Mayo Medical Laboratories

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1 Mayo Medical Laboratories Virtual Lectures 2014 MFMER 2016 MFMER slide-1

2 Virtual Lectures Planning Committee Disclosure Summary As a provider accredited by ACCME, College of Medicine, Mayo Clinic (Mayo School of CPD) must ensure balance, independence, objectivity and scientific rigor in its educational activities. Course Director(s), Planning Committee Members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of these relevant financial relationships will be published in activity materials so those participants in the activity may formulate their own judgments regarding the presentation. Listed below are individuals with control of the content of this program who have disclosed Relevant financial relationship(s) with industry: None No relevant financial relationship(s) with industry: Karen Fritchie, M.D. program speaker Curtis Hanson, M.D. program planning committee Sharon Preuss program planning committee Bobbi Pritt, M.D., MSc, DTMH program planning committee Melissa Peterson program planning committee 2016 MFMER slide-2

3 Presenter: Karen Fritchie, M.D. Consultant, Anatomic Pathology Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, Minnesota MFMER 2016 MFMER slide-3

4 Lipomatous tumors Karen Fritchie, MD Associate Professor of Laboratory Medicine and Pathology Mayo Clinic, Rochester, Minnesota 2016 MFMER slide-4

5 Karen Fritchie, M.D.: Disclosures Relevant Financial Relationship(s) None The DLMP Grand Rounds Planning Committee members listed below declare that they have nothing to disclose in relation to this presentation: Loralie J. Langman, Ph.D. Justin D. Kreuter, M.D. Elitza S. Theel, Ph.D. Thomas Huntley Darci R. Block, Ph.D. Anja C. Roden, M.D. Rondell P. Graham, M.B.B.S. Denise Skudlarek 2016 MFMER slide-5

6 Learning Objectives Upon completion of this presentation, participants should be able to: You Review should classification feel comfortable and general working principles up a well-differentiated of lipomatous lipomatous lesion. tumors Apply principles to common clinical scenarios Discuss utility of fluorescence in situ hybridization (FISH) in workup of adipocytic lesions Review differential diagnoses and pitfalls in fatty tumors 2016 MFMER slide-6

7 How I spend most of my day Carcinoma? Melanoma? Mesothelioma? Lymphoma? Sarcoma? 2017 MFMER slide-7

8 If it s not carcinoma, melanoma, meso, or lymphoma What type of sarcoma? Angiosarcoma? Rhabdomyosarcoma? Leiomyosarcoma? Undifferentiated sarcoma? Back to carcinoma? 2017 MFMER slide-8

9 Not a diagnostic dilemma 2017 MFMER slide-9

10 Goal: You should feel comfortable working up a well-differentiated lipomatous lesion MFMER slide-10

11 Outline Terminology Rules of fatty tumors Cases 2017 MFMER slide-11

12 Terminology Lipoma = benign lipomatous tumor Liposarcoma = malignant lipomatous tumor 2017 MFMER slide-12

13 Terminology Benign Lipoma Malignant Well-differentiated liposarcoma Spindle cell/pleomorphic lipoma Dedifferentiated liposarcoma Angiolipoma Myolipoma Myxoid liposarcoma Pleomorphic liposarcoma Chondroid lipoma Hibernoma Lipoblastoma 2017 MFMER slide-13

14 Behavior of well-differentiated liposarcoma by SITE 2017 MFMER slide-14

15 Atypical lipomatous tumor Atypical lipomatous tumor and well-differentiated liposarcoma are the same entity. Site Extremity Retroperitoneum Terminology Atypical lipomatous tumor Well-differentiated liposarcoma Groin Well-differentiated liposarcoma Mediastinum Well-differentiated liposarcoma 2017 MFMER slide-15

16 Terminology Benign Locally aggressive Malignant Lipoma Atypical lipomatous tumor/ well-differentiated liposarcoma Dedifferentiated liposarcoma Spindle cell/pleomorphic lipoma Myxoid liposarcoma Angiolipoma Myolipoma Chondroid lipoma Hibernoma Lipoblastoma Pleomorphic liposarcoma 2017 MFMER slide-16

17 Outline Terminology Rules of fatty tumors Cases 2017 MFMER slide-17

18 Rules of lipomatous neoplasms 1. Location: Lipomas (generally) occur in superficial soft tissue Liposarcomas (generally) occur in deep soft tissue 2. Do not look for lipoblasts!!! 3. Cytogenetics are often helpful in appropriate classification 2017 MFMER slide-18

