Ronald de Vreeze, research physician Daphne de Jong Petra Nederlof Henrique Ruijter Rick Haas

Multifocal myxoid liposarcoma, metastasis or second primary tumor? A molecular biological

analysis.

• Ronald de Vreeze, research physician• Daphne de Jong• Petra Nederlof• Henrique Ruijter• Rick Haas• Frits van Coevorden

• Multifocality 1% soft tissue sarcomas

• Liposarcoma 20% of all malignancies in adults

• The multifocal (lipo)sarcoma = Myxoid round cell liposarcoma

Introduction

Introduction

Definition

• Multifocal (myxoid lipo)sarcoma: The presence of sarcoma at two separate sites, before

the manifestation of disease in sites where sarcomas most commonly metastasizes, in particular the lungs

Introduction

Purpose

Molecular biological differentiation between metastasis and 2nd primary tumors

• In case of 2nd primary:– Optimal local treatment: Radiotherapy

Surgery

• In case of metastasis: – Systemic treatment : Chemotherapy

Marginal resection

Introduction

Methods• N=15• Clinical data

afterwards inconclusive• Histopatologic classification

not distinctive• Translocation analysis

type translocation: difference or similarity in subsequent lesion can give information:

clonal or 2nd primary

• Loss of heterozygosity analysis difference in pattern can give information:

clonal or 2nd primary

Methods

Translocation frequency

7-2 (type I) 20%

8-2 (type III) 10%

Other types 10%

Methods

Translocation frequency

7-2 (type I) 20%5-2 (type II) 60%8-2 (type III) 10%

Other types 10%

Methods

Loss of heterozygosity

• Clinics already introduced at– Head / neck & lung tumors– Multifocal breast cancer

Methods

Loss of heterozygosity (LOH)

• 12 markers spread over 11 chromosomes

• Patterns of loss of heterozygosity

Methods

LOH ratio < 0,5

Strategy of analysis of clonality

1)Translocation2)Loss of heterozygosity

Methods

Strategy of analysis of clonalityTranslocation

Concordantrare fusion transcript

(i.e.7-2 8-2, 5-3)

Fusion transcript 5-2

Different fusion

transcripts at different sites

Metastasis

Discordant LOH

≤1 LOHor

≤2 AI

≥2 LOHor

≥ 3 AI

Second primary

Second primary

Concordant LOH/AI

(LOHx – LOHx)

≤ 1 LOHor

≤ 2 AI

≥ 2 LOHor

≥ 3 AI

LOH analysis

Discordant LOH/AI

(LOHx – LOHy)

Metastasis?Second Primary?

≥ 1 LOH+

≥ 1 AI

Metastasis

≥1 LOH+

≥ 1 AI

Methods

Results• N=15

• Primary localization – Lower extremity 14– Upper extremity 1

• Localization 2nd lesion– Extremity 4– Abdominal wall 4– Retroperitoneal 3– Head/Neck 1– Other 3

• Median time to 2nd lesion 25 (0-82)

Results

PatientsTime (mnts)

Translocation

1a Thigh1b Neck1c Chest wall

3844

5-35-35-3

2a Thigh2b Th Spine2c Lung2d Abd wall

213030

7-27-2

3a Upper arm3b Back3c Forearm

2064

8-28-28-2

4a Thigh4b Chest wall4c Retroperitoneum

018

8-28-28-2

5a Thigh 5b Retroperitoneal5c Neck5d Buttock5e Hip

14141932

7-27-27-2

6a Calf6b Subclavia6c Axilla6d Lung

002

7-27-27-2

7a Thigh7b Retroperitoneal7c Lung7d Th Spine

022

5-2

Time(mnts)

Translocation

8a Thigh8b Upper arm R8c Shoulder L8d Buttock

747582

5-2

9a Thigh9b Abd. wall9c Omentum9d Omentum9e Hip

12222236

5-25-25-2

10a Thigh10b Retroperitoneal 28

5-25-2

11a Calf11b Hip 22

5-2

12a Thigh12b Buttock 14 5-213a Thigh13b Upper arm13c Retroperitoneal

6571

5-25-25-2

14a Ankle14b Chest wall 58

5-25-2

15a Thigh15b Chest wall15c Back15d Retroperitoneal

202743

5-25-25-2

Results

TranslocationTime

(mnts)Translocation


3844

5-35-35-3


213030

7-27-2


2064

8-28-28-2


018

8-28-28-2


14141932

7-27-27-2


002

7-27-27-2


022

5-2

Time(mnts)

Translocation


747582

5-2


12222236

5-25-25-2


5-25-2

11a Calf11b Hip 22

5-2


6571

5-25-25-2


5-25-2


202743

5-25-25-2

Results

Loss of HeterozygosityTime

(mnts)Translocation


3844

5-35-35-3


213030

7-27-2


2064

8-28-28-2


018

8-28-28-2


14141932

7-27-27-2


002

7-27-27-2


022

5-2

Time(mnts)

Translocation


747582

5-2


12222236

5-25-25-2


5-25-2

11a Calf11b Hip 22

5-2


6571

5-25-25-2


5-25-2


202743

5-25-25-2

Results

ResultsPatient Translocation LOH Decision

1 Clonal Unconvincing Clonal



4 Clonal Suggestive for clonal relation Clonal

5 Clonal Clonal Clonal

6 Clonal Clonal Clonal

7 Suggestive for clonal relation Clonal Clonal

8 Suggestive for clonal relation Clonal Clonal

9 Suggestive for clonal relation Suggestive for clonal relation Suggestive for clonal relation

10 Suggestive for clonal relation Suggestive for clonal relation Suggestive for clonal relation

11 Suggestive for clonal relation Unconvincing Suggestive for clonal relation





Results

Results

• Clonal 8/15• Suggestive for clonal relation 7/15

• Not in a single case development of independent second primary tumors was found

Results

Conclusions

• It is highly suggestive that: multifocal myxoid/ round cell liposarcoma are metastasized tumors

• Primary curative surgical approach is probably not rational• Treatment strategy designed for metastasized disease is more

appropriate

Conclusions

Ronald de Vreeze, research physician Daphne de Jong Petra Nederlof Henrique Ruijter Rick Haas

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