Medenica Day Program Book 2013 - The University of Chicago

Medenica Day Program Book 2013 - The University of Chicago

The 6th Annual Dermatopathology Day at
the University of Chicago
Wednesday, 20 March 2013
1 PM – 5 PM
Center for Care and Discovery, Board Room 7850
Featuring Lecturer:
Thomas Krausz, MD
Professor of Pathology
Director, Anatomic Pathology
The University of Chicago
Dr. Maria Medenica Lecture
"Lipogenic Tumors: From Concepts to Practicalities"
University of Chicago Resident and Fellow Forum
Slide Seminar by Thomas Krausz, MD
Hosted By:
The University of Chicago
Section of Dermatology
5841 S. Maryland Ave, MC 5067
Chicago, IL 60637
Contact: Ms. Moira Goodwin | [email protected] | Phone: (773) 702 0549
The 6th Annual Dermatopathology Day at the University of Chicago
TABLE OF CONTENTS
Dermatopathology Day Program
Page 3
Biography of Thomas Krausz, MD
Page 4
2013 Dr. Maria Medenica Lecture:
Thomas Krausz, MD
Page 5
Resident and Fellow Forum
Page 26
Biography of Maria Medenica, MD
Page 29
List of Donors
Page 30
The 6th Annual Dermatopathology Day at the University of Chicago
Page 2
The 6th Annual Dermatopathology Day at the University of Chicago
PROGRAM
1:00 Opening Comments and
Introduction of Speaker
Christopher R. Shea, MD
1:05 Medenica Memorial Lecture
Thomas Krausz, MD
2:15 Resident and Fellow Forum
Christopher Kinonen, MD
Cindy Davis, MD
Adaobi Nwaneshiudu, MD
Min Deng, MD
Edidiong Kaminska, MD
3:15 Coffee Break
3:30 Slide Seminar
Thomas Krausz, MD
The 6th Annual Dermatopathology Day at the University of Chicago
Page 3
Thomas Krausz, MD
Dr. Thomas Krausz graduated from Semmelweis
University Medical School, Budapest, Hungary, in 1972.
He began his pathology training in Budapest, immigrated
to the United Kingdom, and continued his training at the
Hammersmith Hospital, Royal Postgraduate Medical
School in London (MRCPath, 1981). He was appointed at
the same institution as Senior Lecturer in Histopathology
in 1984, Reader in 1991, and full Professor in 1996.
Following the merger of the Royal Postgraduate Medical
School
and
Imperial
College,
he
became
the
Chief
of
Service
(1998)
in
Histopathology/Cytopathology at the Hammersmith Hospitals NHS Trust within the Division
of Investigative Sciences, Imperial College School Medicine, London, UK. He was recruited
as Professor of Pathology to the University of Chicago in 2000 to be the Director of
Anatomic Pathology.
Dr. Krausz’s main interests are in general surgical pathology/cytopathology,
melanocytic lesions, soft tissue tumor pathology, mesothelioma and gynaecological
pathology including breast pathology. He has taught courses in Europe, USA, Canada, India
and South America. His longest running course was “Diagnostic Pathology of Soft Tissue
Tumors” with Dr. Chris Fletcher, which ran annually for 25 years. His broad interests are
also reflected by his research activities in a wide range of diseases.
Dr. Krausz has become a key figure in his field. He has published over 180 articles in
peer-reviewed journals and is a co-author of the textbook “Pathology of Melanocytic
Disorders”, which is now in its second edition (2007, published by Hodder Arnold). He is on
the editorial board of several scientific journals, and has served in several professional
societies, including: President of the Chicago Pathology Society, Cancer Committee of
College of American Pathologists, Council of Association of Directors of Anatomic and
Surgical Pathologists US, and Council of Royal College of Pathologists, UK.
The 6th Annual Dermatopathology Day at the University of Chicago
Page 4
WHO (2013) classification of adipocytic tumors
Maria Medenica Lecture, March 20, 2013
Lipogenic tumors: from concepts to practicalities
update on the pathology of fatty tumors
Thomas Krausz
University of Chicago
Lipoma
Lipomatosis
Lipomatosis of nerve
Lipoblastoma/lipoblastomatosis
Angiolipoma
Myolipoma
Benign
Chondroid lipoma
Extra-renal angiomyolipoma
Extra-adrenal myelolipoma
Spindle cell/pleomorphic lipoma
Hibernoma
Intermediate (locally aggressive)
Atypical lipomatous tumor/well differentiated liposarcoma
Dedifferentiated liposarcoma
Myxoid liposarcoma
Malignant
Pleomorphic liposarcoma
Liposarcoma NOS
Primary liposarcoma of the skin:
Lipomatous tumors
a rare neoplasm with unusual high grade features
lipogenic and non-lipogenic components
Dei Tos et al, Am J Surg Pathol 1998; 20:332-338
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Liposarcoma rarely occurs as primary cutaneous lesion
Seven cases of primary cutaneous liposarcoma (out of 671
consecutive liposarcomas)
39 to 75 years (median 72 years)
Scalp (4), knee (1), thigh (1), forearm (1)
Pleomorphic liposarcoma (4), atypical lipomatous tumor/WD
liposarcoma (2), myxoid/round cell liposarcoma (1)
Local recurrence (2 cases); no disease related death
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Tumors with obvious lipogenesis:
lipoma, atypical lipomatous tumor- well differentiated adipocytic
liposarcoma (ALT-WDLPS)
Tumors with “hidden” lipogenesis:
spindle cell/pleomorphic lipoma, lipoblastoma, dedifferentiated
liposarcoma, myxoid/round cell liposarcoma, pleomorphic liposarcoma
The relationship between
lipogenic and non-lipogenic cells is poorly understood
Both components are important
not only for diagnosis but also for prognosis and therapy
Lipogenic tumors
Lipomatous tumors
what is the relationship between
the lipogenic and the non-lipogenic cells?
