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Fluorescence In Situ Hybridization for MDM2 Amplification as a Routine Ancillary Diagnostic Tool for Suspected Well-Differentiated and Dedifferentiated Liposarcomas: Experience at a Tertiary Center.

Thway K, Wang J, Swansbury J, Min T, Fisher C - Sarcoma (2015)

Bottom Line: Methods.It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies.There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH for MDM2 amplification is diagnostically contributory.

View Article: PubMed Central - PubMed

Affiliation: Sarcoma Unit, Royal Marsden Hospital, London SW3 6JJ, UK.

ABSTRACT
Background. The assessment of MDM2 gene amplification by fluorescence in situ hybridization (FISH) has become a routine ancillary tool for diagnosing atypical lipomatous tumor (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma (WDL/DDL) in specialist sarcoma units. We describe our experience of its utility at our tertiary institute. Methods. All routine histology samples in which MDM2 amplification was assessed with FISH over a 2-year period were included, and FISH results were correlated with clinical and histologic findings. Results. 365 samples from 347 patients had FISH for MDM2 gene amplification. 170 were positive (i.e., showed MDM2 gene amplification), 192 were negative, and 3 were technically unsatisfactory. There were 122 histologically benign cases showing a histology:FISH concordance rate of 92.6%, 142 WDL/DDL (concordance 96.5%), and 34 cases histologically equivocal for WDL (concordance 50%). Of 64 spindle cell/pleomorphic neoplasms (in which DDL was a differential diagnosis), 21.9% showed MDM2 amplification. Of the cases with discrepant histology and FISH, all but 3 had diagnoses amended following FISH results. For discrepancies of benign histology but positive FISH, lesions were on average larger, more frequently in "classical" (intra-abdominal or inguinal) sites for WDL/DDL and more frequently core biopsies. Discrepancies of malignant histology but negative FISH were smaller, less frequently in "classical" sites but again more frequently core biopsies. Conclusions. FISH has a high correlation rate with histology for cases with firm histologic diagnoses of lipoma or WDL/DDL. It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies. There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH for MDM2 amplification is diagnostically contributory.

No MeSH data available.


Related in: MedlinePlus

(a) Well-differentiated liposarcoma (WDL). This typical example shows differentiated adipose tissue intersected by thick fibrous septa containing spindle cells with enlarged, hyperchromatic nuclei. (b) This WDL shows lobules of mature adipose tissue, with fibrous septa containing minimal atypia, and can be difficult to distinguish from fibrolipoma or lipoma with fat necrosis. (c) Fat necrosis. This can be extensive, with prominent histiocytes containing plump nuclei, making it difficult to distinguish from WDL. (d) Dedifferentiated liposarcoma (DDL) showing a “low grade” pattern of dedifferentiation can be mistaken for a variety of lesions, including benign neoplasms such as neurofibromas, those of intermediate biologic potential such as fibromatosis, or with other sarcomas such as low grade fibromyxoid sarcoma. FISH for assessment of MDM2 amplification status is useful in supporting the diagnosis of DDL. (e) This myxoid variant of DDL bears a striking resemblance to myxoid liposarcoma (MLPS). Evidence of MDM2 amplification with FISH is strongly supportive of DDL, as MDM2 amplification is not described in MLPS. (f) Fluorescence in situ hybridization for MDM2 amplification status. The green CEP 12 signals are located on the centromere of chromosome 12 and the red MDM2 signals are located on the long arm of the same chromosome (12).
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fig1: (a) Well-differentiated liposarcoma (WDL). This typical example shows differentiated adipose tissue intersected by thick fibrous septa containing spindle cells with enlarged, hyperchromatic nuclei. (b) This WDL shows lobules of mature adipose tissue, with fibrous septa containing minimal atypia, and can be difficult to distinguish from fibrolipoma or lipoma with fat necrosis. (c) Fat necrosis. This can be extensive, with prominent histiocytes containing plump nuclei, making it difficult to distinguish from WDL. (d) Dedifferentiated liposarcoma (DDL) showing a “low grade” pattern of dedifferentiation can be mistaken for a variety of lesions, including benign neoplasms such as neurofibromas, those of intermediate biologic potential such as fibromatosis, or with other sarcomas such as low grade fibromyxoid sarcoma. FISH for assessment of MDM2 amplification status is useful in supporting the diagnosis of DDL. (e) This myxoid variant of DDL bears a striking resemblance to myxoid liposarcoma (MLPS). Evidence of MDM2 amplification with FISH is strongly supportive of DDL, as MDM2 amplification is not described in MLPS. (f) Fluorescence in situ hybridization for MDM2 amplification status. The green CEP 12 signals are located on the centromere of chromosome 12 and the red MDM2 signals are located on the long arm of the same chromosome (12).

Mentions: The diagnosis of WDL and DDL can be challenging, particularly in core biopsy material where tissue is sparse, or where the histologic features are subtle. Particular areas of confusion include (a) distinguishing WDL (Figures 1(a)-1(b)) from benign mimics (e.g., lipomas including spindle cell/pleomorphic lipomas and fibrolipomas and fat necrosis (Figure 1(c)), (b) distinguishing DDL from other pleomorphic sarcomas in the absence of a well-differentiated component or antecedent history of WDL, and (c) differentiating morphologic variants of WDL/DDL (Figure 1(d)) from other (pleomorphic and myxoid) LPS (Figure 1(e)). These lead to differences in opinion even amongst soft tissue pathologists, and cases sent to tertiary referral centers often include lipomas that are reclassified as WDL and vice versa [4, 5].


