ASCP SOFT TISSUE

List the WHO 2002 benign lipomatous tumors

• Lipoma
• Lipoblastoma (septated, myxoid background); fetal version of benign fatty tumor/lipoma
• Angiolipoma- often painful
• Myolipoma- smooth muscle and fat
• Chondroid lipoma (rare)
• Angiomyolipoma- in PEComa family, commonly kidney, but in many locations; a/w tuberous sclerosis
• Myelolipoma
• hibernoma (uncommon)
• Spindle cell/pleomorphic lipoma (often confused with malignant ST tumors)

**Malignant- but lipomatous tumors of intermediate malignancy (low-grade)=

• **Atypical lipomatous tumor=Well-differentiated liposarcoma- high propensity for local recurrence, rarely mets

ASCP SOFT TISSUE

This lesion had areas that looked like both of these pics (same tumor)- what is it?

[image]

[image]

ANSWER: Intramuscular lipoma

-benign lipomatous tumor.  The second picture represents atrophic skeletal muscle fibers- not pleomorphic malignant nuclei and do NOT represent transformation.

Intramuscular lipomas are always benign- but b/c they are often deeply located (in deep muscles of extremities), they clinically are confused with malignancy.

ASCP SOFT TISSUE

What is the entity in the picture?

[image]

ANSWER: Hibernoma; or lipoma with hibernomatous change

*don't confuse these with lipoblasts!

ASCP SOFT TISSUE

What entity is in the picture?  What is another growth pattern; what IHC stain is differentiating ftom other ST tumors of this kind?

[image]

ANSWER: angiomyolipoma

in the PEComa family of tumors (Perivascular epithelioid cell)

-coexpress smooth muscle and melanocytic markers (+HMB-45 and/or others)

Another growth pattern is solid- which is quite cellular, without significant fat cells and confused with more malignant entities:

[image]-retains bland perivascular epithelioid cells; and +HMB-45 (and possibly other melanocytic markers) as well as smooth muscle markers (SMA, desmin, etc)

ASCP SOFT TISSUE

A well-circumscribed mass is excised and shown in the pictures- what is the entity and what are characteristic features

[image]

[image]

ANSWER: pleomorphic lipoma

*benign lesion- M>F; usually older (median 60 yrs); commonly shoulders/back/neck!; no recurrence or mets

-well-circumscribed; varying degrees of fat (may have very little); mostly composed of fibroblastic cells- with **Ropey collagen bundles!**- which are NOT seen in atypical lipomatous tumors/WDL

*Also commonly have floret type giant cells- which are characteristic, but not pathognomonic (may be seen in other tumors)

[image]

-the large pleomorphic cells are +CD34 (but so are ATL/WDL- so not very useful)

ASCP SOFT TISSUE

What entity is identified in the pictures, malignant or benign? and what characteristic signals benignity or malignancy?

[image]

[image]

ANSWER: Spindle cell lipoma

-BENIGN; contains bland cells,with **Ropey collagen bundles** (just as with pleomorphic lipoma- and actually, molecularly these entities are related/the same)

-also presents as well-circumscribed mass of the shoulder, neck or upper back; with striking male predominance

-also CD34 +

-A/w del(16q) or del(13q)

(NO MDM2 amplification)

*and the main distinguishing characteristic from a malignant fibrous proliferation is the diffuse strong CD34 positivity

(whereas malignant tumors, though often CD34+ will be more patchy-weak)

[image]

ASCP SOFT TISSUE

What entity is in the pictures?

-what is a defining feature

[image]

[image]

ANSWER: Atypical Lipomatous tumor/Well-differentiated liposarcoma

*grade 1/3 sarcoma, with local recurrence and low risk of mets (unless de-differentiates)

-Consists of bland fat with thickened, dense fibrous septa- which contain dark cells in the fibrous septa

*also don't look for lipoblasts!

[image]

-B/c, benign entities will have lipoblasts.

-often need molecular proof- MDM2 amplification- nearly 100% S/S for differentiating malignant (ATL/WDL) from benign (lipomas)- test with FISH (12q)

-clinical- if completely excised-- cured!

-if incompletely excised- may recur, then progress to de-differentiated higher grade sarcoma- and then have metastatic capability

ASCP SOFT TISSUE

What structures are shown in the picture and what are they a/w?

[image]

left arrow= ring chromosome

right arrow= giant marker chromosome

Both are chromosomes with extra material from long arm of chr12 (12q)

-invariably these structures are found in ATL/WDL

-lead to amplification of several genes in this region- most notably and tested for is MDM2

-(other genes= CDK4)

ASCP SOFT TISSUE

List the benign and malignant myxoid soft tissue lesions

• BENIGN:
• Nodular fasciitis (some growth patterns)
• Myxoma (MC)
• intramuscular
• juxta-articular
• cutaneous
• Nerve sheath tumors
• neurofibroma
• neurothekeoma
• schwannoma

• MALIGNANT:
• Myxoid liposarcoma
• Myxofibrosarcoma (formerly myxoid-MFH)
• Myxoid chrondrosarcoma
• Low-grade fibromyxoid sarcoma (aka Evan's tumor)
• many other sarcomas can show focal myxoid features

ASCP SOFT TISSUE

what is the lesion shown; one distinguishing morphologic feature

[image]

ANSWER: Myxoma

-usually a large, deep-seated mass in older woman

-Distinguishing morphologic feature= scarcity/abscence of blood vessels- only scattered capillaries in loose myxoid matrix

-malignant myxoid lesions have prominent vasculature

-the myxoid matrix is almost always hyaluronic acid

(others= chondroitin sulfate)

Molecular: activating Gsα mutations

ASCP SOFT TISSUE

Name the entity in the picture and what is its most distinguishing feature

[image]

ANSWER: Myxofibrosarcoma

-formerly known as: Myxoid-MFH

-most distinguishing histologic feature= chicken-wire vasculature

+hyperchromatic, atypical large cells

-has no characteristic molecular abnormalities

ASCP SOFT TISSUE

what is the entity in the picture and its main DDx

[image]

ANSWER: Extraskeletal myxoid chondrosarcoma

-chord-like architecture; similar to chordoma (but different location)- located deep extremities

-main DDx: myoepithelioma, which will be cytokeratin+

Molecular: most common= t(9;22)(q22;q12)

-NR4A3/EWS

alternative (t(9;17)(q22;q11)= NR4A3/TAF2N

ASCP SOFT TISSUE

What is the most likely diagnosis?

-what is the de-differentiated form, usual location; age consideration

-histologic patterns within same tumor and what is the typical pattern at the edges

[image]

[image]

ANSWER: Myxoid Liposarcoma

-relatively common= second most common type of liposarc (after ATL/WDL)

-most commonly located in extremities- thigh, popliteal fossa; almost NEVER in retroperitoneum- in this location is much more likely to be ATL/WDL

-in children- a lesion that looks like this is= lipoblastoma- a benign entity

-bland cells; grd 1/3; +/- lipoblasts- but finding them here (in myxoid matrix) is helpful to dx, so LOOK for them here.  +chicken-wire, think branching vasculature

[image]

-frequently show cystic areas- filled with amorphous light blue/purple material

[image]

-At the edges of the lesion- typically show hypercellularity with rounder, more plump cells; try to ignore, focus on the center of lesion; this findings does not indicate transformation

-these tumors are on the spectrum with and typically de-differentiate into Round cell liposarcoma= high grade (grade 3/3)

[image]

-Molecular: Most common= t(12;16)(q13;p11)= DDIT3 (aka CHOP)/FUS- better prognosis

-alternative= t(12;22)(q13;q12)= DDIT3/EWS- bad prog

*FISH for abnormal/breakapart 12q13 (DDIT3, aka CHOP)

ASCP SOFT TISSUE

What is the most likely diagnosis of this tumor

-distinguishing histologic features; molecular abnormalities

[image]

ANSWER: Low grade fibromyxoid sarcoma (aka Evan's tumor)

-NOT to be confused with myxofibrosarcoma, a different entity

-looks very bland/benign; histology- alternating fibrous and myxoid stroma with abrupt change; and elaborate vasculature/thickened- in myxoid stroma; and perivascular collagen rosettes

-Molecular: t(7;16)(q33;p11)= CREBL2/FUS

-alternative: t(11;16)(p11;p11)= CREB3L1/FUS

*both involve 16p11= FUS gene

*NO mutation of DDIT3

ASCP SOFT TISSUE

what is the most likely diagnosis and why

[image]

ASNWER: leiomyosarcoma

-highly pleomorphic, atypical, hyperchromatic cells; with fibrillar eosinophilic background

-IHC:+ for desmin, h-caldesmin, SMA

-may have more bland/leiomyoma-like areas, especially at periphery.

