeculated struc-

tures that surround individual cells and EM shows

matrix vesicles. Collagen is laid down in parallel

bands/bundles and does not completely surround

the cells (see Figure 22.1).

Immuno/stains do not help distinguish benign vs.

malignant bone-forming lesions as all osteogenic

cells have a similar phenotype and all may show

+vity for alkaline phosphatase (ALP)

Reactive soft tissue lesions: have a Hx of trauma,

grow rapidly, show many mitoses (of normal mor-

phology), have tissue culture-type myoﬁbroblasts

and some attempt at zonal maturation

Reactive bone shows:  osteoblastic rimming (single layer continuous lining of activeosteoblasts)

 maturation of osteocytes i.e. the surface osteoblasts become smaller when

surrounded by osteoid to become internal osteocytes)

 an attempt at orderly architecture of trabeculae (esp. arches/arcades)

Malignant bone shows:  a suggestive clinical and radiological context

 no rimming and no osteoclast maturation (lacy osteoid surrounds large

malignant osteoblasts that look the same as those on the surface)

 disorderly architecture of trabeculae and no maturation to a bony shell

 invasion into and around pre-existing trabeculae of the medulla (called

‘permeation’ in the literature =‘invasion’ or ‘inﬁltration’ in this chapter)

Metastatic Tumours

Usu. multiple (but may appear solitary in early stages)

Usu. carcinomas (esp. the 5 ‘B’s: breast, bronchus, bidney, byroid and brostate)

Usu. lytic but sclerotic ones (e.g. prostate and breast) result in ↑↑ serum ALP (unlike d/dg myeloma)

Usu. in sites of haemopoietic marrow (rare in the distal limb bones): may → leukoerythroblastic PB

! May be adjacent to/mixed in with fracture callus (due to pathological fractures)

Fracture Callus

Shows features of reactive bone (vide supra) ± variable amounts of necrotic bone

Mixed chondro-osseous tissue and cartilage that is proliferativeand cellular and matures (hypertrophies)

before ossifying (i.e. looks like endochondral ossiﬁcation in a normal epiphyseal growth plate)

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Osteoarticular 333

Zonation (superﬁcial to deep): proliferating ﬁbroblasts (± ‘tissue culture’-like) → primitive bone and

cartilage → maturing woven bone. (this zonation is reversed in d/dg myositis ossiﬁcans)

Marrow spaces are vascular with proliferative ﬁbroblasts that decrease in cellularity with time

! Do not miss metastatic carcinoma cells or HX within fracture callus (is the fracture explained?)

d/dg PTFOL in the rib: but that lesion lacks osteoblastic rimming

d/dg sarcoma (more likely to be a problem with early callus lesions that are cellular with very little

bone and in callus that ‘inﬁltrates’ skeletal muscle adjacent to the fracture site):

 chondrosarcoma: endochondral-type maturing ossiﬁcation is not seen in chondrosarcoma

 osteosarcoma: callus lacks atypia (of cells and mitoses), soft-tissue tumour necrosis and fea-

tures of malignant bone (see p. 332). The ‘marrow spaces’ in osteosarcoma may be ﬁlled with

malig. cells

Myositis Ossiﬁcans

See d/dg under Osteosarcoma (p. 337); see also p. 309.

Bizarre Parosteal Osteochondromatous Proliferation (BPOP)

Usu. under the periosteum in the tubular bones of the hands and feet (rarely other limb bones)

Marrow spaces are packed with spindle ± ‘tissue culture’-like cells

Irregular islands of basophilic chondroid showing irregular (but endochondral-type) ossiﬁcation

Highly cellular and irregular cartilage cap with plump nuclei and binucleate forms

d/dg subungual exostosis is a similar condition but affects the distal phalanges (unlike BPOP)

d/dg osteosarcoma: wrong site and no cytological atypia in the spindle cells

d/dg chondrosarcoma ex ecchondroma: wrong site and no continuity of marrow space with underlying

bone

Cysts in Bone

Solitary bone cyst (simple / unicameral / multicameral / latent bone cyst)

Radiol: lucent cyst abuts the diaphyseal surface of the physis in children but may grow away from it to

become detached in the diaphysis (= latent cyst). Cortical thinning → pathological fracture