the non-lipogenic components
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Spindle cells: spindle cell lipoma, dedifferentiated liposarcoma
(DDLPS)
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Pleomorphic stromal cells:
pleomorphic lipoma, ALT-WDLPS/DDLPS, pleomorphic liposarcoma

Round cells: myxoid/round cell liposarcoma
Heterologous components: bone, cartilage, muscle
(lipoma, ALT-WDLPS, DDLPS)
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The answer lies in the factors of embryologic fat development
and in the specific genetic/molecular alterations of lipogenic tumors
Adipocytes are not “born” as adipocytes and
lipoblasts are not “born” as lipoblasts
(they develop from mesenchymal precursor/stem cells)
Lipogenesis is a complex process and signals differentiation
Non-lipogenic cellular components represent the proliferative
compartment of lipogenic tumors
Page 5
Prominence of non-lipogenic elements in atrophic adipose tissue
non-lipogenic spindle cells, branching capillaries
Lipoma
Translocation: 12q13-15 with no amplification
Lipoma is obviously lipogenic
with mature adipocytes but also
rare non-lipogenic cells
fibrolipoma
myxolipoma
Angiolipoma
non-lipogenic elements in variants of lipoma
Osteolipoma
“Heterologous” non-lipogenic differentiation in variants of lipoma
fibrolipoma
lipoma with
Spindle cell lipoma: prominence of non-lipogenic cells
Myolipoma
Chondroid lipoma
Spindle cell lipoma: what do the non-lipogenic spindle cells represent?
ropey collagen
Page 6
the spindle cells are not fibroblasts in
spindle cell lipoma
fibroblasts for comparison in a
desmoplastic fibroblastoma
The spindle cells in reality are CD34 positive (S100 negative) dendritic cells
CD34
Spindle cell lipoma
13q14 deletion
loss of RB1
 Rb is an important tumor suppressor protein that plays a role in cell
cycle progression
loss of nuclear Rb expression
 Loss of Rb protein leads to cell proliferation
 Rb also has a role in adipocytic differentiation
 13q14 deletion in spindle cell and pleomorphic lipomas
account not only for tumorigenesis but also focal block of lipogenesis
spindle cell lipoma
Spindle cell lipoma
and its variants show no expression of MDM2, CDK4, p16
(in contrast to WDLS/DDLS)
 Conventional
 Spindle cell predominant
 Vascular
 Pseudoangiomatous
 Myxoid
 Multiple
 Mixed spindle cell/pleomorphic lipoma
MDM2
p16
Spindle cell lipoma - vascular
Pseudoangiomatous spindle cell lipoma
Page 7
Myxoid spindle cell lipoma
Myxolipoma
myxoid spindle cell lipoma differs from myxolipoma
myxoid spindle cell lipoma
CD34
S10
Hibernoma - spindle cell type
Mixed spindle cell/pleomorphic lipoma
Pleomorphic lipoma sclerotic
Lipoblast
loss of nuclear Rb expression
Pleomorphic lipoma - myxoid
Floret cells
CD34
Page 8
Looks pleomorphic lipoma but in reality it is an atypical lipomatous tumor
Intradermal
spindle cell/pleomorphic lipoma
 Twenty (12.7%) intradermal tumors (14 spindle cell, 6
intramuscula
r
pleomorphic) identified among 157 spindle cell/pleomorphic
lipomas
lipoblasts
floret cells
CD34
p16
 20 to 85 years (median 42 years)
 70% female
 Head & neck, shoulder/upper back, lower limbs, trunk, upper limbs
 Infiltrative margins
 One case recurred after 21 years
French CA et al, Am J Surg Pathol 2000; 22:496-502
MDM2
Lipomatous tumors
CD34 positive non-lipogenic cells
 Spindle cell lipoma: all the spindle cells are positive but adipocytes
are negative
 Pleomorphic lipoma: both spindle cells and pleomorphic stromal
cells are positive
 Well-differentiated liposarcoma: some pleomorphic stromal cells
are positive but lipogenic cells are negative
 Key question: what do these CD34 positive non-lipogenic spindle
cells represent? Part of the answer can be found in embryonic
development of adipose tissue
Intradermal spindle cell lipoma
Embryonic tissue, 8 weeks
Developing adipose tissue, preadipocytic stage
Embryonic skin/subcutis, 8 weeks
CD34
CD34
CD34
Developing adipose tissue, preadipocytic stage
Page 9
Adipose tissue
Embryonic development of
stages of prenatal adipose tissue development
 Stage I: spindle cells in myxoid matrix
 Stage II: spindle cells condense around blood vessels
 Stage III: spindle preadipocytes in rich lobular capillary network
 Stage IV: accumulation of
multiple lipid droplets in spindle cells
(multivacuolated fat cells)
 Stage V: further accumulation of intracytoplasmic
lipid
adipose tissue
Develops from perivascular non-lipogenic spindle cells:
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Down-regulation of wnt10b, foxa-2 and pref-1
Up-regulation of C/EBPβ,δ,α and PPAR-  lipogenesis 
development of lipoblasts/adipocytes
Lipogenesis: associated with deposition of
collagen IV and laminin around lipoblasts/adipocytes and
expression of S100 protein
(unilocular fat cells)
Developing adipose tissue (18 weeks)
Embryonic development of adipose tissue
upregulation of adipogenic factors
PPARγ1/2
C/EBP
β
C/EBP
δ
Mesenchymal
progenitor cells
Adipose tissue
adipocytes
C/EBPα
Mostly spindle cells (prelipoblasts) in a richly vascular myxoid matrix – also rare lipoblasts
Developing adipose tissue (21 weeks)
Foxa-2 still upregulated
spindle cells (prelipoblasts) and multivacuolated lipoblasts
Developing adipose tissue (26 weeks) - Lipogenesis
mostly multivacuolated lipoblasts
downregulation of Foxa-2
Page 10
Late stage of lipogenesis (26-weeks)
Well-differentiated liposarcoma
versus
Atypical lipomatous tumor
Synonyms
Coll. IV
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Same morphology, cytogenetics, molecular genetics
Complete surgical excision is curative
No metastatic capability
WHO classification: intermediate (locally aggressive) category
However, if excision is incomplete, local recurrence is common and
5-15% risk of malignant progression termed dedifferentiation with
acquisition of metastatic potential
PPAR-
Preferred diagnostic term according to anatomic sites
Well-differentiated liposarcoma
Atypical lipomatous tumor
 Retroperitoneum
 Spermatic cord
 Mediastinum
 Skin
 Subcutis
 Muscle of extremities
Not to underestimate the
significance of such a
diagnosis!