ASCP SOFT TISSUE

list the pleomorphic sarcomas with differentiation and what is used to identify them

• Pleomorphic liposarcoma- find pleomorphic lipoblasts

• Pleomorphic MPNST- nerve origin; arise from neurofibroma, S-100+ in NF, but may be (-) in MPNST- so is essentially useless; dx of exclusion

• Pleomorphic leiomyosarcoma- diffuse SMA/MSA/desmin or h-caldesmin

• Pleomorphic rhabdomyosarcoma- rare, large pleomorphic, rhabdoid cells; skeletal muscle markers (=myogenin is the best)

• Extraskeletal osteosarcoma- uncommon, has malignant osteoid/bone formation

ASCP SOFT TISSUE

List the pseudosarcomas with MFH-like pattern and how to identify

• Sarcomatoid carcinoma-  use multiple cytokeratins (will often be negative for some), most commonly from SCC (use CK 5/6, or p63)
• Sarcomatoid mesothelioma-  CAM 5.2 (LMW ck)
• Melanoma-  S-100, (+/- melanocytic markers)
• Anaplastic lymphoma (ALK-1, CD30)

ASCP SOFT TISSUE

What is the most likely diagnosis?

-what is the growth architecture described as?

-list the 3 varied clinical growth patterns; histology findings and clinical features

[image]

[image]

ANSWER: Nodular fasciitis

-described as "tissue culture" growth architecture; composed of bland cells, with open chormatin, small nucleoli (=myofibroblasts)

-consists of cellular lesion with vague fascicles; and focal myxoid degeneration is almost invariably present.

-MAY have numerous mitoses, but they should not be atypical

-later lesions may have ancient/hyalinization

-IHC: diffuse SMA+ (negative for desmin!)=myofibroblasts

-clinical: peak age young (20-35); presents as RAPIDLY growing mass, at site of trauma (but may not have hx of trauma); tx with local excision only.  Even if not treated- will scar down/self-limited

Other histologic types:

• Proliferative fasciitis- similar background, with scattered large, ganglion-like cells
• [image][image]
• Ischemic fasciitis- aka atypical decubital fibroplasia, consists of zonal fibrinoid necrosis next to myofibroblastic areas with atypical/degenerating cells (smudgy nuclei)
• [image][image]

ASCP SOFT TISSUE

what is the most likely diagnosis and what stain is useful

[image]

[image][image]

ANSWER: cellular schwannoma

-highly cellular, composed almost entirely of Antoni A without verocay bodies

-encapsulated, with lymphoid aggregates in capsule; composed of bland, benign wavy schwann cells making short intersecting fascicles

-have characteristic thick walled, hyalinized bv's

-IHC: diffuse strong S-100+** (as compared to MPNST- which will be only focally S-100+)

[image]

ASCP SOFT TISSUE

what is the main ddx with this architectural pattern; IHC

[image]

What is the most likely diagnosis- same tumor both pictures

[image]

-what is a characteristic feature of this type of tumor

ANSWER: Malignant Peripheral Nerve Sheath tumor (MPNST)

-Marbled growth pattern- main DDx= MPNST and monophasic synovial sarcoma

-however, by the second picture- see classic schwann cells, with wavy nuclei- however are more hyperchromatic, with nucleoli (compared to cellular schwannoma)

-S-100 will be patchy + at best (sometimes completely negative)- can differentiate from cellular schwannoma

-A characteristic fx- often undergo focal divergent differentiation, most commonly rhabdoid and the rhabdoid cells will be focally desmin +

[image][image]

-of MPNSTs: 50% are in pts with NF-1

-earlier age

-M>F

-central>extremity

[5% of pts with NF-1 will develop MPNST]

-MPNSTs develop from neurofibromas

CLinically indicated by pain or sudden enlargement of a neurofibroma

ASCP SOFT TISSUE

What is the diagnosis?

[image]

ANSWER: biphasic synovial sarcoma

-rare entity; sarcomatous spindle backgorund, with gland-like spaces

ASCP SOFT TISSUE

what is the most likely diagnosis (same tumor both pictures)

[image]

[image]

ANSWER: monophasic synovial sarcoma

-4 identified patterns of synovial sarcoma: (a) Biphasic; (b) Monophasic- fibrous (by far the most common); (c) monophasic-epithelioid (extremely rare); (d) Poorly differentiated (when the other subtypes de-diff to high-grade)

-histologically- have the same "marbled" pattern as MPNST, with small bland spindle cells; commonly has dense collagen and even ossification (not generally seen in other sarcomas)

[image]

-may have hemangiopericytoma-like pattern (focally)-[image]

-and rarely have epithelioid pattern, with plump cells, which may eve be CK+

[image]

-usually young (med age 26 yrs)

-M>F

-often palpable, PAINFUL, deep-seated

-MC- lower extremities; but found everywhere

-RARELY within joint cavities

-A helpful IHC to differentiate MSS vs MPNST:

-MSS= +CK7 and CK19

and less known but better IHC= TLE1 +in MSS only

-Molecular: t(X;18)(p11;q11)- *18q11 (formerly SYT)- now SS18 gene

-with one of three targets: SSX1 >>SSX2>SSX4

-use FISH breakapart probe for 18q11 to find all 3 translocations

ASCP SOFT TISSUE

Round cell pattern-

What is the most likely diagnosis?; -the more differentiated version?; IHC, molecular

[image]

ANSWER: Ewings/PNET

-the picture shows uniform small round blue cells, with fine chromatin, small nucleoli= classical Ewings

-the more differentiated version= Peripheral neuroectodermal tumor (PNET)-which has fibrous septae and Homer-wright rosettes (no lumen, central fibrinous core)

[image]

-IHC: CD99+ - with membranous staining, +in this family of proteins (but not as specific- also +in most T-ALL)

-Molecular: **t(11;22)(q24;q12)= FLI1/EWS is the most common; but others also involving EWS (22q12)= t(21;22) (ERG); t(7;22) (ETV); t(17;22) (FEV); t(2;22) (E1AF)

ASCP SOFT TISSUE

True or False.

Abnormalities of 22q12 are specific for only Ewings/PNET

FALSE

Many other tumors have translocations involving EWS gene at 22q12

• t(11;22) and t(21;22)- EWS/PNET
• t(11;22)- WT-1/EWS- in desmoplastic small round cell tumor (DSRCT)
• t(12;22)- Clear cell Sarcoma (ATF-1/EWS)
• t(9;22)- Extraskeletal myxoid Chondrosarcoma (NR4A3/EWS)
• t(2;22)- Angiomatoid fibrous histiocytoma (CREB1/EWS)

And others have mutations/translocations involving 22q12

ASCP SOFT TISSUE

What is the diagnosis?  What is the prognosis of this tumor

[image]

[image]

ANSWER: Alveolar Rhabdomyosarcoma

-one of the round cell pattern sarcomas

-most commonly, round cells with scant cytoplasm, sloughed into alveolar spaces

-CAN also be solid (2nd pic)- with nested architecture, and fibrovascular network, but cells haven't lost cell cohesions to cause alveolar pattern

-Molecular: t(2;13)(q35;q14)= PAX3/FKHR is the most common;

-less commonly- t(1;13)(q36;q14)= PAX7/FKHR

-up to 25% lack either of these translocations-however, confirmatory test with FISH for 13q14 breakapart probe is useful

*FKHR gene (13q14) is NOW known as FOXO1A)

-Must differentiate from embryonal rhabdomyosarcoma- which most commonly has spindle-ovoid cells with most fibrillary background

[image]-embryonal RMS

-However, MAY have more rounded up cells

[image]=embryonal

-IHC: all rhabdo's will be + for myogenin and MyoD1 (among other less specific muscle stains); these are the best 2 stains

-Alveolar RMS- has the worst prognosis (very poor) 

-intermediate prog= Embryonal

-Favorable= botryoid, spindle cell

ASCP SOFT TISSUE

What is the most likely diagnosis? -prognosis, IHC

[image]

[image]

ANSWER: Desmoplastic Small Round Cell Tumor (DSRCT)

-islands of small round blue cells, separated by desmoplastic stroma- often confused for metastatic carcinoma

-focally may show rhabdoid differentiation

-younger pts; M>>F; most commonly in abdominal cavity

-prognosis is POOR, but may respond to aggressive therapy (ewing's protocol)

-IHC: coexpresses MANY markers- CK's, vimentin, WT-1, Desmin, NSE and some CD99

-desmin shows characteristic perimuclear globular staining

[image]

-molecular- t(11;22)

-WT1/EWS

-can FISH with EWS 22q12 breakapart probe to confirm

LEFKOWITCH SOFT TISSUE

the soft tissue tumor with a characteristic t(9;22)(q22;q12) translocation:

-what are the genes involved, what is the product of the translocation

-what are the main ddx and differing features of each

ANSWER: Extraskeletal myxoid chondrosarcoma

-fusion of NR4A3 (9q22) with EWS (22q12)-->very different genes involved than BCR-ABL t(9;22)

-fusion product is a potent transcription activator

-other less common translocations:

  --t(9;17)(q22;q11) NR4A3:TAF2N

  --t(9;15)(q22;q21) NR4A3:TCF12

-ESMC- generally effects deep soft tissue of extremities (esp thigh), middle age; slow growing; characteristically have late metastases.  Histologically- generally low grade, only focally and weakly +S-100; EMA+, CD57+