19 Location, location, location. Superficial = above the fascia Think benign (lipoma, spindle cell lipoma, reactive processes) Deep = below fascia (intramuscular), retroperitoneum, groin or mediastinum Worry about liposarcoma Skin Subcutaneous fat FASCIA Skeletal muscle Bone 2017 MFMER slide-19

20 Lipoblasts MFMER slide-20

21 Never look for them. Why? There are A LOT of mimics Lipoblasts are found in benign entities Lipoblasts are not necessary for the diagnosis of liposarcoma Silicone implant reaction Fat necrosis Fat atrophy 2017 MFMER slide-21

22 Atypical hyperchromatic stromal cells: Diagnostic cell of atypical lipomatous tumor/welldifferentiated liposarcoma 2017 MFMER slide-22

23 Atypical hyperchromatic stromal cells 2017 MFMER slide-23

24 Atypical hyperchromatic stromal cells Vessel walls Fibrous septa 2017 MFMER slide-24

25 Importance of cytogenetics in lipomatous neoplasms Genetic event Lipoma Translocations involving 12q13-15 Spindle cell/pleomorphic lipoma Lipoblastoma Hibernoma Chondroid lipoma Myxoid liposarcoma Round cell liposarcoma Well-differentiated liposarcoma Dedifferentiated liposarcoma Loss of 16q, 13q (RB1) Translocations involving 8q11-13 (PLAG1) Translocations involving 11q13, 10q22 Fusions involving C11orf9 and MKL2 FUS-CHOP (DDIT3) FUS-CHOP (DDIT3) Amplification of MDM2 Amplification of MDM MFMER slide-25

26 Rules of lipomatous neoplasms 1. Location: Lipomas (generally) occur in superficial soft tissue Liposarcomas (generally) occur in deep soft tissue 2. Do not look for lipoblasts!!! 3. Cytogenetics are often helpful in appropriate classification 2017 MFMER slide-26

27 Outline Terminology Rules of fatty tumors Cases 2017 MFMER slide-27

28 Easy cases 2017 MFMER slide-28

29 40 year old male with 5 cm subcutaneous thigh mass. 1. Location 2. Atypical hyperchromatic stromal cells? 3. Cytogenetics Diagnosis: Lipoma Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-29

30 40 year old male with 5 cm subcutaneous thigh mass. Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-30

31 40 year old male with 5 cm subcutaneous thigh mass. Diagnosis: Lipoma with fat necrosis Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-31

32 Lipoma Age: Mobile, painless No fibrous or solid areas; <10 cm No atypical hyperchromatic stromal cells 55-75% have chromosomal aberrations 2017 MFMER slide-32

33 60 year old with 15 cm intramuscular thigh mass. Diagnosis: Atypical lipomatous tumor Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-33

34 80 year old with 20 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-34

35 20 cm, 2 sections???? 2017 MFMER slide-35

36 Case 3: 20 cm retroperitoneal mass more sections Diagnosis: Well-differentiated liposarcoma Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-36

37 Atypical lipomatous tumor/well differentiated liposarcoma 6 and 7 th decades of life M=F Deep soft tissue sites Deep muscles of extremities (ALT) Groin/retroperitoneum (WDL) Mediastinum (WDL) Non-metastasizing Rate of local recurrence related to site May dedifferentiate 2017 MFMER slide-37

38 Tougher cases 2017 MFMER slide-38

39 45 year old with 20 cm intramuscular thigh mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-39

40 45 year old with 20 cm intramuscular thigh mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-40

41 45 year old with 20 cm intramuscular thigh mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-41

42 Atrophic skeletal muscle: Mimic of atypical hyperchromatic stromal cells Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-42

43 What next? Rule #3. Cytogenetics are often helpful in appropriate classification 2017 MFMER slide-43

44 2017 MFMER slide-44

45 2017 MFMER slide-45

46 How do we see these rearrangements, ring chromosomes and marker chromosomes? Send fresh tissue (ie, frozen section lab) for conventional cytogenetics. Remember this technique!!! It s a valuable resource MFMER slide-46

47 What about consult material or if we forgot to send fresh tissue for cytogenetics or if we work at an institution without access to conventional cytogenetics? 2017 MFMER slide-47

48 2017 MFMER slide-48

49 These cells have amplification of MDM2. And so do these MFMER slide-49

50 2017 MFMER slide-50

51 2017 MFMER slide-51

52 2017 MFMER slide-52

53 FISH for MDM2: MDM2 amplification status Lipoma Atypical lipomatous tumor Negative Positive Well-differentiated liposarcoma Positive *In the context of well differentiated lipomatous neoplasms MFMER slide-53

54 Back to our case: 20 cm Intramuscular thigh mass No cytologic atypia Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-54

