American Journal of Surgical Pathology Dysplastic lipoma: a distinctive atypical lipomatous neoplasm with anisocytosis, focal nuclear atypia, p53 overexpression and a lack of MDM2 gene amplification by FISH. A report of 66 cases demonstrating occasional multifocality and a rare association with retinoblastoma. --Manuscript Draft-Manuscript Number: Full Title:
Dysplastic lipoma: a distinctive atypical lipomatous neoplasm with anisocytosis, focal nuclear atypia, p53 overexpression and a lack of MDM2 gene amplification by FISH. A report of 66 cases demonstrating occasional multifocality and a rare association with retinoblastoma.
Article Type:
Original Article
Keywords:
Anisometric cell lipoma; Atypical lipoma; Atypical lipomatous tumor; Dysplastic lipoma; Lipoma with fat necrosis; p53; RB1 gene; Retinoblastoma; Soft tissue tumor; Well-differentiated liposarcoma
Corresponding Author:
Michael Michal Charles University, Biomedical Center, Faculty of Medicine in Plzen and Charles University Hospital Plzen Pilsen, CZECH REPUBLIC
Corresponding Author Secondary Information: Corresponding Author's Institution:
Charles University, Biomedical Center, Faculty of Medicine in Plzen and Charles University Hospital Plzen
Corresponding Author's Secondary Institution: First Author:
Michael Michal
First Author Secondary Information: Order of Authors:
Michael Michal Abbas Agaimy, Professor Alejandro Luiña Contreras Marian Svajdler, PhD. Dmitry V. Kazakov, Professor Petr Steiner Petr Grossmann, PhD. Petr Martinek, PhD. Ladislav Hadravsky, PhD. Kvetoslava Michalova, PhD. Peter Svajdler Zoltan Szep, PhD. Michal Michal, Professor John F. Fetsch
Order of Authors Secondary Information: Abstract:
In our routine and consultative pathology practices, we have repeatedly encountered an unusual subcutaneous fatty tumor with notable anisocytosis, single cell fat necrosis, and patchy, often mild, adipocytic nuclear atypia. Because of the focal atypia, Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation
consultative cases have most often been received with concern for a diagnosis of atypical lipomatous tumor (ALT). Similar tumors have been described in small series under the designations "subcutaneous minimally atypical lipomatous tumors" and "anisometric cell lipoma". Sixty-six cases of this tumor type were collected and reviewed. Immunohistochemistry for p53, MDM2, CDK4, Retinoblastoma-1 (RB-1) protein, CD34, S100, and CD163 was performed. Cases were tested for MDM2 gene amplification and RB1 gene deletion with FISH and for TP53 mutations by Sanger sequencing. Next generation sequencing (NGS) analysis using a panel of 271 cancerrelated genes, including TP53, RB1 and MDM2, was also carried out. Our patient cohort included 57 males, 8 females and 1 patient of unstated gender, who ranged in age from 22-87 years (mean: 51.2). All tumors were subcutaneous, with most examples occurring on the upper back, shoulders or posterior neck (86.4%). Ten patients had multiple (2 -5) lipomatous tumors, and the histology was confirmed to be similar in the different sites in 4 of them, including one patient who had a retinoblastoma diagnosed at age 1. The tumors were generally well-circumscribed. At low magnification, there was notable adipocytic size variation with single cell fat necrosis in the background associated with reactive histiocytes. Adipocytic nuclear atypia was typically patchy and characterized by chromatin coarsening, nuclear enlargement and focal binucleation or multinucleation. Focal Lochkern change was frequent. In most instances, the degree of atypia was judged to be mild, but in 3 instances, it was more pronounced. Spindle cells were sparse or absent, and when present, cytologically bland. Thick ropy collagen bundles were absent. In all cases, p53 immunoexpression was noted (range: 2 to 20% of adipocytic nuclei), characteristically highlighting the most atypical cells. Twenty of 50 cases had MDM2 immunoreactivity, usually in 45% of the cells by FISH (our threshold value for reporting a positive result) with an additional 3 cases being very close to the required cutoff value. MDM2 gene amplification was absent in all 60 cases tested, including those with the greatest MDM2 immunoexpression and most pronounced atypia. All five tested cases showed no TP53 mutation with Sanger sequencing. Due to material quality issues, NGS analysis could be performed in only 3 cases, and this did not reveal any recurrent mutations. All tumors were managed by simple local excision. Follow-up was available for 47 patients (range: 1-192 mos.; mean: 27 mos) and revealed 2 local recurrences and no metastases. Dysplastic lipoma is a distinctive atypical fatty tumor variant that has p53 overexpression and RB1 gene abnormalities and lacks MDM2 gene amplification by FISH. These tumors have a strong male predominance and a notable tendency to involve the subcutaneous tissue of the shoulders, upper back and posterior neck. Multifocality is frequent (18.9% of patients with follow-up information), and there is a rare association with retinoblastoma. This tumor warrants separation from ordinary lipoma with fat necrosis, fat-rich spindle cell lipoma and the conventional form of atypical lipomatous tumor that features MDM2 gene amplification.