Macro: trabeculated lining; may be unilocular (unicameral) or have dividing septa (= multicameral)

Uncomplicated: ﬁbrous lining with no or clear ﬂuid contents ± ﬁbrin deposits (may mineralise)

± Osteoclasts (i.e. giant cells), haemosiderin, foamy M, granulation tissue and fracture callus

◦

sarcomatous change is case-report-rare

d/dg ABC (esp. in any bridging septa)

d/dg cementoma (due to the mineralising ﬁbrinoid)

Aneurysmal bone cyst (ABC)

Radiol: lytic, eccentric ‘blowout’ lesions; macro: partly solid with cavernous blood-ﬁlled spaces

Cellular mitotic ﬁbrous tissue, giant cells, haemosiderin but no necrosis unless pathological #

Woven bone (parallel to septa) ± calciﬁed chondroid ‘blue bone’ (a useful feature if present)

d/dg must exclude an underlying lesion (see ‘Giant Cell Rich Lesions’, pp. 331–332)

d/dg: solid ABC vs. GCT of bone: ABC contains woven bone/chondroid, has an irreg. distribution of

giant cells, the mononuclear cells are spindled (ﬁbrous tissue) and the site may be unusual for GCT

d/dg telangiectatic osteosarcoma (has cytological atypia, abnormal mitoses ± tumour necrosis) and

low grade osteosarcoma (are less cellular/mitotic)

d/dg giant cell reparative granuloma: ABC is a related entity .

. use CPC

d/dg solitary bone cyst: may be impossible by histology esp. in complicated multicameral cases

Other cysts

Epidermoid, intraosseous ganglion (called subchondral cyst if below joint cartilage), hydatid, etc.

Mesenchymal Hamartoma of the Lateral Chest Wall (Mesenchymoma) in Infants

Like osteo/chondroblastoma plus lobules of cartilage

mitoses, haemorrhage, vasc. spaces ± ABC-like areas

d/dg: osteosarcoma has features of malignancy (p. 332) and has different site and age distribution

d/dg mesenchymal chondrosarcoma (p. 339)

Eosinophil Granuloma (Histiocytosis X)

Radiol: well-deﬁned lytic lesion in a child ± periosteal reaction (d/dg osteomyelitis/Ewing’s)

Histology of HX (see pp. 57–58)

d/dg osteomyelitis: Langerhans cells and unusual sites (e.g. skull) favour HX

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Osteoarticular 334

Metaphyseal Fibrous Defect (Non-Ossifying Fibroma, Fibrous Cortical Defect or just ‘Fibroma’)

Radiol: eccentric, scalloped lesion in the cortex (MFD) or cortex and medulla (NOF) of a youth. Regress

± Jaffe-Campanacci syndrome:

◦

polyostotic NOF,

◦

skin pigmentat

◦

endocrine/mental defects

(may also have giant cell reparative granuloma(s) of the jaws); d/dg NF-1 may also show

◦

and

◦

Fibrosis (cellular, proliferative, ± storiform but no cytological atypia), haemosiderin ± siderophages

Lipid foamy cell nests ± cholesterol clefts (called xanthoﬁbroma

if prominent)

d/dg GCT: NOF osteoclast giant cells are fewer and less nucleate and it doesn’t extend to joint surface

d/dg periosteal desmoid of the distal femur: ≈ NOF but less cellular. Requires no Rx – ! do not confuse

with d/dg desmoplastic ﬁbroma (a locally aggressive intraosseous desmoid tumour that lacks giant

cells and osseous metaplasia and shows spindle collagenous fascicles without the cytological atypia,

hypercellularity and ↑ mitoses of ﬁbrosarcoma or leiomyosarcoma – see Chapter 21: Soft Tissues)

d/dg metastatic RCC vs. foam cell nests

d/dg: BFH (rare): similar histology but bigger tumour in older patients ± at site not typical for NOF

d/dg xanthomatous PTFOL: xanthoﬁbroma has giant cells and lacks woven-to-lamellar zonation

Fibrous Dysplasia (FD)

Radiol: well-deﬁned ‘ground glass’ lesion typically in ribs, long bones, skull of a child/young adult