Main DDx:

• Chordoma: intraosseous, in axial skeleton (midline), and contains physaliphorous cells [image][image].  Chordoma- coexpress cytokeratins (esp CK8 and CK19) and most diffuse S-100 than ESMC
• Mixed tumor of adnexal origin (ddx of subcutaneous variant of ESMC- which diffusely express cytokeratin and S-100; as well as myoepithelial markers -p63 and calponin

LEFKOWITCH SOFT TISSUE

Deep-seated shoulder mass in 25 yr old female, with the following histology:

[image]

ANSWER: Aggressive fibromatosis (desmoid)

-usually affect young persons (<40 yo); in deep muscles (shoulder, chest wall, UE, thigh, H&N).  F>M; non-tender

-composed of uniform spindle cells arranged in long fascicles in collagenous matrix, with long-stretched vessels

-IHC: +SMA, but only focally desmin; S-100 and CD34 -neg

-clonal process; some have trisomy 8 or 20

Main DDx:

• Fibrosarcoma- more cellular with herringbone pattern; more mitoses
• Solitary myofibromas- lesion of infants; smaller, biphasic histology with a hemangiopericytic centrally and myofibroblastic peripherally
• Smooth muscle tumors (leiomyoma, leiomyosarc)- diffuse strong + desmin, SMA, MSA, etc

LEFKOWITCH SOFT TISSUE

Nodular mass in skin of back of middle aged man, looks like:

[image][image]

ANSWER: DFSP

-slow and progressive growth; from plaque-like to nodular

-entrapment of collagen fibers, uniform fibroblasts, in monotonous storiform pattern; with checkerboard fatty infiltration

-may undergo fibrosarcomatous transformation- req's at least 1 cm or 10-30% of tumor to call transformation

-A rare variant- showing melanocytic differentiation with melanin pigment (and  +melanocyte markers) = Bednar tumor

-juvenile variant: giant cell fibroblastoma

-IHC: +CD34

-Neg: S-100, SMA, desmin, CK, EMA

-molecular: recurrent translocation=

t(17;22)(q22;q13) or ring chromosomes with material from chr 17 and 22

LEFKOWITCH SOFT TISSUE

the tumor(s) with a t(12;16)(q13;p11) translocation-

-histology description (what is the hallmark feature)

-transformation

-genes involved

-DDx

Answer: Myxoid Liposarcoma/Round cell liposarcoma

-two ends of the same spectrum of tumor a/w t(12;16)(q13;p11)= fusion of CHOP (12q13) and FUS (16p11)

(rare variant= t(12;22)-EWS:CHOP

-MLS- multinodular, abundant myxoid matrix (hyaluronic acid), small spindle cells with scatt-rare lipoblasts (univacuolated lipoblasts=hallmark of MLS; AND delicate chicken-wire vascular network is helpful); increased cellularity at periphery (is not round cell change)

-these lesions tranform to round cell sarcoma

-IHC is not helpful

-usually affects deep soft tissue of extremities (usually intramuscular)

-DDx:

• Myxoid lipoma- no lipoblasts nor chicken-wire vascular network
• Intramuscular myxoma- spindle and stellate cells, consists predominantly of myxoid matrix; sparse capillaries (no vascular network)
• Myxoid DFSP- confined to dermis/subQ; IHC- diffuse CD34+
• WDLS- typical multivacuolated lipoblasts; thickened fibrous septae, with large hyperchromatic cells, lacks the vascular network of MLS
• Lipoblastoma- lobular architecture, looks very much like MLS- BUT is ONLY is early childhood

LEFKOWITCH SOFT TISSUE

the tumor with a t(X;18)(p11;q11) translocation-

-describe histology and variants

-what genes involved

-IHC

-DDx

Answer: Synovial Sarcoma

-three (or four) histologic variants= biphasic (epithelial and spindle); monophasic (fibrous*, rarely epithelioid); pleomorphic

-well-circumscribed, originates adjacent to large joint (RARELY involves joint space)

-IHC: simple keratins+ (CK7, CK19), EMA, CD99 and Bcl-2.  Usually (-) for CD34; some cases +S-100

-Molecular: t(X;18)(p11;q11)= SYT (now SS18) (18q11) fused (most commonly) with SSX-1 or SSX2 (rarely SSX-4) all on chr X

DDx:

• the biphasic pattern can be confused with carcinomas
• Monophasic -
• hemangiopericytoma: CD34+, Neg for CK
• fibrosarcoma- neg for epithelial markers (CK, EMA)
• MPNST- originates around large nerves, commonly in a/w NF-1
• Pleomorphic- can be confused with Ewing's/PNET

LEFKOWITCH SOFT TISSUE

a young child, with a rapidly growing mass in nasal cavity with following morphology:

[image]

[image]

-other variants/types of this tumor

-describe histology, prognosis

-which type has a specific translocation and what is it?

ANSWER: Botryoid rhabdomyosarcoma

-Botryoid: resemble embryonic/fetal muscle; consists of haphazard cells, with rhabdomyoblasts and scattered "strap cells"- contain cross-striations

[image]=strap cell

-Also has a characteristic prominent submucosal layer of increased cellularity= cambium layer

-Types:

• Good prognosis:
• Botryoid- GU, retroperitoneum, H&N 
• Spindle cell- predilection for paratesticular
• both subtypes of embryonal
• Intermediate prognosis:
• Embryonal
• Poor prognosis:
• Alveolar

-RMS is the most common malignant soft tissue tumor of children

-Only one RMS has a specific translocation= alveolar,

t(2;13)(q35;q14)- most commonly= FKHR (13q14) with PAX-3 (2q35)

-less common is t(1;13)- FKHR with PAX-7 (1q36)

LEFTKOWITCH SOFT TISSUE

A young man with multiple ulcerated lesions on the forearm, histology looks like:

[image]

[image]

-most common location?; prognosis?; histologic description and variants

-IHC; DDx

Answer: Epithelioid Sarcoma

-most common sites= fingers, hands, forearms (usually presents distal extremities

-intermediated prognosis, typically have late metastases; 5-yr survival 75%; 10-yr=50%

-Histology: single or multiple well-circumscribed nodues, with central necrosis; lined by viable tumor cells, consisting of epithelioid cells with abundant eosinophilic cytoplasm

-variants: spindle cell, angiomatoid, rhabdoid

-IHC: + vimentin, EMA and some CK (CK7 usually); almost always (-) for CK20.  rare desmin, S-100; neg for melanocytic markers

DDx:

• Superficial lesions: resemble rheumatic or infectious diseases with caseating granulomas (GA, TB, RA, etc)
• Angiomatoid variant- can look like borderline or malignant vascular tumors (angiosarc, etc)
• Spindle variant- can look like benign lesion (DF, nodular fasciitis, etc) or possibly synovial sarc (usually deep)
• Rhabdoid variant: looks like rhabdomyosarcoma- however, RMS is usually deep-seated
• Classical histology- may look like carcinoma, melanoma, IHC is needed.

LEFKOWITCH SOFT TISSUE

Tumor from leg of young man, with following staining pattern, + for:

-vimentin, S-100, HMB-45, CD57, NSE

looks like:

[image]

[image]

Answer: Clear Cell Sarcoma

-small clusters, nests, fascicles of uniform round to oval cells with clear to eosinophilic cytoplasm, surrounded by delicate fibrous septae; often with vesicular chromatin and large nucleoli

-Very aggressive tumor; predilection for foot and ankles; distal extremities of 2nd-3rd decade; local recurrences and metastases

-deep-seated, with close proximity to tendons and aponeuroses

-IHC: + S-100, melanocytic markers (most), CD57, vimentin and c-kit.

