Adamantinoma

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Adamantinoma

• Maggi Coplin
• 23january04

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Case Study

• 20 year old 311 pound white female
• 2 months history of left ankle pain
• no trauma history

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Case Study Plain film erosive lesion distal
fibula breaking out of the cortex causing lytic
expansion and destruction of bone
Example
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Case Study

• MRI 4x12cm multiloculated tumor distal third
  fibula involving soft tissue and medial distal
  tibia
• No distant mets on staging

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Case Study

• Bone biopsy 10/25/00
• Sheets of small-intermediate sized cells
• Several small lace like paucicellular osteoid
  (excludes Ewings and PNET)
• Diagnosis osteosarcoma, small cell variant

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Small cell Osteosarcoma

• SCO is a high-grade variant of osteosarcoma
• incidence of up to 4 of all osteosarcomas
• affects patients of the same age group and has
  the same anatomic location as conventional
  osteosarcoma
• Appears to have a prognosis that is the same as
  or slightly worse than that of conventional
  osteosarcoma.

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Case Study

• Plan
• 2 months neoadjuvant Adriamycin/Ifosfamide
  alternating with MTX chemotherapy
• Surgery
• Further chemo

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Case Study

• NO response to neoadjuvant chemotherapy
• BKA was performed 3 months later

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Histology (x20, x90)basophilic strands of
epithelioid component (squamous metaplasia with
keratin pearl formation) andimmature mesenchymal
stroma
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Characteristic and a principal diagnostic feature
of????
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Adamantinoma

• Final path -
• high grade Adamantinoma-like Ewings sarcoma
• few small foci had a solid proliferation of small
  cells simulating Ewings
• The osteoid was actually collagen
• IHC showed heterogenous reactivity to O13,
  pancytokeratin, EMA and vimentin
• These are c/w either adamantinoma or Ewings but
  not osteosarcoma

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Sowhat the hell is that and how do we treat
it???
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Adamantinoma

• Etymology Latin adamant-, adamas an unbreakable
  or extremely hard substance
• A rare, low grade malignant tumor of epithelial
  origin
• .1-.5 of all primary bone tumors
• Usually in jaw or tibia/fibula stage I
• Age 20-50, malesgtfemales
• 20 of pts will eventually have mets (2-24yrs)
• 34 of cases in one series were misdiagnosed at
  first biopsy

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Characteristic Xray

• eccentric, well-circumscribed, lytic lesion
• sclerotic border, cortical thinning but little
  periosteal reaction
• Soap bubble appearance
• occasionally an associated soft tissue mass (in
  15 of cases)

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Pathogenesis

• Two distinctly different origins
• Epithelial origin composed of squamous cells
• Mesenchymal origin composed of immature
  mesenchymal cells and spicules of dysplastic
  bone.
• The mesenchymal component resembles fibrous
  dysplasia and its variant ossifying fibroma (may
  be the malignant variant of fibrous dysplasia).

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Osteofibrous dysplasia

• possible precursor to adamantinoma
• similar histologic features,
• Similar immunohistochemistry
• same clonal abnormalities
• overlapping skeletal distribution
• simultaneous occurrence in the tibia and fibula

Clinical Orthopaedics Related Research.
(408)256-61, 2003 Mar
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Natural History

• Mean survival after mets is 12 years!
• Reported mortality 13-18

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Histology

• Cytokeratin 14, 19, 5()
• Vimentin
• Epithelial Membrane antigen (EMA)
• Confirmed by EM showing tonofilaments and
  desmosomes and basal membranes

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Cytogenetics of classic type

• 40 of adamantinomas have an aneuploid eptihelial
  component (near diploid)
• 48 are p53()
• Trisomies 7,8,12,19,21 common in both
  osteofibrous dysplasia and adamantinomas
• Structural translocations, deletions, inversions
  were only seen in adamantinoma

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Treatment

• Surgical
• Marginal resection leads to local recurrence in
  as many as 31 of patients between 3 months to 19
  years postoperatively
• XRT and chemo dont work

Clinical Orthopaedics Related Research.
(408)256-61, 2003 Mar
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Ewings Sarcoma

• Highly malignant tumors of neuroectodermal origin
• Uniform densely packed small cells
• NSE() , vimentin(), CD99() MIC2 gene product
• Variably Leu 7, synaptophysin(), PAS()
• CK 8,18, 19 () 20 of cases
• 90-95 are t(11,22)(q24q12) FLI1/EWS
• Small blue cells without epithelial features so
  no reason to suspect a relationship between this
  and adamantinoma

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Van Haelst 1975

• Described a malignant tumor of the second
  metatarsal in a 13 year old girl
• Symptoms for 2 years, then biopsy
• Histology Read as adamantinoma
• Treated with amputation
• At final path read as non typical Ewings

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Van Haelst 1975

• Treated with Actinomycin D and XRT
• 4 months later pulmonary mets
• XRT/Actinomycin? CTX/VCR?CXR(-)
• 2 months later LN mets?XRT/Actin?(-)
• 1 month later- lung-? chemo
• 1month later calf mass? XRT
• 1 month later lung?chemo?SD
• 3 months later?lung?adria?death

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Van Haelst 1975

• Pathology
• Pro ADAM - squamous changes in central part of
  tumor, pearl formation, keratin, tonofilaments
  with frayed ends, desmosomes on EM
• Pro EWS glycogen granules, age, locale, Xrays,
  most of histology, was chemo sensitive, had
  progressive downhill course
• Called it Poorly differentiated Adamantinoma of
  small bone clinically simulating Ewings