± Albright’s syndrome =

◦

polyostotic FD,

◦

patchy pigmentation and

◦

precocious puberty

Woven bone (in ‘lobster claw’, ‘Chinese character’ or psammoma-body-like conﬁgurations)

The bone is metaplastic i.e. directly formed from ﬁbrous tissue (no surface osteoblasts)

The ﬁbrous tissue has a ‘patternless pattern’ (± focal storiform areas) of bland stubby spindle cells

Nodules of cartilage ± myxoid foci (! do not misdiagnose as d/dg chondromyxoid ﬁbroma)

d/dg parosteal osteosarcoma (q.v.): if the lesion is on the bone (cf. in it) consider parosteal osteosarcoma

d/dg ﬁbrous dysplasia-like osteosarcoma (q.v.): this shows inﬁltration around pre-existent normal tra-

beculae

d/dg osteoﬁbrous dysplasia and adamantinoma (q.v.)

Osteoﬁbrous Dysplasia (Ossifying Fibroma)

Inﬁltrates cortex of long bones in children (usu. ≤10 years old)

Osteoblast-formed (± rimmed) bone at the periphery, metaplastic bone at centre

More aggressive cf. FD (may be a variant of adamantinoma – they share similar sites and radiol.)

Immuno: may have single CK +ve cells .

. this alone is insufﬁcient to diagnose d/dg adamantinoma

d/dg adamantinoma: always search for epithelial strands and nests if an adult presents with FD or

osteoﬁbrous dysplasia

Post-traumatic Fibro-osseous Lesion (PTFOL) of the Rib

Zonally maturing lace-like bone (woven centrally, lamellar peripherally), osteoblasts are few/absent

Stroma is bland, amitotic and vascular ± central sheet of xanthomatous cells

d/dg: FD (lacks woven-to-lamellar zonation, xanthoma cells are not in sheets and trabeculae have typical

slender shapes – vide supra)

d/dg osteoid osteoma: this has osteoblast rimming – not seen in PTFOL

Osteoma

A hamartomatoid/reactive outgrowth of bland lamellar bone that may be cortical +/ cancellous

Usu. in the skull, jaws, sinuses and may be part of Gardner’s syndrome. They are very rare

d/dg bone island is an intramedullary focus of cortical-type bone (called osteopoikilosis if multiple)

d/dg reactive osteosclerosis: can be indistinguishable microscopically

Osteoid Osteoma

Clin.: pain relieved by aspirin; radiol: lucent ‘nidus’ ± surrounding sclerosis (d/dg Brodie’s abscess)

Macro: nidus is red and granular and usu. <1.5cm  ; specimen radiographs may help locate it

Nidus: irregular, cellular (usu. small) trabeculae of osteoid, variable mineralisation to woven bone, focal

osteoblastic rimming ± crenated (Pagetoid) cement lines. No cartilage (unless fracture callus).

Other: surrounding osteosclerosis (thick trabeculae/cortex); RhA-like inﬂam

synovitis (if near a joint)

d/dg osteoblastoma: if histology overlaps, use arbitrary size cut-off (>1.5 cm  = osteoblastoma)

d/dg osteosarcoma (see ‘Osteoblastoma Family of Lesions’, below)

xanthomatous change in bone is ≈ always a 2

◦

change .

. if you want to call something a ‘xanthoma’ look for the underlying lesion

e.g. NOF, BFH, ABC, simple cyst, or whatever

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Osteoarticular 335

Osteoblastoma Family of Lesions

cf. osteoid osteoma these are larger (usu. >2cm), more often axial and don’t have the typical radiol.

At the margin it merges with the non-lesional bone – but does not inﬁltrate into its marrow spaces

d/dg usual-type osteosarcoma:

 lack of invasiveness (into surrounding bone or soft tissues)

 lack of cartilage (unless related to fracture callus)

 rim of osteosclerosis, when present, favours osteoblastoma

 solid sheets of cells (without matrix) favours malignancy

Benign osteoblastoma

cf. osteoid osteoma these have a more open trabecular pattern and are more vascular

The surrounding bone is normal or only slightly sclerotic

Pseudomalignant osteoblastoma

Plump osteoblasts with ancient change (large nuclei with smudged, Arias-Stella-like, chromatin)

Aggressive osteoblastoma (= Malignant osteoblastoma)