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Cover Letter
Dear editor in chief,
May 24th, 2018
we are submitting our paper named „Dysplastic lipoma: a distinctive atypical lipomatous neoplasm with anisocytosis, focal nuclear atypia, p53 overexpression and a lack of MDM2 gene amplification by FISH. A report of 66 cases demonstrating occasional multifocality and a rare association with retinoblastoma.“ which we would like to publish in American Journal of Surgical Pathology.
Ethics and conflict of interest: The authors have no conflict of interest to disclose. Informed consent was not required for our study. Supported in parts by the National Sustainability Program I (NPU I) Nr. LO1503 and by the grant SVV–2017 No. 260 391 provided by the Ministry of Education Youth and Sports of the Czech Republic.
Michael Michal M.D. Department of Pathology, Charles University, Medical Faculty and Charles University Hospital Plzen, Alej Svobody 80, 323 00 Pilsen, Czech Republic. Email:
[email protected], cellular phone: +420603792671
Manuscript (include title page, abstract, references, figure legends) Click here to download Manuscript (include title page, abstract, references, figure legends) Dysplastic lipoma version 11.docx
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Dysplastic lipoma: a distinctive atypical lipomatous neoplasm with anisocytosis, focal nuclear atypia, p53 overexpression and a lack of MDM2 gene amplification by FISH. A report of 66 cases demonstrating occasional multifocality and a rare association with retinoblastoma. Running head: Dysplastic Lipoma Michael Michal1, 2, 3; Abbas Agaimy4; Alejandro Luiña Contreras5; Marian Svajdler 1, 3; Dmitry V. Kazakov1, 3; Petr Steiner1, 3; Petr Grossmann1, 3, Petr Martinek1, 3; Ladislav Hadravsky6; Kvetoslava Michalova1, 3; Peter Svajdler7; Zoltan Szep8; Michal Michal1, 3; John F. Fetsch5 1 Department of Pathology, Charles University, Faculty of Medicine in Pilsen, Pilsen, Czech Republic 2 Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Pilsen, Czech Republic 3 Bioptical Laboratory, Ltd., Pilsen, Czech Republic 4 Institute of Pathology, Friedrich‐Alexander University Erlangen‐Nürnberg, University Hospital, Erlangen, Germany 5 The Joint Pathology Center, Silver Spring, MD, USA 6 Department of Pathology, First Faculty of Medicine, Charles University in Prague, Czech Republic 7 Department of Pathology, Louis Pasteur University Hospital, Kosice, Slovakia 8 Cytopathos, Ltd., Bratislava, Slovakia Address for correspondence: Michael Michal M.D. Department of Pathology, Charles University, Medical Faculty and Charles University Hospital Plzen, Alej Svobody 80, 323 00 Pilsen, Czech Republic. Email:
[email protected], cellular phone: +420603792671
Ethics and conflict of interest statement and acknowledgements: The authors have no conflict of interest to disclose. This study was approved by the ethics committee of both Faculty of Medicine and Faculty Hospital in Pilsen, Czech Republic. Informed consent was not required for the study. Supported in parts by the National Sustainability Program I (NPU I) Nr. LO1503 and by the grant SVV–2017 No. 260 391 provided by the Ministry of Education
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Youth and Sports of the Czech Republic. The Joint Pathology Center contributions are covered by research protocol IRB17-0099.