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Meister 1979

• 1968 29yr old LU arm pain for 4 years
• Bx c/w lipid granuloma
• 1973 re-biopsy adamantinoma
• Surgery with tibial implant
• 1974 10cm local recurrence ?surgery
• 1975 L axillary node?surgery (interthoraco-scapu
  lar amputation) adria VCR then MTX, CTX, VBL
• Months later lung mets and scar recur?XRT
  without success

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Meister 1979

• 1976 - patient refused chemo secondary to side
  effects and turned to a quack for medical
  advice..
• 1977 local recur L cw and lung ?died 13 years
  after initial symptoms

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Meister 1979

• Pathology over time
• fibrous connective tissue and narrow chains of
  tumor cells
• Occasional PAS() cytoplasm
• Rare mitosis c/w ADAM
• 1974 larger solid cellular tumor c/w EWS
• 1975 both histologies but more EWS over time (no
  eptihelial morphology but () desmosomes)

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Meister 1979

• Pro-ADAM pathology, age, sex, locale, indolent
  (9yrs)
• Lytic(cystic), sclerosis on Xray, pulm mets,
  strands of cells and fibrous stroma
• Pro EWS solid cells, large cells, occ PAS(),
  mesenchymal structure
• Called Ewing-like Adamantinoma

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Lipper 1983

• Had a patient with
• ADAM small epith cells in trabeculae and nests
  supported by fibrous stroma
• EWS primitive mesenchymal cells, rich in
  glycogen but united by desmosome-like
  condensations
• primitive pluripotential stem cells that undergo
  squamous differentiation

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Fukunaga 1998

• 15 yr old boy with tibial tumor, well 16mo after
  surgery
• Path
• Epitheloid cells were Leu() and
  synaptophysin(), NSE(), O13() (EWS-like)
• Lesional cells were pancytokeratin() and EMA(),
  periosteal locale, epith elements (ADAM)
• Concluded it was a variant of adamantinoma,
  possibly related to Ewings

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Hauben 2001

• To test the hypothesis that these two are related
  they studied 12 pts with confirmed adamantinoma
• Checked for t(11,22) or t(21,22) by PCR
• None had the fusion transcipts
• Further, Ewings is CK 8,18() and adamantinomas
  are not (14,19,5)
• Concluded the overlap is morphologic, not
  cytogenetic or immunohistochemical
• Recommend in rare cases, check cytogenetics and
  IHC to make diagnosis!

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Hazelbag Dec 2003

• claims to have a new morphologic variant of
  adamantinoma with sarcomatoid transformation of
  the epithelial component
• 3 case reports which show the malignant
  progression from OFD to adamantinoma to Ewing
  like lesion (ie tumor plasticity)

Hazelbag et al AM J Surg Path 2003271530
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Case 1

• 83 yr old tibial fracture
• Biopsy - 4cm lesion met of sarcomatoid
  carcinoma with osteochondroid matrix
• No primary tumor
• BKA solid tumor 7cm, well 7 yrs later

Hazelbag et al AM J Surg Path 2003271530
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Case 2

• 63 yr old man left tibia swelling/pain
• Surgery classic adamantinoma
• 8 months later recur sarcomatous degeneration
  of adamantinoma
• XRT done
• 4 yrs later patient is fine

Hazelbag et al AM J Surg Path 2003271530
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Case 3

• 2 yr old male radiographic dx of fibrous
  dysplasia of left tibia
• 5yr old fracture treated conservatively
• 37 years breakthrough cortex, biopsy classic
  adamantinoma?surgery with marginally negative
  margins
• 40 yr old lesion at distal allograft bx
  showed high grade sarcomatous tumor with
  epithelial phenotype
• LN and lung mets and refused treatmnet
• Died 14 months later

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Results of Histology

• Case 1 and case 2 recurrence were similar
• Foci of classic adamantinoma and gradual
  transformation to a diffuse growing pattern of
  cells with loss of clear epithelial
  differentiation
• Increased nuclear pleomorphism
• Case 3 recurrence had no adamantinoma, had
  necrosis, large cells

Hazelbag et al AM J Surg Path 2003271530
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Results of IHC

• All tumors were pancytokeratin positive, vimentin
  () and EGFR() (though recurrences were more
  EGFR)
• Ki-67 was increased in recurrent cases 2,3
• Case 3 had increase in p53 staining in recurrence
• Case 1 CK14, 19
• Case 2 CK8,18 focal in primary, increased in
  recurrence (more Ewing-like)
• Case 3 primary CK19 lost in recur

Hazelbag et al AM J Surg Path 2003271530
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Ewings/Adamantinoma Relationship

• 1 study showed 3 cases of nontypical Ewings (2 of
  which werent in the tibia)
• all were PCRt(11,22)
• The retro study by Haubin on 12 documented
  adamantinomas
• showed NONE had t(11,22)
• The two entities show overlapping IHC and
  morphology, so PCR can differentiate

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Case Study

• Since it was a high grade lesions with features
  of Ewings, she was treated with post op
  Adria/Ifos/VCR alt with VP16/Ifos for three
  cycles
• CTs every 3 months
• Close followup exams
• Doing well 4 years out (still weighs over 300
  pounds)

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Conclusion

• The relationship between osteofibrous dysplasia,
  adamantinomas, and Ewings is still to be defined.