-neg for EMA and keratins

-Molecular: specific translocation:

-t(12;22)(q13;q12)= ATF-1 (12q13) with EWS (22q12)

DDx:

• *** Melanoma- has junctional component usually; lacks translocation
• synovial sarc- histology is different and is +for EMA and keratin

LEFKOWITCH SOFT TISSUE

deep-seated mass in chest wall of young man

[image]

-cell of origin?; common sites; tissues involved; prognosis; -IHC/SS

-DDx

Answer: granular cell tumor

-schwann cell origin

-commonly of soft tissue, GI and respiratory tracts

-superficial- dermis/skin; ST= UE, chest wall, thigh; mucosae

-predilection for african-american

-in cutaneous/mucosal lesions, a/w overlying pseudoepitheliomatous hyperplasia

-poorly circumscribed, sheets, or cords and nests of large, rounded to spindly cells with abundant granular PAS+ (d-R) granules (=phagolysosomes); wiht delicate fibrous septa

-benign lesion (>98%); RARE malignant (<2%)

-IHC: diffuse strong +S-100; +CD68; and NSE, laminin, myelin; (-) for GFAP

DDx:

• carcinoma and smooth muscle neoplasms- IHC
• hibernoma- typically vacuoles rather than granules
• rhabdomyomas- well-circum; appear very similar, however, have more peripherally located  nuclei rather than central (GCT); and IHC- muscle markers+

LEFKOWITCH SOFT TISSUE

Thigh mass young person

[image]

[image]=PAS

ANSWER: Ewing's sarcoma

-along the same spectrum of tumor (but with more differentiation= PNET (peripheral neuroectodermal tumor))

-histology: solide proliferation of round cells with round to oval nuclei, scant cytoplasm; abundant glycogen in cytoplasm (PAS+); atypical Ewings- cells are larger with more irregular nuclear contours and prominent nucleoli

-PNET- Homer-wright rosettes (central core filled wiht fibrillary neuropil like substance)

-prognostically: most important features are size at dx; location (proximal tumors are worse); and stage

-mainly affect young adults and adolescents (=second most common solid soft tissue tumor in children (after RMS)); arise in deep soft tissue; prefer paravertebral or retroperitoneum; but also involve extremities, chest wall, skin and visceral organs

-IHC: CD99 (not specific); also +FLI1, NSE, CD57, CK

Molecular: recurrent translocations involving EWS (22q12)- most commonly t(11;22)(q24;q12) (EWS:FLI1)

less commonly t(21;22)(q22;q12)= ERG:EWS

others rare- t(7;22), t(17;22), t(2;22)

DDx:

• Neuroblastoma- esp if paravertebral location; usually younger pts (<5yrs), elevated urine VHA/UMA (catecholeamine metabolites); no glycogen
• Rhabdomyosarcoma- also CD99+; but has muscle markers (myogenin, myoD1)
• Round cell liposarcoma- also may be CD99+; but if excision, usually can find at least some areas with typical myxoid liposarc; and have different typical recurrent translocation t(12;16)(q13;p11)= CHOP:FUS
• malignant lymphoma- IHC veyr different
• Poorly differentiated synovial sarc- has typical translocation t(X;18); and usually +EMA and keratins
• MPNST- may have similar areas, but most of the tumor will look more typical of MPNST and doesn't have the translocation

LEFKOWITCH SOFT TISSUE

Tongue lesion in young child with a characteristic translocation identified which look like this:

[image]

[image]

-what is the translocation involved and the genes; histologic description, IHC, and SS; DDx

ANSWER: Alveolar Soft part sarcoma

-affects children and young adults; MC- buttocks, thigh; however, in young children- mc sites are tongue and orbit; slow growing

-histology: compartments separated by dense fibrous septa filled with tightly packed tumor nodules with delicate vascular meshwork; cells lose cohesion to form alveolar pattern; vascular invasion is common

-cells have abundant pale to eosinophilic cytoplasm, with d-PAS+ crystals

-IHC: variably +desmin; +vimentin

-Neg for myogenin/myoD1, CKs, chromo/synapto, and S-100

Molecular: the recurrent translocation is unbalanced, t(X;17)(p11.2;q25)= TFE3 (Xp11) and ASPL (17q25)

DDx:

• Paraganglioma- neuroendocrine markers; Granular cell tumor- S-100+ no vascular meshwork
• metastatic melanoma- usually older pts; lacks translocation
• Metastatic renal cell carcinoma- the subset that effects young children actually has a TFE3-ASPL translocation which is slightly different than ASPS: it's balanced t(X;17)(p11;q25); RCC has epithelial differentiation- with IHC
• Epithelioid sarcoma- lacks alveolar pattern and delicate capillaries; is +keratins and CD34 and neg for desmin

LEFKOWITCH SOFT TISSUE

18 yr old male with antecubital fossa mass

-thick fibrous capsule, with prominent cuff of chronic inflammatory cells (occ germinal centers)

-center of lesion had large blood-filled spaces

ANSWER: angiomatoid fibrous histiocytoma

-textbook defining description- thick fibrous pseudocapsule with prominent lymphoid infiltrate and center eith blood-filled spaces

[image][image]

-variable desmin+; +CD68, CD99

-children and young adults; prefers extremities, especially in sites where lymph nodes are- ie antecubital and popliteal fossae

-indolent; rare recurrence

DDx:

• any metastatic tumor to lymph node- IHC needed
• Dendritic reticulum cell tumor- CD21 and CD35+[image]
• Aneurysmal fibrous histiocytoma- lacks dense fibrous pseudocapsule and inflammatory infiltrate; is desmin(-)

[image][image]

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(X;17)(p11.2;q25)

ANSWER: Alveolar soft part sarcoma

-unbalanced translocation

-involving TFE3 (Xp11) with ASPL (17q25)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(8;12)(p12;q15)

ANSWER: aggressive Angiomyxoma

-involves HMGIC gene

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

Losses of chr 7 and 22; Gains of chr 5, 8, 20

ANSWER: Angiosarcoma

several genes

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(9;22)(q22;q12)

ANSWER: extraskeletal myxoid Chondrosarcoma

-Main translocation =t(9;22)(q22;q12)= NR4A3 (9q22) with EWS (22q12)

Less commonly:

-t(9;17)(q22;q11)= NR4A3 with TAF2N (17q11)

-t(9;15)(q22;q21)= NR4A3 with TCF12 (15q21)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(12;22)(q13;q12)

ANSWER: Clear cell sarcoma

-t(12;22)(q13;q12)= ATF-1 (12q13) with EWS (22q12)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

-Ring chromosomes with material from chr 17 and 22

-or t(17;22)(q22;q13)

two entities (same genetics)

ANSWER: Dermatofibrosarcoma protuberans and it's exclusively childhood counterpart= Giant cell fibroblastoma

several genes involved in ring chromosomes

-translocation makes fusion product of: COL1A1 (17q22) with PDGFB (22q13)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(11;22)(p13;q12)

ANSWER: Desmoplastic small round cell tumor

-fusion of Wilm's tumor-1 (WT-1) (11p13) with EWS (22q12)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(11;22)(q24;q12)

ANSWER: Ewing's/PNET

-the main translocation= t(11;22)(q24;q12)= fusion of FLI-1 (11q24) with EWS (22q12)

Additional, less common translocations, all involving EWS (22q12)

-t(21;22)(q22;q12)= ERG (21q22) with EWS

Rare:

-t(7;22), t(17;22), t(2;22)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(12;15)(p13;q25)

ANSWER: Congenital/infantiles fibrosarcoma

-t(12;15)(p13;q25)= fusion of ETV6 (12p13) with NTRK3 (15q25)

this same cytogenetic abnormality is seen in congenital mesonephric blastoma (?related tumors)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

complex rearrangements involving 11q13

ANSWER: Hibernoma

-several genes involved in the large deletions of 11q13 or translocations

-including but not limited to MEN1, GARP, CCND1, FGF3, ARIX, PGYM

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

children or young adult with translocation involving 2p23

ANSWER: Inflammatory myofibroblastic tumor

-ALK-1 gene (2p23)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

rearrangements of 8q12

ASNWER: Lipoblastoma

-PLAG1 gene (8q12)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(12;16)(q13;p11)

ANSWER: Myxoid/round cell liposarcoma

-t(12;16)(q13;p11)= fusion of CHOP (12q13) with FUS (16p11)

rare alternate= t(12;22)(q13;q12)= CHOP:EWS

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

supernumary "ring" and giant marker chromosomes with amplification of 12q14-15

ANSWER: Well-differentiated Liposarcoma/ aka Atypical Lipomatous tumor

-12q14-15 causes amplification of several genes, but hallmark tested for in ATL/WDL = MDM2

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

loss of large portion of short arm of Chr 1 (involving 1p36.2-1p36.3)

and

Amplification of MYCN (2p24)- similar to c-myc protooncogene

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(2;13)(q35;q14)

ANSWER: Alveolar rhabdomyosarcoma

-most common translocation= t(2;13)(q35;q14)= FKHR (13q14) with PAX3 (2q35)

-less commonly: t(1;13)(p36;q14)= FKHR with PAX 7 (1q36)

LEFKOWITCH SOFT TISSUE

Name the tumor a/w the genetic abnormality and the genes involved

t(X;18)(p11;q11)

ANSWER: Synovial sarcoma

- SYT (now SS18) gene on chr 18q11 with one of three genes- SSX1 (most commonly), SSX2, SSX4 on Xp11

LEFKOWITCH SOFT TISSUE

What is the most common type of angiosarcoma?