Disclaimer: The views expressed in this manuscript are those of the authors and do not necessarily reflect official policy or position of the Joint Pathology Center, the Department of the Army, the Department of Defense, or any other Department or Agency within the U.S. Government.
Abstract
In our routine and consultative pathology practices, we have repeatedly encountered an unusual subcutaneous fatty tumor with notable anisocytosis, single cell fat necrosis, and patchy, often mild, adipocytic nuclear atypia. Because of the focal atypia, consultative cases have most often been received with concern for a diagnosis of atypical lipomatous tumor (ALT). Similar tumors have been described in small series under the designations “subcutaneous minimally atypical lipomatous tumors” and “anisometric cell lipoma”. Sixty-six cases of this tumor type were collected and reviewed. Immunohistochemistry for p53, MDM2, CDK4, Retinoblastoma-1 (RB-1) protein, CD34, S100, and CD163 was performed. Cases were tested for MDM2 gene amplification and RB1 gene deletion with FISH and for TP53 mutations by Sanger sequencing. Next generation sequencing (NGS) analysis using a panel of 271 cancer-related genes, including TP53, RB1 and MDM2, was also carried out.
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Our patient cohort included 57 males, 8 females and 1 patient of unstated gender, who ranged in age from 22–87 years (mean: 51.2). All tumors were subcutaneous, with most examples occurring on the upper back, shoulders or posterior neck (86.4%). Ten patients had multiple (2 -5) lipomatous tumors, and the histology was confirmed to be similar in the different sites in 4 of them, including one patient who had a retinoblastoma diagnosed at age 1. The tumors were generally wellcircumscribed. At low magnification, there was notable adipocytic size variation with single cell fat necrosis in the background associated with reactive histiocytes. Adipocytic nuclear atypia was typically patchy and characterized by chromatin coarsening, nuclear enlargement and focal binucleation or multinucleation. Focal Lochkern change was frequent. In most instances, the degree of atypia was judged to be mild, but in 3 instances, it was more pronounced. Spindle cells were sparse or absent, and when present, cytologically bland. Thick ropy collagen bundles were absent. In all cases, p53 immunoexpression was noted (range: 2 to 20% of adipocytic nuclei), characteristically highlighting the most atypical cells. Twenty of 50 cases had MDM2 immunoreactivity, usually in 45% of the cells by FISH (our threshold value for reporting a positive result) with an additional 3 cases being very 3
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close to the required cutoff value. MDM2 gene amplification was absent in all 60 cases tested, including those with the greatest MDM2 immunoexpression and most pronounced atypia. All five tested cases showed no TP53 mutation with Sanger sequencing. Due to material quality issues, NGS analysis could be performed in only 3 cases, and this did not reveal any recurrent mutations. All tumors were managed by simple local excision. Follow-up was available for 47 patients (range: 1-192 mos.; mean: 27 mos) and revealed 2 local recurrences and no metastases. Dysplastic lipoma is a distinctive atypical fatty tumor variant that has p53 overexpression and RB1 gene abnormalities and lacks MDM2 gene amplification by FISH. These tumors have a strong male predominance and a notable tendency to involve the subcutaneous tissue of the shoulders, upper back and posterior neck. Multifocality is frequent (18.9% of patients with follow-up information), and there is a rare association with retinoblastoma. This tumor warrants separation from ordinary lipoma with fat necrosis, fat-rich spindle cell lipoma and the conventional form of atypical lipomatous tumor that features MDM2 gene amplification.