Atypical lipomatous tumor
well differentiated liposarcoma
 40-45% of liposarcomas
 Peak age fifth to seventh decade
 Mostly limbs and retroperitoneum
 Mostly deep-seated but also in subcutaneous tissue and
rarely in the skin
 History of large, long-standing mass
 Mortality: 0% for extremity and >80% for retroperitoneal cases
 Recent rapid growth - dedifferentiation
Atypical lipomatous tumor
well-differentiated liposarcoma
Histologic types
 Adipocytic (lipoma-like)
 Sclerosing
 Inflammatory

ALT – WDLPS (adipocytic) lipoblast-rich variant
Rarely: focal heterologous well differentiated osseous, cartilagineous,
smooth or striated muscle differentiation – NOT dedifferentiation
Page 11
Relationship between non-lipogenic and lipogenic cells
is poorly understood, however ....
Atypical lipomatous tumor
well-differentiated liposarcoma
Cytogenetic changes: supernumerary
Molecular genetics: amplifications
ring chromosomes and long marker
chromosomes from 12q 14 - 15
MDM2 (100%) and HMGA2
CDK4 (85%)
Lipoblasts
Well differentiated LPS/ATL
FISH
Rings with no centromeres only
“neocentromeres”
atypical non-lipogenic stromal cells
WD liposarcoma/atypical lipomatous tumor - MDM2
immunohistochemistry
WD liposarcoma/atypical lipomatous tumor - CDK4
FISH
Courtesy of J. Bridge
also over-expression of p16
WD Liposarcoma - inflammatory
MDM2 - CDK4 – p16
role of immunohistochemistry in the diagnosis of
well differentiated and dedifferentiated liposarcomas
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Most ALT/WDL/DDL express MDM2 (90%) CDK4 (86%) p16 (93%)
68% of ALT/WDLS and 72% of DDLS express all three antigens
100% of ALT/WDLS and 93% of DDLS express at least two
antigens
Useful in differentiating ALT/WDLS from benign fatty tumors
Useful in differentiating DDLS from pleomorphic liposarcoma and
myxoid liposarcoma
Useful in differentiating DDLS from other poorly differentiated
sarcomas
Thway K et al, Am J Surg Pathol 2012; 36:462-469
inflammatory reaction – scattered non-lipogenic bizarre tumor cells
Page 12
MDM2
WD liposarcoma - inflammatory
CDK4
WD liposarcoma – inflammatory
non-lipogenic bizarre tumor cells with hyaline globules (secondary lysosomes - thanatosomes)
inflammation - apoptosis - phagocytosis
Proposed model for the formation of hyaline globules
WD Liposarcoma - sclerosing
Scattered non-lipogenic and lipogenic cells
apoptosis (“thanatosomes”) – phagocytosis - cytoplamic blebbing - protein insudation
phagocytosis
nuclear condensation/fragmentation
cytoplasmic blebbing
protein insudation in the various cell compartments
plasma protein insudation
Papadimitriou JC et al: Human Pathol. 2000; 31:1455-65
Fine fibrillary collagen
WD liposarcoma versus hibernoma
ATL/WD liposarcoma, adipocytic
selected differential diagnoses
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Lipoma variants
Conventional
Hibernoma: 11q13
Lipomatous hibernoma
Lipoma-like angiomyolipoma
Giant retroperitoneal lipoma
lipoma-like hibernoma
Page 13
Lipoma-like angiomyolipoma
Giant retroperitoneal lipoma (32 cm)
no bizarre stromal cells – no lipoblasts in 60 blocks examined
HMB45
Lipoma with classic t(3;12)(q27;q15)
In one block, in the septum: “floret-type” stromal cells in a giant retroperitoneal lipoma
see reference: Schmack I et al, Subconjunctival herniated orbital fat, Am J Surg Pathol, 2007; 31:193-198
Malignant lipogenic tumors
conceptual classification
based on clinicopathologic and molecular genetic characteristics
 Dedifferentiated liposarcoma
still a lipoma and NOT a liposarcoma
 Myxoid liposarcoma /round cell liposarcoma
 Pleomorphic liposarcoma
no amplification of MDM2 and CDK4
Chromosomal aberrations
Dedifferentiated Liposarcoma
malignant lipogenic tumors
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Atypical lipomatous tumor
well differentiated liposarcoma
Supernumerary ring chromosomes
and long marker chromosomes from
amplified segments of 12q14 -15
Dedifferentiated liposarcoma
Same as above, but increase
in gene dosage effect and ….