ANSWER: Cutaneous Angiosarcoma not associated with lymphedema

-Other types: Post-radiation, AS a/w lymphedema (ie after mastectomy with axillary dissection); AS of breast parenchyma; deep soft tissue AS; and AS of liver and spleen

-AS- superficial, has predilection for scalp and forehead; lower grade lesions more common in superficial locations

-Histology: irregular vascular spaces, dissecting through normal structures (dermis, subQ), lined by large endothelial cells wiht hyperchromatic nuclei and pseudostratification and piling-up to form papillary structures

[image][image]

-higher grades- have more atypia and mitoses; poorly diff- more solid growth

-IHC: CD31, CD34 (50%), factor VIII (in well-diff); +others (Ulex europaeus, CD141=thrombomodulin; VEGFR, FLI1

-the epithelioid type (and some others) may be CK + (esp CK7, 8, 18)

-Angiosarc's a/w losses of chr 7 and 22; and gains of 5, 8, and 20

LEFKOWITCH SOFT TISSUE

middle aged man with superficial tumor of skin on upper extremity; composed of epithelioid cells, abundant myxoid stroma with strands and nests of cells- with "signet ring appearance"; a large vein is at the center of the lesion and is involved

[image][image]

ANSWER:  Epithelioid hemangioendothelioma

-low-grade malignancy; wide age range (rare in children); predilection for skin and ST; also in deep organs (liver and lung)

-in ST: up to 30% metastasize; usually solitary, painful; origin from a vein often found

-tumor cells radiate into soft tissue surrounding the involved vein; often with myxoid-chondroid matrix.  tumor cells may have signet-ring appearance (primitive intracyoplasmic lumina)

[image][image]

-IHC: diffusely +CD31, variable, less consistently with CD34 and fVIII; focally+ for ck's (CK 7, 8, 18)

-DDx:

• Epithelioid hemangioma: aka angiolymphoid hyperplasia with eosinophils; central vessel surrounded by cloud of well-formed small vessels; NO solid sheets/cords or nests or tumor cells; infiltrated by eosinophils, lymphs with gc's and pc's[image]
• Angiosarcoma- does not arise from a vein and is not angiocentric; AS with epithelioid fx is usually more deep-seated; tumor necrosis; and more cytologic atypia
• Epithelioid sarcoma- IHC- ES is diffusely + for CK's and CD34; neg for other vascular markers (CD31, fVIII)

LEFKOWITCH SOFT TISSUE

65 yr old woman with mass under scapula, composed of fibrous tissue interspersed with mature fat

[image]

ANSWER: Elastofibroma

-usually older (6th-7th decades); F>M; h/o repetitive maual labor or chronic trauma

-arises from connective tissue between chest wall and scapula and adheres to costal periosteum

-usually large

-histology: composed of fibrous tissue with variable amt of mature fat, paucicellular; fibrous matrix contains thick, convoluted elastic fibers (elastic stain+)

[image]

LEFKOWITCH SOFT TISSUE

Young boy with large mesenteric abdominal mass; showing spindle cell lesion with prominent inflammatory infiltrate (lymphs, histio, PC's, eosinophils); no recurrence or mets after excision

[image][image]

ANSWER: Inflammatory myofibroblastic tumor

-many lesions are in hte lung (also called plasma cell granuloma);  of the extrapulmonary IMT- mesentery and omentum are mc sites; predilection for young children (<10yr)

-histology: a proliferation of bland spindle cells and variable patterns: myxoid (nodular fasciitis-like), cellular with storiform-fascular pattern; dense stromal (aggressive fibromatosis-like)

-with prominent inflammatory infiltrate

[image]

-IHC: Vimentin, SMA, HHF-35, focal desmin; CD68 in histiocytes; S-100 neg

-up to 60% + ALK-1

DDx:

• Hodgkin's lymphoma- RS and RS-like cells, CD15 and CD30+
• Congenital/infantile fibrosarcoma- malignant, present at birth or in 1st yr; rarely in mesentery, a/w t(12;15)
• Desmoid- usually develop in mesentery after surgery; commonly in pts with Gardner syndrome

LEFKOWITCH SOFT TISSUE

multiple skin lesions, young child/infant and lytic bony lesions; well-circumscribed, unencapsulated with spindle and hemangiopericytic patterns

[image][image]

ANSWER: Myofibromatosis

-most commonly presents as single superficial lesion= solitary myofibroma

-most freq in young children/infants- where is typically superficial, but can be in deep ST, bone, visceral organs

-Adult version- solitary and superficial only

-Histology: biphasic morphology, fascicular myofibroblastic cells at periphery and hemangiopericytic-like center (which may be hyalinized, necrotic, calcified, etc)

-adults usually more multinodular with less evidence hemangiopericytic pattern

[image]=adult myofibroma

-IHC: for typical myofibroblastic markers- SMA, HHF-35, neg for desmin; S-100 (-)

DDx:

• Nodular fasciitis- more subQ with fascial involvement; lacks zonation/biphasic pattern
• Fibrous histiocytoma (aka dermatofibroma)- lesion of adulthood, with epidermal hyperplasia and lacks biphasic pattern
• Hemangiopericytoma- uncommon in young; lacks biphasic (and different IHC)
• Deep lesions- ddx= congenital fibrosarcoma- lacks biphasic pattern; recurrent translocation- t(12;15)(p13;q25)= ETV6:NTRK3

LEFKOWITCH SOFT TISSUE

A large intraabdominal mass- spindle cell lesion with alternating areas of hemangiopericytic, fibrous and myxoid areas

[image][image]

ANSWER: Solitary Fibrous Tumor

-affects adults, usually in pleura, or other serosa-lined cavities (peritoneum, orbit, meninges, ST, etc)

-Histology: polymorphic- alternating, variable areas of cellular fibrous or hemangiopericytic patterns with dense collagenous or myxoid hypocellular areas.  Uniform spindle cells, low mitotic rate

-Rare malignant cases- have more cytologic atypia and mitoses >4/10hpfs

-IHC: consistent CD34+

DDx:

• Hemangiopericytoma- both are CD34+; with classic staghorn vasculature throughout- HPC; with prominent fibrous areas= SFT
• Fibrosarcoma- herringbone pattern, CD34(-); +for myofibroblastic markers
• Monophasic synovial sarcoma- usually +cytokeratins and EMA, and focal S-100
• GIST- if in abdominal cavity- may also be CD34+; but also +c-kit (CD117)

LEFKOWITCH SOFT TISSUE

middle aged man with acromegaly, spotty pigmentation of face, paravertbral tumor= spindle cell with pigment

-what is the complex and genes affected

ANSWER: Carney Complex

-acromegaly, spotty pigmentation of face and a pigmented melanotic schwannoma- in this case

-Major Dx'c criteria: spotty skin pigmentation, myxomas of different organs, pigmented nodular adrenal cortical dz, large cell calcifying Sertoli cell tumor, thyroid carcinoma, psammomatous melanotic schwannoma, epithelioid blue nevi, breast duct adenomas; + family hx and mutation of PRKARIA gene

-autosomal dominant, genes on 17q22-24 (CNC1)- contains tumor suppressor gene PRKARIA; and 2p16 (CNC2)- unknown

*not to be confused with Carney triad= nonfamilial association= GIST, pulmonary chondroma and extra-adrenal paraganglioma; F>M

LEFKOWITHC SOFT TISSUE

Decribe features of McCune-Albright syndrome

LEFKOWITCH SOFT TISSUE

Describe features and gene invovled in:

-MEN1

-MEN2A

-MEN2B

-familial medullary thyroid cancer syndrome

• MEN1- aka Wermer's syndrome, mutation of MEN1 (11q13)
• Parathyroid hyperplasia and adenomas
• Pancreas- endocrine tumors
• Pituitary adenomas (esp prolactinomas)
• MEN2 (all):  constitutional activation of RET (proto-oncogene) (10q11.2)- includes MEN2A, MEN2B and familial medullary thyroid ca
• MEN2A- aka Sipple's syndrome
• Pheochromocytoma (adrenal)
• Thyroid- medullary carcinoma and C-cell hyperplasia
• Parathyroid hyperplasia
• MEN2B- contains all tumors/features of MEN2A+
• mucocutaneous ganglioneuromas
• marfanoid habitus
• Familial medullary thyroid carcinoma syndrome- variant of Type 2A with strong predisposition to medullary thyroid carcinoma

LEFKOWITCH SOFT TISSUE

Infant with the following skin lesion

[image][image]

ANSWER: Juvenile Xanthogranuloma

-infants and young children (<20 yrs); benign; usually superficial, solitary lesions; may be deep or multiple

Histology- mostly bland mononuclear cells, with abundant pink or vacuolated cytoplasm; interspersed Touton-type giant cells and scattered inflammatory cells

-commonly have many mitosis and cytologic atypia

-IHC: fascin, CD68, fXIIIa, CD45, HLA-DR, CD4; some with S-100

-neg for CD1a, CD3, CD21, CD34 and CD35

DDx:

• Main ddx= langerhans cell histiocytosis- also of younf children, with histiocytes; lack Touton giant cells, and are CD1a+, and diffusely S-100
• Rosai-dorfman disease- mainly in lymph nodes, can present extranodal; S-100+ and CD1a neg; large histiocytes with emperipolesis
• Dermatofibroma- older age group, lacks giant cells
• Xanthoma- uniform foamy histiocytes.