55 Fluorescence in situ hybridization for MDM2 Our case Positive control: MDM2 amplified 2017 MFMER slide-55

56 Back to our case: 20 cm Intramuscular thigh mass No cytologic atypia FISH for MDM2 negative Diagnosis: Intramuscular lipoma Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-56

57 When do I do FISH studies for MDM2 amplification? 2017 MFMER slide-57

58 2017 MFMER slide-58

59 70 year old male with a 3 cm subcutaneous shoulder mass Diagnosis: Pleomorphic lipoma Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-59

60 70 year old male with a 3 cm subcutaneous shoulder mass Diagnosis: Pleomorphic lipoma Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-60

61 Spindle cell/pleomorphic lipoma Head, neck, back, posterior shoulder Older males Asymptomatic long-standing subcutaneous nodule Mature adipose tissue, spindle cells, ropey collagen CD34 positive Benign 2017 MFMER slide-61

62 Spindle cell lipoma 2017 MFMER slide-62

63 Spindle cell lipoma = fat, spindle cells, ropey collagen 2017 MFMER slide-63

64 CD34 immunostain 2017 MFMER slide-64

65 2017 MFMER slide-65

66 Spindle cell lipoma: pseudoangiomatous pattern 2017 MFMER slide-66

67 Spindle cell lipoma: myxoid 2017 MFMER slide-67

68 Pleomorphic lipoma 2017 MFMER slide-68

69 The importance of a karyotype 2017 MFMER slide-69

70 65 year old with 23 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-70

71 60 year old with 20 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-71

72 60 year old with 20 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-72

73 What next? Rule #3. Let s FISH for MDM2 amplification MFMER slide-73

74 FISH for MDM2: negative Courtesy of Dr. Reid Meyer and Dr. Robert Jenkins 2017 MFMER slide-74

75 Back to our case: 23 cm Retroperitoneal mass No cytologic atypia FISH for MDM2 negative What would make me feel even better about calling this a lipoma? 2017 MFMER slide-75

76 Courtesy of Dr. Reid Meyer and Dr. Robert Jenkins 2017 MFMER slide-76

77 Back to our case: 23 cm Retroperitoneal mass No cytologic atypia FISH for MDM2 negative Karyotype consistent with lipoma Diagnosis: Lipoma 2017 MFMER slide-77

78 48 year old with 16 cm intramuscular thigh mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-78

79 48 year old with 16 cm intramuscular thigh mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-79

80 48 year old with 16 cm intramuscular thigh mass FISH for MDM2 amplification is negative. Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-80

81 Back to our case: 16 cm Intramuscular thigh mass No cytologic atypia FISH for MDM2 negative Diagnosis? Lipoma? 2017 MFMER slide-81

82 Courtesy of Dr. Patricia Greipp 2017 MFMER slide-82

83 Back to our case: 16 cm Intramuscular mass No cytologic atypia FISH for MDM2 negative Karyotype suggestive of hibernoma 2017 MFMER slide-83

84 48 year old with 16 cm intramuscular thigh mass Diagnosis: hibernoma 2017 MFMER slide-84

85 Hibernoma Benign fatty tumor Variable brown fat Young adults (mean 38 years) Thigh>trunk/chest/upper extremity Typically subcutaneous Median size 9 cm Rearrangements in 11q MFMER slide-85

86 Tricky cases 2017 MFMER slide-86

87 60 year old with 20 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-87

88 60 year old with 20 cm retroperitoneal mass Diagnosis? Hibernoma? Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-88

89 Diagnosis: Well-differentiated liposarcoma Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-89

90 80 year old with 20 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-90

91 80 year old with 20 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-91

92 Well-differentiated liposarcoma + High grade sarcoma = Dedifferentiated liposarcoma 2017 MFMER slide-92

93 Dedifferentiated liposarcoma Malignant lipomatous tumor ALT/WDL showing progression to sarcoma* Accounts for most pleomorphic sarcomas in the retroperitoneum Retroperitoneum>>Extremities Middle aged to elderly High recurrence rates Capable of distant metastases 2017 MFMER slide-93

94 Sarcoma* Old definition of dedifferentiated liposarcoma Sarcoma = high grade non-lipogenic But, dedifferentiation can also be low-grade MFMER slide-94

95 Dedifferentiated liposarcoma with low-grade dedifferentation 2017 MFMER slide-95

96 Sarcoma* Old definition of dedifferentiated liposarcoma Sarcoma = high grade non-lipogenic But, dedifferentiation can also be low-grade. And, dedifferentiation can be lipogenic MFMER slide-96