Myxoid/round cell liposarcoma
t(12;16)(q13;p11)
t(12;22)(q13;q11-12)
Pleomorphic liposarcoma
Complex aberrations
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Accounts for 10% of liposarcomas – substantial amplification of MDM2
Well-differentiated liposarcoma which shows abrupt transition, either
in the primary tumor or in a recurrence, usually to a non-lipogenic sarcoma
of variable histologic grade
Rarely, the high grade component may be lipogenic
90% de novo
10% in recurrences
Retroperitoneum : somatic soft tissue = 5:1
occurrence in subcutis very rare
5-year metastatic risk is 15 - 20%
Page 14
Dedifferentiated liposarcoma - metastatic rate: 15 - 20%
Dedifferentiated liposarcoma – broad histologic spectrum
retroperitoneum, deep-seated tissue, rarely superficial location
 High grade pleomorphic non-lipogenic sarcoma
 Myxoid non-lipogenic sarcoma resembling
lipogenic
non-lipogenic
low grade myxofibrosarcoma
 Low grade spindle cell non-lipogenic sarcoma (fibromatosis-like)
 With meningothelial-like whorls
 Richly vascular, nested, paraganglioma-like pattern
 With heterologous differentiation
 Rarely focal lipogenic pleomorphic liposarcoma-like areas
WD liposarcoma
MDM2
Dedifferentiated liposarcoma
CDK4
Dedifferentiated liposarcoma with meningothelial-like whorls and ossification
p16
SMA and focal Claudin-1 – ? myofibroblastic and possibly perineurial differentiation
Dedifferentiated liposarcoma – heterologous cartilaginous differentiation
Lipogenic tumors
heterologous elements do not always indicate dedifferentiation
Heterologous differentiation may occur not only in DD liposarcoma
but also in ALT/WD liposarcoma and lipoma
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Focal cartilaginous differentiation
Focal osseous differentiation
Focal smooth muscle differentiation
In cases of “real” dedifferentiation the heterologous elements are
histologically malignant and mixed with other dedifferentiated
sarcomatous components showing mitotic activity
MDM2
Page 15
Intramuscular mass of arm
When to consider a diagnosis of
dedifferentiated liposarcoma?
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atypical lipomatous tumor with focal cartilaginous differentiation – NOT dedifferentiation
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Not only in the classic histologic setting
Soft tissue sarcomas which are difficult to classify
Pleomorphic “undifferentiated” sarcomas without identifiable
well differentiated liposarcomatous component
Sarcomas with heterologous differentiation
Sarcomas showing meningothelial-like whorls
in the absence of other specific lineage of differentiation
Richly vascular, nested, paraganglioma-like neoplasm
not expressing neuroendocrine markers
Dedifferentiated liposarcoma – round cell areas
Dedifferentiated liposarcoma
CDK4
Progression of atypical lipomatous tumor – WD liposarcoma
to dedifferentiated liposarcoma
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Atypical lipomatous tumor – WD liposarcoma: composed mainly of
lipogenic cells (adipocytes, rare lipoblasts) and
scattered non-lipogenic cells (atypical stromal cells)
Dedifferentiated liposarcoma: composed of mitotically active nonlipogenic cells (spindle cells, pleomorphic cells, or heterologous
tissue components)
Key question: what molecular changes drive tumor progression from
a biologically intermediate tumor to an aggressive neoplasm with
metastatic capability and usually absence of lipogenecity?
MDM2
Progression of ALT-WDLPS to DDLPS traditional concept:
further amplification of sequences of 12q14-15
oncogenesis
(MDM2,CDK4)
G1
p53
inactivated
E2F
RB
phosphorylated
S
G0
--------------
MDM2
Decreased apoptosis
12q15
amplicon
Increased cell survival
G2
M
CDK4
G1 – S progression
Increased cell proliferation
12q14
amplicon
Cancer cell
Page 16
Progression of ALT-WDLPS to DDLPS traditional concept:
further amplification of sequences of 12q14-15
oncogenesis
Progression of WD liposarcoma to dedifferentiated liposarcoma
recent data: better understanding of tumor progression and
blocked lipogenecity
(MDM2,CDK4)
treatment - clinical trials
Nutlin-3 MDM2 inhibitor reactivates
the p53 pathway
inactivated
Flavopiridol CDK4 inhibitor causes
decreased cell proliferation
G1
p53
E2F
RB
phosphorylated


S
G0
MDM2
-------------Decreased apoptosis
12q15
amplicon
Increased cell survival
G2
M
CDK4

G1 – S progression
Increased cell proliferation
12q14
amplicon
Cancer cell
1p32
JUN
oncogene
amplification
Dedifferentiated liposarcoma – CGH
6q23
ASK1
MAP3 kinase
amplification
Jean-Michel Coindre et al, Virchows Arch 2009
In addition to the 12q14-15 amplicon, there is co-amplification of
JUN at 1p32 or ASK1 at 6q23 in dedifferentiated liposarcoma
Co-amplification of JUN and ASK1 are mutually exclusive and
never seen in pure WDLPS
WD liposarcoma – Dedifferentiated liposarcoma
mechanism of progression

12q14-15
MDM2 HMGA2 CDK4
amplification
General concept: dedifferentiation of WD liposarcoma likely to occur
via multiple alternative genetic alterations
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Amplified c-Jun in dedifferentiated liposarcoma is interspersed with
amplified MDM2 in ring and giant marker chromosomes which
suggests that c-Jun is amplified at a similar time in the evolution of
the tumor
c-Jun amplification and expression can be found in the
well-differentiated component of dedifferentiated liposarcoma,
suggesting that c-Jun amplification may occur before
dedifferentiation
c-Jun protein is expressed in the majority of dedifferentiated
liposarcomas (91%) and their well differentiated components (59%),
but only in the minority of pure well-differentiated liposarcomas (27%)
c-JUN over-expression
• c-JUN
• MDM2
• co-amplification
Dedifferentiated Liposarcoma
Fletcher CDM et al, J Pathol 2009
dedifferentiated liposarcoma
Page 17