LEFKOWITCH SOFT TISSUE

40 yr old woman, pelvic mass, infiltrative margins, large

[image][image]

ANSWER: Aggressive angiomyxoma

-locally aggressive, mostly only women affected; reproductive ages; typically in pelvis and perineum

-local recurrence common, rare metastasis

-Histology: infiltrative margins, hyppcellular, composed of uniform spindle to stellate cells in loose variably collagenous matrix; prominent open vascular channels with thickened walls and bundles of smooth muscle a/w vessels

IHC: +vimentin, desmin, ER and PR*; sometimes SMA, MSA and CD34; Ki-67 <1%;

-S-100(-)

Molecular: rearrangements of 12q15 (no single recurrent translocation);= HGMIC (a fetal gene)

DDx:

• Angiomyofibroblastoma- smaller, limited to vulva; delicate vasculature and cell crowding around vessels
• Intramuscular myxomas- RARE in genital/pelvic region; lack prominent vessels
• Myxoid liposarcoma- chicken-wire, prominent vasculature; and lipoblasts
• Spindle cell lipoma- subQ of neck, posterior shoudler or back; dual population of spindle cells and fat; lack open vasculature
• Superficial angiomyxoma- dermis and subQ of genital region; less cellular, with abundant acid mucopolysaccharide; sparse vascularity; and are ER and PR (-)

ASCP BONE

young pt, bony lesion extending from metaphysis of distal femur, along origination of tendon tract

looks like:

[image]

ANSWER: Osteochondroma

-benign bone tumor, usually solitary, young pts (60% <20 yo); most commonly in metaphysis of long bones:

-Distal femur> proximal humerus>prox tibia

=an exostosis= outgrowth of cortical and medullary bone- which is continuous with underlying bone cavity; completely covered by periosteum

[multiple hereditary exostosis- an autosomal dominant d/o]

-Rad: lesional cortex and medullary cavity continuous with originating bone; often arise at site of tendon insertion and grow in direction of tendon)

[image]

-grossly- sessile or pedunculated; with a thin regular blue/gray cap- usually <2 cm in thickness (if >2cm may indicate malignancy); exception: kids usually have a large cap, over cancellous bone

[image]

-histology: the cartilage cap= chondrocytes in lacunae- peripherally in clusters and in columns near the base (simulates nl epiphysis); stalk composed of cancellous bone surrounded by fat and bone marrow

[image][image]

DDx:

1. Parosteal osteosarcoma- looks worse radiographically; stalk has fibrous tissue, NOT BM and fat
2. Chondrosarcoma arising in osteochondroma- these get real big
3. Bizzare parosteal osteochondromatous proliferation (Nora's lesion)- surface of small bones- unsure is reactive or neoplastic
4. Heterotopic ossification- reactive, no cartilage cap
5. subungual exostosis- usually big toe of kids

ASCP BONE

cartilaginous tumor in bone of hand, intramedullary mineralization, looks like:

[image]

ANSWER: Enchondroma

-benign, intramedullary cartilage tumor; very common; most are 15-40 yo

-50% located in small bones (hands, feet)

-most commonly as a solitary tumor

-Two clinical syndromes a/w enchondromas:

1. Ollier's disease: multiple enchondromas involving entire skeleton, half the body or one limb; look more worrisome, b/c show increased cellularity
2. Mafucci's syndrome: multiple enchondromas and soft tissue hemangiomas; increased risk of chondrosarcoma

-Rad: intramedullary rarifaction; +/- mineralization

-long bones: no cortical erosion or destruction

-small bones: may have thinned/expanded cortex due to size--> pathologic fx

[image]

Gross- usually curetted out, cartilaginous tissue, NO myxoid or mucoid quality (=more susp for chondrosarc)

-histology: cartilage (benign)

-long bones: hypocellular, bland cytology, occassional degenerative change

-short bones: moderately cellular (more than long bones), increased nuclear size; may have some myxoid change; NO invasion of medullary or cortical bone

[image]

*however, usually consists of lobules of cartilage which with mineralization around edges can look like destruction of bone.

[image]

-lesion abuts cortical bone without destruction

DDx:

1. Chondrosarcoma: atypia, large cells, hypercellular, destruction of cortical bone
• in between category: atypical enchondroma

ASCP BONE

benign appeared radiograph, tumor in distal femur, looks like:

[image]

ANSWER: Chondroblastoma

-uncommon benign bone tumor; 60% in long tubular bones

-distal femur> prox humerus> prox tibia

-young pts (2nd decade)

-Rad: benign radiographic appearance; lucent defect at end of bone: 40% epiphysis only, 60% epiphysis and metaphysis

-50% have sclerotic rim

[image]

-histology:

-lobules of pink chondroid matrix surrounded by sheets of mononuclear cells, with well defined cell boundaries, eosinophilic cytoplasm

-cartilaginous matrix, but looks pink rather than blue

-35% lacy, chicken-wire calcification, also can calcify chunky

-MNGC are common

[image][image]=Ca2+

DDx:

1. Giant cell tumor- also at end of bones, lacks chondroid matrix
2. Chondromyxoid fibroma- chondroid is more blue
3. osteosarcoma- rad- looks malignant, cytologically atypical

ASCP BONE

radiographically benign bone lesion at metaphysis, looks like:

[image]

ANSWER: Chondromyxoid fibroma

-rare tumor; 2nd-3rd decades; occur in long bones: prox tibia> distal femur; flat bones: ilium, ribs; and hands and feet

Rad: benign appearing, usually at metaphysis, located eccetrically, circumscribed and scalloped/sclerotic rim

[image][image]

-histology: lobulated- either macrolobules or microlobules; oval to spindle cells with cytoplasmic extensions, myxoid-chondroid matrix; and MNGCs

[image][image]

[image]

DDx: chondroblastoma, chondrosarcoma

ASCP BONE

describe radiographic and histologic features of conventional chondrosarcoma

Conventional Chondrosarcoma

-M>F; most in 4th-6th decade; most in pelvic and shoulder girdle; +upper ends of femur and humerus; <3% distal to wrist/ankle

-Rad: Large (avg9.5 cm), 75% mineralization, poorly marginated; MOST have cortical abnormalities- endosteal scalloping, cortical destruction, expansion, thickening

-40% with assoc soft tissue mass

Gross: lobulated, blue/white, solid or partially cystic; myxoid change; degenerative/liquefactive necrosis/hemorrhage; grossly permeative

[image]

Histology:

-hypercellular

-nuclear enlargement/hyperchromasia

-permeation of cortical and medullary bone

-myxoid stromal changes

[image]=permeation

[image]=myxoid change

-designated into 3 grades based on cellular atypia, most cases are grade 1-2, grd 3 is rare

[image]=Grade 1

[image]=Grade 2

[image]=Grade 3

Tx:

-requires wide excision

-NON-responsive to chemo and radiation

ASCP BONE

older person, pelvic girdle, large tumor originating in bone with aggressive soft tissue component

looks like:

[image]

ANSWER: De-differentiated Chondrosarcoma

-**bimorphic pattern- sampling important; consists of low-grade chondrosarcoma juxtaposed to a high grade sarcoma (=osteosarc, HG spindle cell sarc, pleomorphic undifferentiated sarcoma)

[image]

-older adults (one decade older than conventional), occurs de novo or in recurrent tumors;

-most common in pelvic and shoulder girdle

-Rad: central portion appears as normal cartilaginous tumor (still malignant), but with areas of lucency and predominantly the ST component- looks aggressive

[image]

DDx

-metastatic sarcomatoid carcinoma -CK+

-Primary sarcoma of bone

Tx: en bloc resection; +/- chemo

prog: worse than conventional chondrosarc

ASCP BONE

what is the tumor, where is it usually located, main histologic features

[image]

ANSWER: Clear Cell Chondrosarcoma

-extremely uncommon

-M>F

-tends to involve ends of long bones (prox femur and humerus)

-4th-5th decades

Rad: lytic, extending to end of bone; may look benign; <50% with calcification

-Histology: lobulated; tumor cells have *distinct cytoplasmic boundaries; central nucleus and clear cytoplasm

-trabeculae of woven bone/osteoid present commonly

-50% contain nodules of conventional chondrosarc

[image][image]

DDx:

-chondroblastoma

-osteoblastoma

-osteosarcoma (esp chondroblastic osteosarc)

ASCP BONE

bone tumor in jaw, 20 yo male, looks like:

[image]

ANSWER: Mesenchymal chondrosarcoma

-2/3 in bone, 1/3 in ST

-2nd-3rd decade

**Jaw- common site

-also- ilium, spine, ribs

-malignant radiographic appearance

-histology: well-differentiated hyaline cartilage, merging or juxtaposed to high-grade small blue cell tumor- with branching staghorn vascular pattern

[image][image]

ASCP BONE

What is the following entity?[image]

[image]

-radiographic findings, pt demographics, common site, histology

ANSWER: Osteoid Osteoma

-a nidus, sharply demarcated originating in cortex, composed of irregular trabeculae of woven bone, with loose fibrovascular stroma;  trabeculae lined by benign appearing osteoblasts

-almost all <1.5 cm

-most common in adolescents/young adults (5-24yrs)

*-Painful!- relieved with NSAIDS

-most commonly in proximal femur

Rad: sclerosis and new bone surrounding nidus- centered in cortex; CT most helpful in identifying nidus- often missed on plain XR

[image][image]

-gross: well-demarcated red-brown nidus, surrounding sclerotic or cortical bone

[image]

ASCP BONE

what is the lesion?