97 Dedifferentiated liposarcoma with homologous lipoblastic differentiation 2017 MFMER slide-97

98 The faces of dedifferentiated liposarcoma 2017 MFMER slide-98

99 2017 MFMER slide-99

100 40 year old with 6 cm esophageal mass Dedifferentiated lipsarcoma 2017 MFMER slide-100

101 Dedifferentiated liposarcoma Most common pleomorphic sarcoma in the retroperitoneum It can look like ANYTHING Have a high degree of suspicion for dedifferentiated liposarcoma when looking at a high grade malignancy in this retroperitoneum 2017 MFMER slide-101

102 Dedifferentiated liposarcoma: genetics Most have ring or giant marker chromosomes Consistent amplification of MDM2 More complex events and amplification/alternations of other genes 2017 MFMER slide-102

103 FISH for MDM2: MDM2 amplification status Lipoma Atypical lipomatous tumor Negative Positive Well-differentiated liposarcoma Positive Dedifferentiated liposarcoma* Positive *Other malignancies (carcinoma, lymphomas) can have MDM2 amplification MFMER slide-103

104 (Back to) Terminology Benign Locally aggressive Malignant Lipoma Atypical lipomatous tumor/ Dedifferentiated liposarcoma Well-differentiated liposarcoma Spindle cell/pleomorphic lipoma Myxoid liposarcoma Hibernoma Pleomorphic liposarcoma Angiolipoma Myolipoma Hibernoma Lipoblastoma 2017 MFMER slide-104

105 70 year old with retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-105

106 70 year old with retroperitoneal mass What now? Think about common things carcinoma, melanoma, lymphoma. Done. Now what? What is the most common pleomorphic sarcoma in the retroperitoneum? + sarcoma = dedifferentiated liposarcoma Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-106

107 70 year old with retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-107

108 70 year old with retroperitoneal mass Well-differentiated liposarcoma + High grade sarcoma = Dedifferentiated liposarcoma 2017 MFMER slide-108

109 Dedifferentiated liposarcoma Most common pleomorphic sarcoma in the retroperitoneum It can look like ANYTHING Have a high degree of suspicion for dedifferentiated liposarcoma when looking at a high grade malignancy in this retroperitoneum Careful sampling of fatty areas is KEY!!! 2017 MFMER slide-109

110 Not everything with fat is a lipomatous neoplasm 2017 MFMER slide-110

111 45 year old female with 10 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-111

112 Our case: 10 cm Retroperitoneum No cytologic atypia FISH for MDM2 negative Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-112

113 45 year old female with 10 cm retroperitoneal mass Location, atypical hyperchromatic stromal cells, cytogenetics 2017 MFMER slide-113

114 45 year old female with 10 cm retroperitoneal mass 2017 MFMER slide-114

115 45 year old female with 10 cm retroperitoneal mass HMB45 HMB45 Smooth muscle actin Diagnosis: Angiomyolipoma 2017 MFMER slide-115

116 Perivascular epithelioid cell neoplasm (PEComa) Mesenchymal neoplasm composed of PECs Angiomyolipoma without fat Broad group that includes: Angiomyolipoma Clear cell sugar tumor of the lung Lymphangioleiomyomatosis Female predominance Show smooth muscle AND melanocytic differentiation Most are benign 2017 MFMER slide-116

117 Other mesenchymal tumors that can occur in the retroperitoneum and have a component of mature fat PEComa (angiomyolipoma) Solitary fibrous tumor Genital stromal tumors Mammary-type myofibroblastoma Cellular angiofibroma Angiomyofibroblastoma Ganglioneuroma 2017 MFMER slide-117

118 Mammary-type myofibroblastoma 2017 MFMER slide-118

119 Solitary fibrous tumor, lipomatous variant 2017 MFMER slide-119

120 Lipomatous ganglioneuroma 2017 MFMER slide-120

121 Benign Locally aggressive Malignant Lipoma Atypical lipomatous tumor/ Dedifferentiated liposarcoma Well differentiated liposarcoma Spindle cell/pleomorphic lipoma Myxoid liposarcoma Angiolipoma Pleomorphic liposarcoma Myolipoma Chondroid lipoma Hibernoma Lipoblastoma 2017 MFMER slide-121

122 Rules of lipomatous neoplasms 1. Location: Lipomas (generally) occur in superficial soft tissue Liposarcomas (generally) occur in deep soft tissue 2. Look for atypical hyperchromatic stromal cells!!! 3. Cytogenetics are often helpful in appropriate classification 2017 MFMER slide-122

123 Questions & Discussion 2017 MFMER slide-123

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