Large (epithelioid) osteoblasts, ↑ cellularity, ↑mitoses, ↑peripheral osteosclerosis, basophilic spicules

ABC-like foci are more likely. They are locally recurrent but not metastatic

Osteoblastoma-like osteosarcoma

Like osteoblastoma but inﬁltrates adjacent pre-existing normal bone trabeculae. Mets occur

Adamantinoma

Usu. in the upper tibia of a young adult. Blood and lymphatic mets may occur eventually

Osteoﬁbrous dysplasia-like with islands/strands of epithelium (occ. spindled), keratin is unusual

Epithelium may have peripheral palisading and central stellate reticulum (like ameloblastoma)

d/dg metastasis: site (mets are rare distal to elbow/knee), epithelium not dysplastic or keratinising

Giant Cell Tumour of Bone (and Giant Cell Tumour of Soft Tissues)

Spans epiphyseal line to include epiphysis; rare in immature skeleton; ≈ never centred in diaphysis

GCT in the jaw or tubular bones of hands and feet and multiple GCT can happen, but is very rare (think

d/dg brown tumour of ↑ PTH [p. 330] or GC reparative granuloma [p. 331])

Uniform distribution of giant cells – but giant cells may be sparse

Ovoid bland mononuclear cells have similar nuclei to giant cells and mitoses (not atypical): these are

the neoplastic cells (= inactive osteoblasts), they recruit and activate the osteoclast giant cells

Immuno: mononuclear cells are vimentin and 

AT +ve, S100 −ve

Stroma: vascular ± vasc. invasion (! does not imply malignancy), ± haemorrhage, necrosis and foam

cells

Typically, no collagen (or other matrix) is produced by tumour cells: these typical features must be seen

in substantial areas of a tumour to call it GCT, however there may be foci of osteoid or ﬁbrogenesis and

NOF-like areas with spindled mononuclear cells can be seen – esp. at the periphery

Cartilage (non-callus) suggests d/dg chondroblastoma (if well diff) or osteosarcoma (if chondroid)

Variant: GCT of soft tissues (same histology but rare, occurs in elderly and is centred in soft tissues)

Grade ∝ n˜o of mitoses and n˜o of giant cells but is not considered clinically useful

Metastasis of a typical GCT (i.e. the mets also look like typical GCT):

 this is called ‘metastatic GCT’ (not ‘malignant GCT’ – vide infra)

 if multiple mets consider mis-diagnosis (e.g. it may be a GC-rich osteosarcoma)

Malignancy in a GCT =a frank high grade sarcoma (usu. osteosarcoma, ﬁbrosarcoma or MFH) arising:

 in a typical GCT at 1

presentation (= ‘1

◦

malignant GCT’), or

 as a recurrence after surgery/radiotherapy

d/dg osteosarcoma can be difﬁcult unless: there is cytological atypia, it arises in the immature skeleton,

it does not span the epiphysis, there is malignant bone and typical radiol., it shows soft tissue inﬁltration

(NB benign GCT may extend into soft tissue but has a well-deﬁned outline. It is also well-deﬁned within

the medullary cavity)

d/dg ABC (p. 333) and other ‘Giant Cell Rich Lesions’ (pp. 331–332)

Ewing’s Sarcoma

See also p. 58.

Clin. (fever, ↑WCC and ESR), radiol (‘moth-eaten’, ‘onion skin’) and macro (≈pus) d/dg osteomyelitis

SBRCT, indistinct cell borders (syncytial) and bubbly cytoplasm (glycogen), few mitoses

Atypical (large cell) Ewing’s: prom. nucleoli, larger cells and mitoses ++ (but prog. is no different)

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Osteoarticular 336

Cytogenetics: PNET t(11;22)(q24;p12)(FLI1;EWS) – unlike d/dg DSRCT (see p. 58)

Immuno: CD99 +ve (membranous), vimentin +ve (dot-like, at least focally), Fli-1 +ve in 75% (also

in PNET and Merkel cell tumours but not other childhood-type SBRCT), S100 −ve, CK −ve

d/dg:

 osteomyelitis: it may require a thorough search to ﬁnd the Ewing’s cells amongst reactive

changes of necrotic bone, marrow ﬁbrosis and mixed inﬂam

 EM shows no speciﬁc organelles in Ewing’s: d/dg NB (dense core neurosecretory granules),

carcinomas (tight junctions), RMS (sarcomeres), lymphomas (absence of glycogen)

 lymphoma: Ewing’s is glycogen +ve and LCA −ve with little intercellular reticulin

 metastatic neuroblastoma – but neuroblastoma has ↑ urinary catecholamines, ﬁbrillary tissue