Dedifferentiated Liposarcoma
Dedifferentiated Liposarcoma
both c-JUN and ASK1 oncogenes can block the adipocyte differentiation program
both c-JUN and ASK1 oncogenes can block the adipocyte differentiation program
Clinical trials:
PPARγ1/2
P
C/EBP
β
c-JUN
1p32
P
JNK
Thioredoxin – ASK1 antagonist
Aplidin – JNK activation - apoptosis
PPARγ1/2
P
P
C/EBP
β
ASK1
6q23
C/EBP
δ
c-JUN
1p32
P
P
JNK
ASK1
6q23
C/EBP
δ
Well differentiated
liposarcoma
Dedifferentiated
liposarcoma
Well differentiated
liposarcoma
C/EBPα
WD liposarcoma – Dedifferentiated liposarcoma
models of progression
Dedifferentiated
liposarcoma
C/EBPα
Progression of well differentiated liposarcoma to
dedifferentiated liposarcoma
(Fletcher CDM et al, J Pathol 2009)
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Model 2 is in accordance with the observation that all of the c-Junamplified tumors published so far presented with dedifferentiation
(Helias-Rodzewicz Z et al, Genes Chromosomes & Cancer 2009; 48:943 - 952
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Amplicon:
MDM2
HMGA2
c-Jun or ASK1
Amplicon:
MDM2
HMGA2
Model 2: not only MDM2 and HMGA2 but also c-Jun or ASK1
amplification providing additional oncogenic stimulus leading to
increased proliferation, faster progression and
dedifferentiation at the time of diagnosis
WD liposarcoma – Dedifferentiated liposarcoma
another suggested mechanism of dedifferentiation

Pathway 2
Pathway 1
Model 1: minimum number of oncogene (MDM2 and HMGA2)
amplification associated with indolent tumor,
low rate of dedifferentiation and WD liposarcoma at presentation
Indolent tumor
Low rate of dedifferentiation
Presents as WD liposarcoma
Aggressive tumor
High rate of dedifferentiation
Presents as DD liposarcoma
Selective elimination of CDK4 sequences in micronuclei
correlates with spontaneous adipocytic differentiation in liposarcoma
Helias-Rodzewicz Z et al Genes Chromosomes & Cancer 2009; 48:943-952
5-MC
CDK4
Merge
DNA
DD liposarcoma: amplified segments of CDK4 gene is often integrated
into chromosome arms, which are stable – CDK4 protein promotes cell
proliferation, thus precluding adipocytic differentiation
WD liposarcoma: amplified segments of CDK4 gene are located in ring
chromosomes which are unstable - CDK4 segments are often eliminated
in the form of micronuclei
lipogenecity (lipoblasts, adipocytes)
In tissue culture, a dramatic increase of of adipocytic differentiation seen
in cells that have eliminated copies of CDK4 gene in micronuclei
Page 18
Myxoid Liposarcoma
Myxoid/round cell liposarcoma
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30 - 35% of liposarcomas
Peak age 3rd to 5th decade
Slight male predominance
Predilections for limbs, especially thigh (rare in retroperitoneum)
Mostly deep-seated but rarely also in subcutaneous tissue
Multiple soft tissue metastasis
5-year survival, pure myxoid: 90%
5-year survival, pure round cell: 25%
Microcystic, lymphangioma-like variant of myxoid liposarcoma with myxoid pools
Myxoid liposarcoma
only rare lipoblasts
Myxofibrosarcoma mimicking myxoid liposarcoma
Myxoid liposarcoma
differential diagnosis
 Myxofibrosarcoma, low grade
 Well differentiated liposarcoma with myxoid change
 Lipoblastoma
 Myxolipoma
 Intramuscular myxoma
 Spindle cell lipoma, myxoid vascular variant
Pseudolipoblasts with mucosubstance rather than lipid in their cytoplasm
Page 19
WD Liposarcoma with myxoid change
mimicking myxoid liposarcoma
Lipoblastoma – immature myxoid
mimicking myxoid liposarcoma
Lipoblastoma
Lipoblastoma
chromosomal rearrangements of 8q11-13 with activation of PLAG1
 Lower extremities
 Upper extremities
 Head and neck
 Trunk
 Mediastinum
 Mesentery
 Retroperitoneum
Liposarcomas in children
 Benign fatty tumor
 Occurs in infancy and early childhood
 90% of cases present before 3 years of age
 40% of cases occur before 1 year of age, occasionally at birth
 Sporadic examples above the age of 10 years
 Some lipomas in adults with 8q11-12 aberration could represent
fully mature lipoblastomas
 Recurrence rate:
14 – 25%
Round cell liposarcoma
 Exceedingly rare - most cases reported before 1959 probably
represent lipoblastomas
 90% of pediatric liposarcomas occur in the second decade of life
 Median age: 13 years (Schmookler and Enzinger, 1983),
18 years (LaQuaglia et al., 1993)
a poorly differentiated form
of myxoid liposarcoma
 No credible example below the age of 3 years
 Histology: myxoid liposarcoma (majority), well-differentiated,
round cell, pleomorphic (rarely)
Page 20
Round cell liposarcoma – mostly non-lipogenic cells
S-100
Round cell liposarcoma
Calretinin
PPAR
Myxoid - Round cell liposarcoma – focal lipogenecity
Myxoid/round cell liposarcoma
correlation with clinical outcome
Round cell population
 0 – 5%
23%
 5 -10%
35%
 >25%
58%
Myxoid/round cell liposarcoma
 Less than 5% of round cell differentiation:
grade I, “myxoid liposarcoma”
 5 - 25% of round cell differentiation:
grade II “mixed myxoid and round cell liposarcoma”
 More than 25% of round cell differentiation:
Metastasis
Myxoid liposarcoma
“transitional area”




Histologically between myxoid and
round cell liposarcoma
Hypercellular compared with the
low cellularity of typical myxoid liposarcoma
Tumor cells (mostly non-lipogenic) are
separated some myxoid stroma
Plexiform vascular pattern is discernible
grade III, “round cell liposarcoma”
Page 21
Spectrum of myxoid liposarcoma
Myxoid/round cell liposarcoma
genetic aberrations
 t(12;16)(q13;p11) – 95% of cases
fusion protein FUS(TLS)-DDIT3 (CHOP)
pure myxoid, 5-year survival 90%
pure round cell, 5-year survival 25%
 t(12;22)(q13;q12) – 5% of cases
fusion protein EWS-DDIT3 (CHOP)
 Additional activating PIK3CA mutation or alternatively
homozygous loss of PTEN in round cell liposarcomas
round and myxoid, 5-year survival variable
t(12;16)(q13;p11) FUS-DDIT3 fusion