Key words: Anisometric cell lipoma, Atypical lipoma, Atypical lipomatous tumor, Dysplastic lipoma, Lipoma with fat necrosis, p53, RB1 gene, Retinoblastoma, Soft tissue tumor, Well-differentiated liposarcoma
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Introduction In our routine and consultation practice, we have repeatedly encountered a distinctive subcutaneous fatty neoplasm with notable adipocytic size variation, focal (usually mild) adipocytic atypia and patchy, often single cell, fat necrosis. Because of the size variation and atypia, these tumors are usually received with a submitting diagnosis of atypical lipomatous tumor, but they are consistently negative for MDM2 gene amplification by FISH. Similar tumors have been reported under the designations “subcutaneous minimally atypical lipomatous tumor” and “anisometric cell lipoma” (1-3). This study was undertaken to analyze a large cohort of these lesions. Our results indicate this fatty tumor variant, for which we propose the designation “dysplastic lipoma”, is a distinctive and relatively common clinicopathologic entity that has a strong male predominance, a characteristic anatomic distribution, and reproducible histologic, immunohistochemical and molecular genetic findings. Materials and Methods The 66 cases constituting the subject of this study were retrieved from the routine biopsy archives (5 cases) and consultation files (61 cases) of 5 institutions. Thirtytwo of the cases are from the Joint Pathology Center, including 23 from a patient population with no gender predilection and 9 from a patient population strongly skewed towards males. The clinical information was abstracted from the medical 5
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records, and follow-up data was obtained when possible. Most cases (60) were recent, collected from material submitted over the past two years. Cases 6 – 10 have been reported previously (3). To retrospectively identify appropriate cases, the authors searched their registry files for adipocytic tumors coded as anisometric cell lipoma, lipoma with mild atypia of uncertain significance, atypical lipomatous tumor or atypical lipomatous tumor variant. Tumors with appropriate histology were included for further analysis. In addition to the H&E-stained slides, most cases also had immunohistochemically-stained sections, previously documented FISH results for MDM2 gene status, and unstained slides or paraffin blocks for further study.
Immunohistochemistry The IHC analysis was performed using a Ventana BenchMark ULTRA (Ventana Medical System, Inc., Tucson, Arizona). The following primary antibodies were used: CD34 (QBEnd/10, 1:200, Dako, Glostrup, Denmark), RB-1 protein (G3-245, 1:50, BD Biosciences, Franklin Lakes, New Jersey, USA), MDM2 (1F2, 1:100, Thermo Fisher Scientific, Rockford, IL, USA), p16 (E6H4, Prediluted, Ventana Medical System, Inc., Tucson, Arizona), CDK4 (DCS-156, 1:100, Zytomed), CD163 (MRQ-26, Prediluted, Cell Marque, Rocklin, CA), S100 (Polyclonal,
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Prediluted, Ventana Medical System, Inc., Tucson, Arizona). The primary antibodies were visualized employing the enzymes alkaline phosphatase or peroxidase as detecting systems (both purchased from Ventana Medical System, Inc., Tucson, Arizona). When evaluating the expression of RB-1 protein, the surrounding immune cells were used as an internal positive control. The staining results for p16, p53, and MDM2 were divided into 5 groups based on the percentage of positive tumor cells (group 1: 1-5% positive cells; group 2: 610%; group 3:11-15%; group 4:16-20%; and group 5: >20%). Molecular genetic studies Detection of MDM2 amplification and RB1 deletion by FISH The FISH procedure was performed as previously described (4). For the detection of MDM2 amplification we employed the ZytoLight® SPEC MDM2/CEN 12 Dual Color Probe (ZytoVision GmbH, Bremerhaven, Germany). For the detection of RB1 loss, a mix of SureFish 13q14.2 RB1 (SureFish/Agilent Techonologies, Santa Clara, California, USA) and Vysis CEP 17 (D17Z1) probes (Abbott Molecular, IL, USA) were used. FISH interpretation One hundred randomly selected non-overlapping tumor cell nuclei were evaluated in all analyzed samples. Samples were considered positive for amplification (5) 7
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when the ratio of MDM2 probe signals to corresponding chromosome 12 centromeric probe signals was ≥2.0. RB1 gene loss was recorded as the number of cells with loss divided by the total number of cells counted. The RB1 data was collected from 2 separate laboratories that used different cutoff thresholds for reporting a positive test result. In one laboratory, the test was routinely interpreted as positive if 22% of the counted nuclei had gene loss, whereas in the other a positive result was reported when >45% of nuclei had only one signal per nucleus (mean + 3 standard deviations in normal non-neoplastic control tissues). For the purposes of this study, the more stringent criteria were applied to all cases. Detection of TP53 mutation by Sanger sequencing DNA extraction and mutation analysis by Sanger sequencing of coding exons for the TP53 gene have been reported previously (6). Targeted next-generation sequencing Targeted next-generation sequencing (NGS) for a panel of genes including TP53, RB1 and MDM2 was performed using QIAseq technology (Qiagen, Hilden, Germany) in an Illumina’s Nextseq 500 system. In brief, the samples were isolated using macro dissection from formalin-fixed paraffin-embedded (FFPE) blocks using a QIAamp Mini kit on an automated QIAsymphony instrument (Qiagen, Hilden, Germany) according to the manufacturer´s instructions. Concentration and 8