-radiographic features, DDx

[image][image]

ANSWER: Osteoblastoma

- histologically looks very similar to osteoid osteoma (=woven bone, osteoblasts, fibrovascular stroma), usually with more osteoblasts, and MNGCs and solid areas of bone formation

-*as opposed to osteoid osteoma- these are >2cm

-most are young (<25 yo)

-presents in long bones> spine>jawbones

-Gross- tan/red brown, friable; well-demarcated

-*Rad: May have malignant appearance, though is benign

-variable

DDx:

• Osteosarcoma- difficult to differentiate, esp in needle biopsy; show growth into and entrapment of soft tissue and bone
• osteoid osteoma- <1.5 cm, different radiology, less solid bone growth
• ABC
• Giant cell tumor

ASCP BONE

categories of osteosarcomas:

-by location

-histologic types

Osteosarcoma

-Locations:

• Medullary: =conventional osteosarc
• Surface:
• Parosteal
• Periosteal
• High grade surface osteosarc

Histologic types:

• Osteoblastic [image]
• Chondroblastic [image]
• has high grade cartilage component, if low-grade, think something els
• Fibroblastic [image]
• Telangiectatic [image]
• cystic, scraps of high grade tumor with very little bone formation
• Low-grade central
• Giant cell rich
• small cell

-histologic type- not related to prognosis, just for recognition- most are high grade (gr 3-4)

ASCP BONE

what is the lesion?

[image]

-general info, rad features, treatment

ASNWER: Conventional, osteoblastic osteosarcoma

-*is the second most common malignant bone tumor

-in young, 85% are <30 yo

-Distal femur>prox tibia>prox humerus> prox femur

-**metaphyseal of long bones

-Rad: aggressive, destructive

-*"codman's triangle"- lifting off of periosteum

[image]

-lytic, sclerotic "moth-eaten"

-MR and CT needed to evaluate true extent of lesion which is underestimated on XR

[image]

Tx: high dose PRE-OPERATIVE chemotherapy- most respond well; followed by wide surgical resection; +/- post-op chemo

-histologic grade of response to pre-op chemo:

-Huvos grading system

-Grade 1: <50% necrotic

-Grade 2: most of tumor necrotic

-grade 3: 90-99% necrotic

-grade 4: (best prognosis): totally, 100% necrotic

*best predictor of prognosis: response to pre-op chemo:

>90%= good

<90%= poor

ASCP BONE

What is lesion?

[image]

-benign or malignant?; rad features, histology

ANSWER: Parosteal osteosarcoma

-malignant, but one of the few low-grade subtypes of osteosarcoma (together with low-grade central osteosarcoma- rare)

-represents 4% of all osteosarcs; young adults

-Distal femur> prox tibia> prox humerus

*most common site- posterior cortex of distal femoral metaphysis

*tx- wide resection WITHOUT chemotherapy

-Rad- heavily mineralized, mass with broad base attached to underlying cortex (as opposed to osteochondroma- is not continuous with medullary cavity

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Histology:

-well-formed LONG trabeculae; spindle cell stroma with minimal atypia

-cartilaginous differentiation common, may even have cartilage cap (like osteochondroma)

- 15% contain area of high-grade sarcoma (dedifferentiated parosteal osteosarc)

ASCP BONE

what type of malignant bone tumor is this?

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-based on location of bone growth; Rad fx; most common histologic type

ANSWER: Periosteal Osteosarcoma

-most commonly are of a chondroblastic subtype

-moderately differentiated; *grows on the SURFACE of bone

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-uncommon, 1.5% of osteosarcs

-found in children and adolescents

-common sites: diaphysis (or metadiaphysis) of femur and tibia

ASCP BONE

Describe histologic features, congenital syndromes a/w, and common site of this lesion:

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ANSWER: Fibrous dysplasia

-usually monostotic (80%), may be polyostotic (20%)

-de novo/non-familial cases due to somatic mutation in GNAS1. 

-most are <30 yo

-most common site is femoral neck

-1/3 in craniofacial bones

-1/3 in femur or tibia

-~20% in ribs

Familial syndromes:

• McCune-Albright syndrome: =3% of FD pts;  polyostotic fibrous dysplasia; cafe-au-lait pigmentation; endocrinopathies
• Mazabraud's- veyr rare; fibrous dysplasia and soft tissue myxomas

Rad: benign appearing, well-defined, sclerotic rim, hazy mineralization= "ground glass" 

-bowing deformity in long bones; +/- path fractures

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gross- usually solid, tan-white filling medullary cavity; MAY be cystic with hemorrhage

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Histology: Irregular spicules of woven bone ("chinese characters"); embedded in bland spindle cells

-may have foam cells, myxoid change, fibrosis

Tx: observation; currettage is symptomatic

ASCP BONE

what are the characteristic Radiographic features; alternate name; location and histologic features of this bone lesion

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ANSWER: Metaphyseal fibrous defect

-formerly known as: non-ossifying fibroma

-hypercellular fibrogenic stroma, with bland nuclei and MNGCs; plump spindle cells in storiform pattern, looks like a fibrohistiocytic lesion

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-Rad: metaphyseal, eccentric

-trabeculated, with sclerotic rim; well-circumscribed; often Dx'd on XR alone

-may have path fracture

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-80% in distal femur, distal or prox tibia

-present in children and adults

ASCP BONE

-this lesion is the 4th most common primary bone tumor; commonly in the pelvic girdle and lower extremities

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ANSWER:Ewing's sarcoma

-small round blue cell tumor

-4th most common primary bone tumor; male predilection

-75% in first 2 decades 

-most in pelvic girdle and LE

-femur>ilium>fibula

-Rad: permeative,destructive, poorly defined

-characteristic "onion skin" appearance- due to lifting off of periosteum

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-diaphysis or metaphysis- can involve full length or long segments of bone by filling up the marrow spaces (similar to lymphoma)

-consists of sheets of small round blue cells; clear-indistinct cytoplasm

-a small % have anaplasia

-with prominent rosette formation--> PNET (maturation)

-IHC:

-CD99+- sensitive, but NOT specific

-CK's + in 32%

-FLI-1+ (also helpful)

Molecular:

-most commonly= t(11;22)(q24;q12)= FLI-1:EWS

alternate: t(12;22)(q22;q12)- ERG:EWS

Tx with neoadj chemo +wide resection and adjuvant chemo +/-radiation

-as with osteosarc, degree of response (necrosis) to neoadj chemo= predictor of survival

ASCP BONE

Poor prognostic factors of Ewing's

-Older age (>17 yo)

-pelvic tumor (difficult to remove)

-large tumor size (>8 cm)

- metastatic disease

ASCP BONE

What are the 3 main primary bone tumors that predominantly originate at the very end/epiphysis of long bones?

-Chondroblastoma

-Clear cell chondrosarcoma

-Giant cell tumor of bone

ASCP BONE

What is the lesion?

benign/malignant?, Rad findings, histologic features

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ANSWER: Giant Cell Tumor (of bone)

-benign, may be locally aggressive

-relatively common (=20% of benign bone tumors)

-most are solitary; -mc in 3rd to 5th decade (rare in children)

-Female predilection*

-**mc in end/epiphysis of long bones:

-distal femur> prox tibia> distal radius> sacrum

*and in spine- prefers anterior elements (=body)

-Rad: eccentric, purely lytic, at end of bone; with cortical destruction, and may have soft tissue mass with shell of bone, sclerotic rim

-25% look aggressive/malignant

[image][image]

Gross- classic red-brown +/- degenerative changes, extends to end of bone without further destruction (vs malignant tumors continue to grow through surrounding soft tissue)

-Commonly shelled out in morcellated pieces

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-Histology: NUMEROUS MNGCs, scattered within a monotonous, mononuclear ovoid to spindle stroma with pink cytoplasm,

*the stroma nuclei look identical to the MNGC nuclei

-+mitoses, +/- foam cells, reactive new bone

-prominent spindle areas may look like metaphyseal fibrous defect (non-ossifying fibroma) ; may also look like ABC on bx

[image][image]

ASCP BONE

Multicystic lesion in bone, with fluid-levels, histology looks like:

[image]

ANSWER: Aneurysmal Bone Cyst (ABC)

-may arise primary or secondarily adjacent/in other tumors- predominantly chondroblastoma and giant cell tumor

-most common in 1-2 decade, younger patients

-metaphysis, of distal femur or prox tibia (knee)

-when in spine- prefers posterior/dorsal elements

Rad: lucency in metaphysis, with fluid-fluid levels (layers) on CT and MR

[image][image]

-Gross- red brown, solid or cystic; usually comes in pieces or just bx

-Histology: multiple cystic spaces separated by septa; with occassional solid patter

-fibrous septa- spindle cells without atypia; +mitoses, +MNGCs; NO endothelial lining the cystic spaces (vs telangiectatic osteosarc);