Therapy 1. Trabectedin (a natural marine compound) causes detachment of the
FUS-DDIT3 chimera from the targeted promoters and induces differentiation in
myxoid/round cell liposarcoma
FUS-DDIT3 oncogene of myxoid/round cell liposarcoma
blocks the adipocyte differentiation program
2.Troglitazone treatment
PPARγ1/2
PPARγ1/2
PPAR
γ
C/EBP
β
C/EBP
β
FUS-DDIT3
eIF4E
FUS-DDIT3
C/EBP
δ
C/EBP
δ
mesenchymal
progenitor cells
myxoid/round cell
liposarcoma
mesenchymal
progenitor cells
C/EBPα



myxoid/round cell
liposarcoma
C/EBPα
Peroxisome Proliferator-Activated Receptor-Gamma
(PPARγ)


eIF4E
Pleomorphic liposarcoma – complex genomic profile
absence of MDM2/HMGA2/CDK4 amplification
 Lower extremity (36.5%), upper extremity (16%),
thoraco-abdominal wall (9.5%), internal trunk (20.9%)
A member of nuclear receptor family
A key transcriptional regulator of cell differentiation and
lipid metabolism
Main role in adipocyte differentiation
 Most cases arise in deep soft tissue but about 25% develop in
subcutaneous tissue and rare cases are located in the dermis
 Three major histologic types: high-grade pleomorphic sarcomalike, epithelioid/carcinoma-like, round cell liposarcoma-like
Most round cell, dedifferentiated and pleomorphic liposarcomas
express PPARγ
 Presence of lipoblasts are necessary for the diagnosis
Biological receptor for the thiazolidinedione class of
antidiabetic drugs (troglitazone, rosiglitazone etc.)

but their number varies considerably
Aggressive behavior with metastatic rates of 30 – 50% and 5-year
survival of about 60%
Page 22
Pleomorphic liposarcoma – high-grade pleomorphic sarcoma-like
round cell liposarcoma-like
epithelioid/carcinoma-like
MDM2
Pleomorphic liposarcoma
Cutaneous and subcutaneous
Diagnosis of liposarcoma
pleomorphic liposarcoma






Pleomorphic liposarcoma is an uncommon form of liposarcoma that
rarely occurs in the skin and subcutis
29 cases; dermis (4), dermis and subcutis (10), subcutis 15
Extremity (15), trunk (7), head & neck (7)
Liposarcoma unqualified is not a diagnosis
0.8 to 15 cm (median 2 cm)
Pleomorphic spindled (24), epithelioid (5)
Local recurrences in four but no metastasis or death from disease
Gardner JM et al, Am J Surg Pathol 2012; 36:1047-1051
Diagnosis of liposarcoma
 Reliable diagnosis of liposarcoma can not always be made
on histological ground alone, especially on needle core biopsies
 Patient’s age
 Location of tumor
 Tissue plane
Lipoblasts and
the diagnosis of liposarcoma
 Identification of lipoblasts is helpful in the diagnosis of liposarcoma
 Lipoblasts do not automatically make the diagnosis of liposarcoma
valid
 Liposarcoma can be diagnosed in the absence of lipoblasts
 Lipoblast is only one of the cellular constituents of liposarcoma
 Non-lipogenic tumor cells are equally important during diagnostic
considerations
Page 23
Lipoblast
multivacuolated or signet-ring
NUCLEUS
LIPID VACUOLE
 normochromatic
 hyperchromatic
 single
 multinucleated
 must be indented
 perfectly clear
 sharp margin
 circular
 single or multiple
appropriate histologic background with non-lipogenic tumor cells
Mutivacuolated and signet-ring lipoblasts
pseudolipoblast (myxofibrosarcoma)
silicon granuloma
mimics of lipoblasts
lipogranuloma (lipid in macrophages)
Lipogenic tumors
Lipomatous tumors in “disguise”
lipogenecity is hidden or only focally present
Summary
 Both lipogenic and non-lipogenic cellular elements are important
not only diagnostically and but also biologically
 Non-lipogenic cells represent the proliferative compartment of
lipogenic tumors
 Lipogenesis signals differentiation and decreased cell proliferation
 Molecular pathways of lipogenic tumors can be exploited for
therapy
 Lipogenic tumors may occur in “disguise” when the lipogenic
vacuolated GIST





Lipoblastoma/lipoblastomatosis
WD inflammatory and sclerosing liposarcoma
Dedifferentiated liposarcoma
Myxoid/round cell liposarcoma
Pleomorphic liposarcoma
elements are hidden or only focally present
Page 24
Dominance of non-lipogenic elements = increased proliferation rate, metastatic potential
round cell liposarcoma
dedifferentiated liposarcoma
pleomorphic liposarcoma
Ki67
Page 25
Resident and Fellow Forum
Christopher L Kinonen, MD
2012-2013 Dermatopathology Fellow, Section of Dermatology, University of Chicago
“Dermal hypersensitivity reaction: a PCR-confirmed pattern of herpetic dermatitis”
Herpetic dermatitis due to herpes simplex virus (HSV) and varicella zoster virus (VZV)
can present with similar clinical and histopathologic features. Further confounding matters, viral
cytopathic changes are not always observed in biopsy specimens. Therefore, use of polymerase
chain reaction (PCR) analysis can play an integral role in the definitive diagnosis of herpetic
dermatitis and in the distinction of HSV-1/HSV-2 from VZV. Forty patients with skin biopsies
(2004–2011) had PCR analysis performed to detect HSV-1/2 or VZV. Patient demographics,
clinical impression and histopathologic characteristics were reviewed and correlated with PCR
findings. Overall, there was complete correlation between clinical impression, histopathology
and PCR results in 21 of 40 cases. In 19 cases, clinical impression and histopathology were
discrepant and in 15 of these cases PCR confirmed HSV or VZV infection. We also describe 3
cases of herpetic dermatitis, without viral cytopathic changes, that histopathologically
demonstrate the pattern of a dermal hypersensitivity reaction. The results of this study suggest
that routine use of PCR for definitive diagnosis of herpetic dermatitis should be considered when
there is a clinical suspicion of herpes virus infection, even when there is a lack of specific
histopathologic findings. Additionally, a dermal hypersensitivity reaction should be recognized
as one histopathologic manifestation of herpes incognito.