± ganglion cells and is NB84 +ve and ≈ always CD99 −ve

 PNET and Askin are different differentiation variants of the same entity – see p. 58

 small cell osteosarcoma / mesenchymal chondrosarcoma: presence of matrix (e.g. osteoid)

excludes Ewing’s

 other: true (cf. artefactual) nuclear spindling excludes Ewing’s

Prog.:  worse if: systemic Sx, axial site, large tumour bulk (esp. soft tissue extension)

 better in tumours with exon 6/7 variant of t(11;22)

Osteosarcoma

Clin.: usu. arise in metaphysis in immature skeleton or 2

◦

to Paget’s disease/radiation. Serum ALP is

prognostic

Macro: assess tumour size, local spread (esp. if through the periosteum into soft tissue – e.g. inﬁltration

of skeletal muscle on Bx samples), skip lesions (intra-osseous mets) and % non-viable tumour (=

necrotic + severest form of chemoRx damage)

after chemoRx

Pleomorphic spindle cells (ALP +ve) producing lacy (often basophilic) osteoid/chondroid/cartilage

with features of malignancy (see ‘General Features in the Differential Diagnosis’ p. 332)

Immuno: vimentin +ve, c-erbB-2 (HER2) ±ve, SMA ±ve, membranous CD99 ±ve, S100 +ve in

chondroid areas, CD56 ±ve

Grade is determined by histological type: high grade (most types of central osteosarcoma and juxta-

cortical osteosarcoma), intermediate grade (periosteal), low grade (parosteal, osteoblastoma-like and

FD-like)

Imprint cytology: many pleomorphic cells strongly +ve for cytoplasmic ALP granules in the cor-

rect clinicoradiological setting is diagnostic even if no osteoid/bone on Bx (but ! must exclude d/dg

angiosarcoma/other endothelial tumour because endothelial cells are also ALP +ve)

d/dg: other lesions have ALP +ve cells but are not pleom. (e.g. ABC) or only a small subset stain

(e.g. GCT). Also, differentiating reactive callus or osteoblastoma from low grade osteosarcoma may

not be possible, so if the cells are not pleom. you cannot make a benign diagnosis using ALP

imprints

d/dg osteosarcomatous component of a de-differentiated chondrosarcoma (q.v.)

d/dg 1

◦

or 2

◦

leiomyosarcoma: may be a problem in recurrent/metastatic osteosarcoma that shows

spindle cells but no matrix because both are SMA +ve. ALP should still be +ve in osteosarcoma

(unless anaplastic)

Central osteosarcoma (Medullary osteosarcoma)

Mixed osteosarcoma is the usual type and has osteoblastic, chondroblastic and ﬁbroblastic foci

The more the chondroblastic differentiation, the worse the response to chemoRx .

. estimate % chon-

droblastic

Variants:

 Fibroblastic: predominantly ﬁbrous matrix. d/dg ﬁbrosarcoma/MFH rests on ALP +vity and

CPC

 Chondroblastic: predominantly

◦

lobules malignant cartilage and

◦

peripheral spindle cells

±focal osteoid (usu. at the interface between the two). d/dg chondrosarcoma: ALP +ve cells,

young age with lack of pre-disposing lesion and evidence of rapid growth (incl. no scalloping

or buttressing on radiol) all favour osteosarcoma.