-solid areas may have osteoid and reactive woven bone +/- calcifications

[image][image]

DDx:

• Telangiectatic osteosarcoma- has striking cytologic atypia
• Giant cell tumor- has NUMEROUS MNGCs
• low-grade osteosarcoma- usually not cystic

Tx- curettage

ASCP BONE

medullary bone lesion with thinned but intact cortex and trabeculation, histology looks like:

[image][image]

ANSWER: Unicameral Bone Cyst

- simple cyst

-most in 1-2 decade

- present with pathologic fractures commonly

-mc sites= proximal humerus and prox femur

-Rad: located centrally within medullary cavity, abutting epiphyseal plate- *NO wider than epiphyseal plate (simialr to ABC); thinned, but intact cortex; with trabeculation

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-Histology:

-loose, hypocellular fibrous stroma, bland spindle cells with fragments of bone (less cellular than ABC)

*irregular masses of degenerating fibrin, may calcify

[image][image]

Tx- most are aspirated and injected with steroids; may be curetted

ASCP BONE

midline bone tumor at base of skull; destructive, identified on MRI; looks like

[image]

ANSWER: Chordoma

-malignant tumor, arises from notochord remnants

-uncommon (6% of malignant bone tumors)

-M:F=2:1

-older pts- 5-7th decades

-Sites: sacrum (50%)> base of skull (37%) > mobile spine (13%)

-Rad- difficult to see on XR, need CT/MR to identify- which have aggressive appearance, lytic and destructive

Gross: lobulated, shiny, mucoid

-gray-tan, red-brown, glistening

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-Histology- lobules of mucoid material with cords and nests of tumor cells separated by fibrous septa

-cells with round nuclei and central nucleoli

-scattered cells with intracytopasmic vacuoles (=physaliphorous cells)

[image][image]

IHC: Keratins +

-EMA+; Brachyury+ (negative in carcinomas- to differentiate from metastatic dz)

ASCP BONE

what are the 4 main originating sites for metastatic tumors to bone in adults

-what common childhood tumors metastasize to bone

Adults

• Lung
• Kidney
• Breast
• Prostate

Children

• neuroblastoma, Wilm's tumor, Osteogenic sarcoma (OGS, aka osteosarcoma)- met from another bone site, Ewing's, rhabdomyosarcoma

Rad fx:

most are lytic: kidney, GI, thyroid, melanoma

-Blastic= prostate

-both blastic and lytic- lung and breast

LEFKOWITCH BONE

what is the dx?

[image][image]

ANSWER: Myxoid chondrosarcoma

-uncommon, ST or bone, monotonous proliferation of uniform, small cells with deep pink cytoplasm, in sheets and cords in abundant myxoid matrix

-slowly progressive, BUT high incidence of late recurrences and metastases.

Tx with wide local resection

LEFKOWITCH BONE

what is this biphasic lesion?

[image][image]

ANSWER: Mesenchymal chondrosarcoma

-biphasic pattern, with hemangiopericytoma-like vasculature, and areas with PINK chondroid matrix; with immature, small cells

-Aggressive, highly malignant; local recurrences and high metastatic rate

-jaw bones of young adults

LEFKOWITCH BONE

what is this lesion?

[image]

ANSWER: Ossifying fibroma

-immature trabeculae, rimmed by osteoblasts, assoc w/ calcified spherules

-benign, slow growing; typically mandible

-3rd-4th decades

-*Variant: Juvenile ossifying fibroma- younger pts; has more potential for aggressive local growth and recurrence

LEFKOWITCH BONE

12 yr old boy, normal serum Ca and Phos levels, large expansile lesion in right mandible

[image][image]

ANSWER: Giant cell reparative granuloma

-Now= reparative granuloma

-benign, reactive

-fibroblastic/collagenous stroma with small hemorhagic cysts; and scatt lymphs and MNGCs; a/w reactive new bone formation

-likely related to ABC

DDx:  Giant cell tumor of bone- numerous GCs evenly distributed

Brown tumor of hyperparathyroidism: biochemistry profile- alterations of Ca and phos

LEFKOWITCH BONE

Avascular necrosis-

common causes of idiopathic

two basic types-

(1) post-traumatic- a late consequence of fracture

(2) idiopathis- usually assoc w/ long-term steroid therapy, certain occupations (=deep sea divers, Caisson workers), hemoglobinopathies (esp SS), EtOH abuse, rarely- Gaucher's dz

LEFKOWITCH BONE

What is the lesion

[image][image]

ANSWER: Paget's disease of bone

-waves of osteoclastic bone resorption, followed by new bone formation--> irregular patches of lamellar bonewith scalloped margins, and prominent cement lines forming a mosaic pattern

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-disordered, accelerated bone turnover

-may be monostotic or polyostotic

-present with chalkstick fx of long bones (transverse)

-in polyostotic forms- pts have high serum alkaline phosphatase (high alk phos) and normal Ca and phos

LEFKOWITCH BONE

What are characteristic features of this lesion?

[image][image]

LESION ANSWER: Adamantinoma

-almost exclusively involves tibia (most freq) and fibula

-a rare, low-grade malignant bone tumor, located intracortically in diaphysis of tibia

-biphasic, common histologic variants- spindle, basaloid, tubular, squamous

[image]=basaloid

indolent, but can metastasize (up to 25% in poorly treated)--> lungs, LNs

LEFKOWITCH BONE

Osteomyelitis-

most common organisms in adults and children?

-histology

The #1 most common organism (esp in children) is Staph aureus

-E. coli, Pseudomonas and Klebsiella are other's- usually secondary to UTI.

-spread hematogenously (more common in young) and by direct penetration (more common in adults)

-Histology: acute inflammation, with abscess formation, bone and BM necrosis

-long bones more commonly involved.

LEFKOWITCH BONE

what is the lesion?

-typical staining pattern and histologic features

[image][image]

ANSWER: Langerhans Cell Histiocytosis

-neoplastic proliferation of large specialized dendritic cells, mixed with lymphs, eos, neuts and pc's.

-large histiocyte with abundant cytoplasm and *longitudinal nuclear groove ("coffee bean")

[image]

 formerly known as eosinophilic granuloma

-S-100 and CD1a +

-neg for CD45 and CD68

-EM: Bribeck granule= racket-shaped

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LEFKOWITCH BONE

what is the most likely diagnosis, and primary ddx

[image][image]

ANSWER: Rheumatoid synovitis

DDx:

-Lyme disease

-Systemic lupus erythematosus

-psoriatic arthritis

=synovial villous formation and hyperplasia/hypertrophy, fibrinoid necrosis, chronic inflammation in vascularized stroma; nodules of lymphs surrounded by plasma cells (=more likely RA)

LEFKOWITCH BONE

what is this lesion

-benign or malignant?

[image]

ANSWER: Pigmented Villonodular Synovitis (PVNS)

-proliferative, non-neoplastic lesion, benign- but can cause erosion of adjacent bones

-Sx: pain and swelling

-Intraoperatively- rusty-brown joint fluid and synovial surfaces

-Histology: villous projections of synovial surface with hypertrophy and hyperplasia; and cells heavily laden with hemosiderin pigment; +giant cells filled with pigment

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LEFKOWITCH BONE

what is the lesion?

-it's associated disease and histologic features

[image]

ANSWER: Rheumatoid nodule

-fibrinoid necrosis surrounding by palisading histiocytes; surrounding tissue with minimal inflammatory cells

-nodules commonly occur on the extensor surfaces of extremities, after a bout of symmetri arthritis (RA)

-Granuloma anulare, of the skin, usually in children, is of similar histology, but is not associated with joint/arthritis

LEFKOWITCH BONE

What common genetic abnormalities are associated with osteosarcoma?

-germline mutation of 13q14= Rb gene- gives 500X risk of osteosarc (and pts have retinoblastoma)

-single mutation of 13q14 with "second hit"- osteosarc, +/- retinoblastoma

-Amplification of MDM2, with inactivation of p53

-LOH at chr 3, 7, 18

LEFKOWITCH BONE

Describe Maffucci's syndrome

-cavernous hemangiomas- which may thrombose and calcify, located in skin and ST- overlying enchondromas

-increased risk of chondrosarcoma (as well as tumors of brain and ovaries)

LEFKOWITCH BONE

describe McCune-Albright syndrome

LEFKOWITCH BONE

what syndrome does this describe?

-fibrous dysplasia and myxomas of soft tissue

LEFKOWITCH BONE

what is the syndrome?

-multiple skeletal metastases in neuroblastoma

-ANSWER: Hutchison's syndrome

-Pepper's syndrome- is predom. liver mets in neuroblastoma

LEFKOWITCH BONE

what is this lesion on the synovial surface

[image]

-characteristic histologic feature?

-what suggests malignancy?

ANSWER: Synovial chondromatosis

-benign, proliferation of cartilage nodules in and on synovium

-with characteristic clustering of chondrocytes at the periphery of nodules

-having more diffuse, uniform, oval or spindle shaped small cells- suggests malignant transformation- also necrosis, cyst formation, and nuclear atypia