Cindy L. Davis, MD, MEd
2012-2013 Dermatopathology Fellow, Section of Dermatology, University of Chicago
“Spitzoid Melanocytic Neoplasm in a Child”
The histopathologic diagnosis of spitzoid melanocytic lesions is one of the most
challenging in dermatopathology. The differential diagnosis ranges from benign Spitz nevi to
clinically aggressive spitzoid melanomas with poor outcomes. Although most lesions are readily
identified as benign or malignant on routine histopathologic evaluation, ambiguous lesions with
overlapping features do exist. Furthermore, a subset of these lesions, including some atypical
spitz tumors, can involve sentinel lymph nodes without development of distant metastases and
thus have uncertain biologic potential. In the last decade, molecular diagnostic techniques such
as comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) have
been developed as adjuncts for the diagnosis of difficult melanocytic lesions including those with
spitzoid morphology. The case of a spitzoid lesion in a 4 year old child is presented to illustrate
these considerations with discussion of clinical presentation, histopathologic and molecular
evaluation, and clinical follow up.
The 6th Annual Dermatopathology Day at the University of Chicago
Page 26
Adaobi I. Nwaneshiudu, MD PhD
2012-13 Resident, Section of Dermatology, University of Chicago
“Confocal microscopy in the diagnosis of melanocytic neoplasms”
Confocal microscopy uses point illumination via a spatial pinhole to eliminate outof-focus signals. The pinhole is conjugate to the focal point of the lens allowing for
optimal resolution. The excitation light is provided by a laser, which is scanned across
the specimen causing excitation and fluorescence (emitted light) from the specimen. The
fluorescence is focused on the pinhole and measured by a detector, called the
photomultiplier tube. The detector is attached to a computer that collects all the “point
images” of the sample and reconstructs the image, one pixel at a time, and also facilitates
3-D reconstruction. Confocal microscopy allows for collection of serial optical sections
and surface profiling of specimen such as the skin. In vivo reflectance confocal
microscopy (RCM) generates optical sections within the depth of intact living tissue and
is a great tool for studying the skin surface by providing cellular resolution to a depth of
200mm, i.e. up to the superficial dermis. Melanin acts as a natural contrast agent for
RCM, which has been shown to improve melanoma diagnostic accuracy due to the easy
visualization of pigmented cells in which the melanin appear bright under reflectance.
For example, Guitera et al (2012) used in vivo RCM to define unique features that can
distinguish lentigo maligna from benign pigmented macules on the face. Two major
positive diagnostic features for malignancy were identified, i.e. non-edged papillae and
round large pagetoid cells >20mm. One negative diagnostic feature for malignancy was a
broadened honeycomb pattern, which was seen in benign lesions and normal epidermis.
Confocal microscopy has also been studied in the diagnosis of other cutanesous
malignancies and shows promise as a diagnostic aid; however it does have practical
limitations.
Min Deng, MD
2012-2013 Resident, Section of Dermatology, University of Chicago
“Methotrexate induced accelerated nodulosis in a patient with rheumatoid arthritis”
Methotrexate induced accelerated nodulosis (MIAN) is a rare condition
characterized by the abrupt onset of rheumatoid nodules in the setting of methotrexate
therapy. We report a case of a 50-year-old woman with seropositive, erosive rheumatoid
arthritis who developed non-periarticular subcutaneous nodules and new heart murmurs
following initiation of methotrexate despite good control of her arthritis. Histopathologic
examination demonstrated palisading granulomas with central necrobiotic collagen and a
surrounding dense mixed lymphohistiocytic infiltrate with numerous eosinophils and
neutrophils. MIAN has been associated with HLA-DRB1*0401 as well as the A2756GG
polymorphism of the methionine synthase reductase gene. In vitro studies suggest the
mechanism is via stimulation of adenosine A1 receptor. Treatment is controversial.
The 6th Annual Dermatopathology Day at the University of Chicago
Page 27
Edidiong Kaminska, MD, MBS
2012-13 Resident, Section of Dermatology, University of Chicago
“Borderline sebaceous neoplasm in a renal transplant patient without Muir-Torre
syndrome”
Borderline sebaceous neoplasms are rare tumors that can be challenging to
diagnose because of their admixture of histopathologic features. Most such tumors have
been described in patients with Muir-Torre syndrome (MTS). We report the case of an
immunosuppressed, 82-year-old African-American woman without MTS who developed
a rapidly growing lesion on the left cheek. Histopathology revealed a borderline
sebaceous neoplasm with predominant features of sebaceous adenoma and with focal
features raising concern for the possibility of an evolving, well-differentiated, low-grade
sebaceous carcinoma with a high mitotic index. A reduction of immune surveillance via
medication or infection may contribute to the transformation of a benign sebaceous
neoplasm to carcinoma. In the setting of immunosuppression, borderline sebaceous
neoplasms may occur outside of MTS; careful evaluation and conservative treatment are
recommended in managing such tumors.