 Osteoblastic: predominant matrix is osteoid/bone. Osteoblastoma-like osteosarcoma is a low

grade variant of this and is discussed above under d/dg osteoblastoma (p.335)

may require use of prolif

marker immuno; >90–95% non-viable tumour = good prognosis

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Osteoarticular 337

 Central low grade (= ﬁbrous dysplasia-like): inﬁltrates around pre-existing trabeculae of

bone and does not have typical ‘lobster-claw’ trabeculae or ‘ground glass’ radiol of d/dg

FD. Pleomorphism is mild and there may be maturation of the bone as in parosteal

osteosarcoma

 Small cell – like d/dg atypical Ewing’s but with matrix and ALP +ve (! ± CD99 +ve) cells.

d/dg mesenchymal chondrosarcoma: this has well-developed lobules of cartilage and any bone

is formed by ossiﬁcation of the cartilage (not by malignant cells as in osteosarcoma)

 Telangiectatic: like d/dg ABC but with pleomorphic cells, mitoses ++ and invasion

 Giant cell-rich (Osteoclast-rich): def

: >50% of the tumour must have many benign GC

admixed with malignant bone-forming cells. This is very rare. (see also d/dg GCT of

Bone, p. 335)

 Epithelioid: d/dg carcinomas: use ALP and immuno (one instance where immuno is

helpful)

 Anaplastic: may be ALP −ve .

. need focal evidence of typical osteosarcoma +/ typical CPC

High grade surface osteosarcoma (Juxta-cortical osteosarcoma)

A rare tumour with similar histology and prog. (or worse) cf. high grade central osteosarcoma

Parosteal osteosarcoma

Lobulated, ﬁrm tumour usu. on posterior surface of (± invasion into) the diaphysis of long bones

Superﬁcially: spindle cells (producing collagen, atypia is minimal) and chondroid areas

Mid-to-deep: bone trabeculae (woven and metaplastic-like) mature towards the host bone cortex (where

it may even form lamellar bone and may show signs of remodelling into parallel arrays)

May have de-differentiated foci which worsens the prognosis .

. sample well.

d/dg:  osteochondroma, but  no continuity with the medulla of the bone via a ‘cortical

gap’

 ‘marrow’ spaces are solid spindles not fatty/haemopoietic

 myositis ossiﬁcans, but  opposite zonation (spindles and cartilage superﬁcial, bone

deep)

 no osteoblastic rimming of trabeculae in osteosarcoma

 the spindle cells are ﬁbrogenic in osteosarcoma

 no ‘air gap’ sign on X-ray (see Figure 21.1, p. 309)

 ﬁbrous dysplasia, but  site: this osteosarcoma is on the bone, FD is within it

Periosteal osteosarcoma

Peripheral spindling of mod. pleom. malig. cells, slit-like vascular spaces and soft tissue invasion (these

spindle cells may form ‘arcades’ ! not to be confused with arcades of osteoid/bone in callus)

Centrally there is malig. chondroid lobules with central maturation, calciﬁcation ± ossiﬁcation

Osteoid streamers may rise perpendicular to the surface of the host bone

Macro involvement of the medulla should prompt a re-think to medullary chondroblastic osteosarcoma

d/dg chondrosarcoma: osteosarcoma cells are ALP +ve, also see under chondroblastic osteosarcoma,

p. 336

Extraosseous osteosarcoma

Usu. in the elderly, in the stroma of a malig. phyllodes tumour or rarely as a 1

◦

in other soft tissues

d/dg mixed mesenchymoma (= any combination of ≥2 of osteosarcoma, RMS, liposarcoma without

MPNST)

d/dg myositis ossiﬁcans: the zonation is reversed and the bone is malignant (see p. 332 and p. 309)

Ecchondroma (Osteochondroma/Osteocartilagenous Exostosis)

Pedunculated or sessile cartilage-capped bony outgrowth starts at the physis and migrates down the

bone, growth stops at skeletal maturity

May be multiple (= diaphyseal aclasis / HME and this has an increased risk of chondrosarcoma)

Stalk: cortex and medulla (contains fatty/red marrow ±cartilage islands) of the exostosis is continuous

with the cortex and medulla of the host bone (in radiology this medullary junction is described as the

‘cortical gap’)

Cap: hyaline cartilage covered by perichondrium, <1cm thick in adults and shows endochondral ossi-

ﬁcation

◦

chondrosarcoma (usu. low grade): esp. if axial/proximal site, rapid/resumed growth or pain without

fracture/bursa

d/dg parosteal osteosarcoma (vide supra), BPOP and subungual exostosis (see under BPOP p. 333)

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Osteoarticular 338

Enchondroma

Benign cartilage tumour centred in the medulla, often in the tubular bones of the hands and feet