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purity of isolated DNA were measured using Nanodrop ND 1000 (NanoDrop Technologies Inc., Wilmington, DE, U.S.A.), and DNA integrity was examined by amplification of control genes in multiplex PCR producing fragments from 100 – 600 base pairs. Only cases with DNA integrity of ≥300 bp were analyzed further by NGS. Target enrichment was performed using a panel of 271 cancer-related genes (Comprehensive cancer panel, Qiagen, Hilden, Germany). The NGS library was constructed using 250 ng of DNA with QIAseq reagents (Qiagen, Hilden, Germany). Quality control of the analysis parameters was established by technical duplicates and positive controls. The library was sequenced on the Illumina instrument, aiming at average coverage depth of 350x after deduplication of molecular barcodes to detect 10% allele frequency with 95% sensitivity. Variants were called using Qiagen’s proprietary pipeline (QIASeq DNA enrichment variant caller, Qiagen Hilden, Germany). Subsequently the variants were filtered using the calculated limit of detection for each sample. Furthermore, the variants were annotated using The Genome Aggregation Database (GnomAD) (7) for population statistics and ClinVar database (8) for the relationships among variations and phenotypes. Variants with a frequency of >1% in the GnomAD database were excluded, as well as known benign variants according to the ClinVar database. The remaining subset was checked visually, and suspected artefactual variants were
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excluded (homopolymer or otherwise difficult PCR regions, too many mismatches in the same read). Results Clinical findings The clinical features are summarized in Table 1. There were 57 male and 8 female patients and one individual of unstated gender. The patients ranged in age from 22 to 87 years (mean: 51.2 yrs) (Fig.1). All tumors presented as subcutaneous masses. One tumor (Case 51), located on the neck, also superficially involved the sternocleidomastoid muscle which in this area lies in close apposition to the subcutis. The anatomic locations were available for 64 tumors, and all but 2 tumors involved the head and neck or upper half of the trunk with a predilection for the upper back, shoulders and posterior neck. The two outliers involved the subcutaneous tissue in the inguinal region and hip. Tumor sizes ranged from 1.5 to 14 cm in the greatest dimension, with a mean size of 5.2 cm. Ten patients had multiple synchronous or metachronous lipomatous tumors: 6 individuals had 2 tumors each, 1 had 3 tumors, 1 had 4 tumors, 1 had >4 tumors (exact number unknown), and 1 had 5 tumors. Most additional tumors maintained a predilection for the upper truncal/neck region, but 1 involved the forearm, and 2 involved the scrotal region (both of the latter were subcutaneous in the same patient). The
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patient with 5 fatty tumors, removed over a span of 8 years, had a retinoblastoma at age 1 (this case was previously reported, but the retinoblastoma history was unknown at that time (3)). Of the 10 individuals with multiple fatty tumors, we had an opportunity to review the additional lesions from 5. One patient’s additional fatty tumor (removed from the upper arm) was an ordinary lipoma, but the additional fatty tumors in the other 4 patients (ranging in number from 2 to 5), also had dysplastic lipoma histology. Notably, all fatty tumors removed from the patient with a history of retinoblastoma had dysplastic morphology and none was an ordinary lipoma. All tumors were managed by simple local excision. Follow-up information is available for 47 patients, with an average follow-up interval of 27.3 months (range: 1-192 months). Two individuals (4.2%) experienced a local recurrence, one at 7 months and one at 44 months. No individual (n=6) with 6
ALT
No
No
6
30
80/M
Back
NA
14
Spindle cell lipoma
No
No
4
31
60/M
Occipital
NA
6
No
No
2
32
58/M
Neck
NA
7
No
Recent case
33
50/M
Posterior neck
NA
NA
Regressive lipoma vs ALT Regressive lipoma vs ALT ALT
No
Recent case
34
47/F
Back
NA
1,7
ALT
No
Recent case
35
63/M
5
5,2
No
8
22/F
Months
7,5 cm
Fibrolipoma with fat necrosis LN with rare atypical cells
NA
36
Posterior mid neck R shoulder
Another LN NR
No
25
Other
Colon + prostate cancer (2012, 2013 resp.)