Fluorescence In Situ Hybridization for MDM2 Amplification as a Routine Ancillary Diagnostic Tool for Suspected Well-Differentiated and Dedifferentiated Liposarcomas: Experience at a Tertiary Center.

Thway K, Wang J, Swansbury J, Min T, Fisher C - Sarcoma (2015)

(a) Well-differentiated liposarcoma (WDL). This typical example shows differentiated adipose tissue intersected by thick fibrous septa containing spindle cells with enlarged, hyperchromatic nuclei. (b) This WDL shows lobules of mature adipose tissue, with fibrous septa containing minimal atypia, and can be difficult to distinguish from fibrolipoma or lipoma with fat necrosis. (c) Fat necrosis. This can be extensive, with prominent histiocytes containing plump nuclei, making it difficult to distinguish from WDL. (d) Dedifferentiated liposarcoma (DDL) showing a “low grade” pattern of dedifferentiation can be mistaken for a variety of lesions, including benign neoplasms such as neurofibromas, those of intermediate biologic potential such as fibromatosis, or with other sarcomas such as low grade fibromyxoid sarcoma. FISH for assessment of MDM2 amplification status is useful in supporting the diagnosis of DDL. (e) This myxoid variant of DDL bears a striking resemblance to myxoid liposarcoma (MLPS). Evidence of MDM2 amplification with FISH is strongly supportive of DDL, as MDM2 amplification is not described in MLPS. (f) Fluorescence in situ hybridization for MDM2 amplification status. The green CEP 12 signals are located on the centromere of chromosome 12 and the red MDM2 signals are located on the long arm of the same chromosome (12).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4355609&req=5

fig1: (a) Well-differentiated liposarcoma (WDL). This typical example shows differentiated adipose tissue intersected by thick fibrous septa containing spindle cells with enlarged, hyperchromatic nuclei. (b) This WDL shows lobules of mature adipose tissue, with fibrous septa containing minimal atypia, and can be difficult to distinguish from fibrolipoma or lipoma with fat necrosis. (c) Fat necrosis. This can be extensive, with prominent histiocytes containing plump nuclei, making it difficult to distinguish from WDL. (d) Dedifferentiated liposarcoma (DDL) showing a “low grade” pattern of dedifferentiation can be mistaken for a variety of lesions, including benign neoplasms such as neurofibromas, those of intermediate biologic potential such as fibromatosis, or with other sarcomas such as low grade fibromyxoid sarcoma. FISH for assessment of MDM2 amplification status is useful in supporting the diagnosis of DDL. (e) This myxoid variant of DDL bears a striking resemblance to myxoid liposarcoma (MLPS). Evidence of MDM2 amplification with FISH is strongly supportive of DDL, as MDM2 amplification is not described in MLPS. (f) Fluorescence in situ hybridization for MDM2 amplification status. The green CEP 12 signals are located on the centromere of chromosome 12 and the red MDM2 signals are located on the long arm of the same chromosome (12).
Mentions: The diagnosis of WDL and DDL can be challenging, particularly in core biopsy material where tissue is sparse, or where the histologic features are subtle. Particular areas of confusion include (a) distinguishing WDL (Figures 1(a)-1(b)) from benign mimics (e.g., lipomas including spindle cell/pleomorphic lipomas and fibrolipomas and fat necrosis (Figure 1(c)), (b) distinguishing DDL from other pleomorphic sarcomas in the absence of a well-differentiated component or antecedent history of WDL, and (c) differentiating morphologic variants of WDL/DDL (Figure 1(d)) from other (pleomorphic and myxoid) LPS (Figure 1(e)). These lead to differences in opinion even amongst soft tissue pathologists, and cases sent to tertiary referral centers often include lipomas that are reclassified as WDL and vice versa [4, 5].

Bottom Line: Methods.It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies.There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH for MDM2 amplification is diagnostically contributory.

View Article: PubMed Central - PubMed

Affiliation: Sarcoma Unit, Royal Marsden Hospital, London SW3 6JJ, UK.

ABSTRACT
Background. The assessment of MDM2 gene amplification by fluorescence in situ hybridization (FISH) has become a routine ancillary tool for diagnosing atypical lipomatous tumor (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma (WDL/DDL) in specialist sarcoma units. We describe our experience of its utility at our tertiary institute. Methods. All routine histology samples in which MDM2 amplification was assessed with FISH over a 2-year period were included, and FISH results were correlated with clinical and histologic findings. Results. 365 samples from 347 patients had FISH for MDM2 gene amplification. 170 were positive (i.e., showed MDM2 gene amplification), 192 were negative, and 3 were technically unsatisfactory. There were 122 histologically benign cases showing a histology:FISH concordance rate of 92.6%, 142 WDL/DDL (concordance 96.5%), and 34 cases histologically equivocal for WDL (concordance 50%). Of 64 spindle cell/pleomorphic neoplasms (in which DDL was a differential diagnosis), 21.9% showed MDM2 amplification. Of the cases with discrepant histology and FISH, all but 3 had diagnoses amended following FISH results. For discrepancies of benign histology but positive FISH, lesions were on average larger, more frequently in "classical" (intra-abdominal or inguinal) sites for WDL/DDL and more frequently core biopsies. Discrepancies of malignant histology but negative FISH were smaller, less frequently in "classical" sites but again more frequently core biopsies. Conclusions. FISH has a high correlation rate with histology for cases with firm histologic diagnoses of lipoma or WDL/DDL. It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies. There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH for MDM2 amplification is diagnostically contributory.

No MeSH data available.


Related in: MedlinePlus