Multiple enchondromatosis: if predominantly unilateral = Ollier’s disease; if bilateral + spindle cell

haemangiomas = Maffucci’s syndrome (has ↑ risk of 2

◦

chondrosarcoma and 1

◦

visceral neoplasms)

Typically: solid hyaline matrix without myxoid degeneration, hypocellular, vague clusters of small cells

with small single nuclei, lobular arch. ± a peripheral rim of bone

Arch.: fused lobules ± separate lobules at periphery surrounded by marrow (does not imply invasion)

If multiple or in hands and feet may be ↑ cellular with binucleation ± myxoid (micro) but no invasion

May de-differentiate (see ‘Chondrosarcoma’) .

. prophylactic surgery or F/U may be indicated in the

elderly

d/dg chondrosarcoma (or 2

◦

chondrosarcoma change): microscopic invasion (‘permeation’ – for deﬁ-

nition, see ‘Chondrosarcoma’, below) and macroscopic myxoid change (if high grade) and CPC/radiol.

Periosteal Chondroma

Well circ., small chondroid lesion on the surface of tubular bones (rare in hands and feet)

Causes scalloping erosion of the cortex (‘saucerisation’) but are not inﬁltrative

Very cellular with binucleate and hyperchromatic cells

d/dg chondrosarcoma: small size and circumscription

Soft Tissue Chondroma

(Multi-)lobulated, non-invasive, cellular hyaline cartilage lesions in the soft tissues of the hands and

feet. See also ‘Synovial Chondromatosis’ on p. 341

Chondroblastoma

Centred in epiphysis (or a 2

◦

ossiﬁcation centre) of long bones; may give rise to benign metastases

Polygonal cells with well-deﬁned cytoplasm (pale) and oval nuclei (± grooves and small nucleoli);

generally bland but with ‘random’ atypia; mitoses are present but not numerous; scattered giant cells

Chondroid ± honeycomb pericellular calciﬁcation in a ‘chicken-wire’, ‘lace-like’ or ‘pepper-like’

pattern (may be recapitulated on a retic stain in decalciﬁed preparations) ±fragments of normal physis.

No intercellular matrix (other than the chondroid) ± coagulative necrosis in the mineralised areas

GC nuclei are similar to polygonal cells’ nuclei

Immuno: +ve for vimentin and S100; ±ve for CK, SMA, EMA

d/dg: may have ABC-like areas .

. see ABC, GCT of bone and ‘Giant Cell Rich Lesions’, above

d/dg chondromyxoid ﬁbroma (site and cytology) and clear cell chondrosarcoma (cytology, invasion,

CPC)

d/dg osteosarcoma is invasive with pleom. cells and lacy mineralisation of osteoid (cf. honeycomb

pericellular mineralisation of chondroid matrix)

Chondromyxoid Fibroma

Metaphysis, similar age group to chondroblastoma (i.e. usu. teens or 20s)

Chondroid, myxoid or ﬁbrous lobules (more cellular at the periphery) separated by ﬁbrous septa

Cells are stellate, ovoid or spindled with nuclei of various shapes ± focal worrisome anisonucleosis

Septa are vascular, cellular ± giant cells, ABC-like areas +/ osteoid

Immuno: S100 +ve (may help if chondroid differentiation is not obvious)

d/dg chondroblastoma: some foci may be similar but site and presence of other features help

d/dg chondrosarcoma, esp. grade 2 (myxoid): age, lack of invasion and constellation of features above

Chondrosarcoma

Clin.: usu. in proximal/axial skeleton of old people (unless 2

◦

– usu. to ecchondroma/enchondroma)

Radiol.: shows evidence of slow erosive growth (cortical erosion and buttressing)

Macro: lobules of chondroid with central coalescence ± myxoid/cystic degeneration, necrosis, Ca

Micro: wide sampling is important to ensure conﬁdent diagnosis and grading

Malig. cells produce hyaline chondroid matrix ± central necrosis/Ca

± periph. ﬁbrosis/benign bone

(any malig. bone, not part of a separate de-diff area, should change the diagnosis to osteosarcoma)

Cytological atypia = plump nuclei in many cells (with more than occ. binucleate forms) and giant

chondrocytes (with ≥1 large nuclei ± chromatin clumps)