The 6th Annual Dermatopathology Day at the University of Chicago
Page 28
Maria Medenica, MD
Maria Medenica, MD created an enduring legacy of
dermatopathology at the University of Chicago. Born in Belgrade,
Yugoslavia in 1924, she served the University of Chicago as a
clinical dermatologist, medical scientist, dermatopathologist, and
teacher to countless residents for over thirty years. After receiving
her medical degree in Belgrade in 1954, Dr. Medenica completed her
internship at Ravenswood Hospital in Chicago from 1957 to 1958
followed by her residency in dermatology at the University of
Chicago from 1960 to 1963. For the next three years, she remained at
the University ofChicago as a dermatology research trainee supported
by a US Public Health Service grant, working chiefly in the areas of dermatopathology and
electron microscopy. She received specialty certifications in dermatology in 1965 and in
dermatopathology in 1974.
Between 1967 and 1973, Dr. Medenica served on the dermatologic faculty at the University
of Illinois, at first as Assistant Professor and after 1971 as Associate Professor. There she
taught dermatopathology and notably received a letter of special commendation from the
American Board of Dermatology (ABD) for hersuccess in teaching dermatopathology to
residents, as reflected by their high performance in the histopathologic part of the ABD
examination.
She joined the University of Chicago in 1974 as Associate Professor, where she continued to
carry out investigative dermatologic electron microscopy. Her studies on the comparative
evolution of experimental primary irritant and allergic types of contact dermatitis yielded
important new insights in to the different types of cellular interactions involved in the
development of these reactions. This work attracted wide interest, and subsequent
investigators confirmed its results. Her electron microscopic studies in several dermatologic
disorders provided important new insights into cutaneous pathophysiologic mechanisms. Dr.
Medenica produced a large number of scholarly clinical reports, articles, and reviews based
on the clinical, pathologic, and electron microscopic observations.
Dr. Medenica devoted over more than half of her time to diagnostic work, research, and
teaching in dermatopathology, reviewing and interpreting many thousands of skin biopsy
specimens annually in her laboratory. Her students remember her well for generously
sharing her knowledge and her scientific approach to dermatology with them. Dr. Medenica
retire din May 2005 and was awarded the Gold Key Award from the University of Chicago
Medical and Biological Sciences Alumni Association on June 2, 2006 for her outstanding
work in skin pathology and for her dedication to teaching. In recognition of her signal
service to the Chicago Dermatological Society and to the profession of dermatology, in 2001
she received the prestigious Founders Award from the Chicago Dermatological Society. She
retired from the faculty in July 2005 and died in June 2006.
The 6th Annual Dermatopathology Day at the University of Chicago
Page 29
The 6th Annual Dr. Maria Medenica Lectureship
The Dr. Maria Medenica Lectureship brings renowned dermatopathologists to the University of
Chicago, with the goal of enhancing the education of students, housestaff, and faculty in the
latest concepts and techniques of cutaneous pathology. The Lectureship brings distinction not
only to the recipient, but also to the Section of Dermatology.
To honor Dr. Medenica and her love of dermatopathology, her friends, former students, and
colleagues created a fund for the Dr. Maria Medenica Lectureship. The response has been very
gratifying, and our hope is that through continued interest and support, this lectureship will
continue to commemorate Dr. Medenica in perpetuity.
Inquiries and contributions to the Dr. Maria Medenica Lectureship may be directed to:
Liz Cartwright
The University of Chicago, Section of Dermatology
5841 S. Maryland Avenue, MC5067
Chicago, Illinois 60637
(773) 834 2540 | [email protected]
DONORS
Dr. John G. & Laurie W. Albertini
Drs. Andrew J. & Iris K. Aronson
Dr. & Mrs. Joel E. Bernstein
Dr. Shail Busbey & Mr. Kent D. Daniel
Dr. Carmen C. Casas
Dr. Samantha B. Conrad
Mr. & Mrs. Jeff W. Cummings
Mr. & Mrs. Wilfredo L. Dayon
Dr. Cynthia Dolan
Dr. James O. & Virginia Ertle
Dr. & Mrs. James E. Ethington
Dr. & Mrs. Ahmad Fathizadeh
Dr. Tony Fu
Mr. Guido P Giazzon
Dr. James B. Grossweiner & Mrs. Althea
Grossweiner
Dr. Shelley J. Halper & Mr. Ronald M. Mochizuki
Ms. Judith A. Haugen
Ms. Cheryl A. Isaacs
Dr. Jinxing Jiang
Dr. & Mrs. Everett L. Jones
Dr. John T. Keane
Dr. Sang Hui Kim
Dr. Young P. Kim
Dr. Jeffrey D. Knispel
Dr. Irmgard K. Koehler
Mr. Joseph M. Kolek
Dr. & Mrs. Stanford I. Lamberg
Dr. Anne E Laumann & Mr. Edward O. Laumann
Dr. Lawrence E. Levine
Dr. & Mrs. Tehming Liang
Drs. Ben Z. Cohen & Barbara L. Lukash Cohen
Dr. Carl & Mrs. Margaret Lyda
Dr. & Mrs. Eugene Mandrea
Dr. Martin B. Miller
Dr. Joseph M. Newmark
Drs. J. Kevin & Marianne N. O’Donoghue
Mr. & Mrs. Robert D. Okoniewski
Dr. David S. Pezen
Dr. Susan I. Primmer & Mr. Robert L. Harris
Drs. Arthur H. & Denise Rubenstein
Dr. & Mrs. Christopher R. Shea
Dr. Keyoumars Soltani
Dr. Joseph D. Sosnow
Dr. & Mrs. Gordon H. Stolzner
Dr. & Mrs. Donald E. Temple
Dr. Neda Z. Tkalcevic
Mr. Ernesto L. Torentino
Drs. David Hughes Whitney & Juliana Y.H. Chyu
Drs. Paul a. Nausieda & Evonne M. Winston
Dr. Derek B. & Mrs. Elisabeth Woolner
Dr. Cheuk W. Yung
The 6th Annual Dermatopathology Day at the University of Chicago
Page 30