13
Retinoblastoma at the age 1
8
Glaucoma, diabetes
37
49/M
R hip/L upper arm
>11
5x4,3x1,8
ALT
Yes
No
28
38
36/M
R posterior neck
6
6,4x5,8x1,2
LN with focal atypia
NA
No
7
39
38/M
R chest wall
8
LN with focal atypia, favor ALT
NA
No
22
40
60/M
R upper chest
12
4,6x2,2x1,1 and 2,3x1,4x,4 3,2x2,8x1,6
ALT
NA
No
20
41
39/M
R upper back
8
Spindle cell lipoma
NA
No
19
42
37/F
R back interscapular
60
0,2 to 0,8 (fragmented) 4,5x2,8x1,4
LN with atypia
No
No
19
43
45/M
R back over scapula
12
4,8x4x2,2
LN - ALT?
No
19
44
41/M
L scapula
6
6
Lipoma with atypia
LN on L neck (4,5x3,2x2,5 cm) NR No
No
19
45
28/M
L shoulder
NA
4x2,2x1,5
19
37/M
R neck
>28
4,2x3,8x2,6
Other LN - R side 5 yrs prior, NR No
No
46
Yes
44
47
38/M
L shoulder
Years
3x2,7x2
LN - ALT x lipoblastoma x pleomorphic lipoma? Lipoma with mild atypia ALT
No
No
17
48
46/M
L shoulder
48
3,7x2x1,9
No
No
12
49
36/M
Under chin
18
2,4x1,3x0,7
Fibrolipoma with mild atypia LN with atypia
No
No
4
50
33/M
Posterior neck
60
10x7x3,3 and 2,5x2x,6
Pleomorphic lipoma
No
No
12
Multiple skin tags
51
53/M
R neck
14 to 15 mo
3,5x2,7x1,5
No
No
6
Intramuscular; Pronounced atypia
52
54/M
L posterior neck
3,2x2,4x1,1
No
No
1
53
56/M
5x5x3
LN - rule out ALT
NA
NA
NA
54
47/M
Upper central back Upper back
Many years Months
Variably sized adipocytes, atypia, ALT? LN - ALT?
NA
Fibroadipose tissue with atypia
NA
NA
NA
55
44/M
L shoulder
NA
5x3x1,5 plus fragments up to 2,2 4,5x4,1x2
NA
NA
NA
56
57/M
R shoulder
NA
3,3x3,1x1,8
Favor pleomorphic lipoma, cannot exclude ALT LN with focal atypia
NA
NA
NA
57
45/M
R scapula
NA
NA
NA
NA
NA
58
43/M
R neck anterior
30
4,5x4x3,5
Favor lipoma, cannot exclude ALT LN - lipoma x ALT
NA
NA
NA
59
48/M
L shoulder
NA
4,4x3,5x1,5
LN - favor ALT
NA
NA
NA
60
51/M
Neck
NA
2,4x2,1x0,9
LN - considering ALT
NA
NA
NA
61
42/M
R shoulder
>48
7,5x7x3
ALT
NA
NA
NA
62
51/M
L inferior back
NA
6,2x3,6x2,6
Lipoma with mild atypia
NA
NA
63
67/M
L shoulder
NA
4x3,2x1
NA
NA
64
43/M
Posterior neck
NA
3,3x2,6x1,5/
LN showing changes of ALT Fibroadipose tissue lipoma?
2 other LN, superior back (6,6 cm) and L chest (3,4 cm), NR NA
NA
NA
65
70/M
R shoulder
NA
3,2x2,6x1,5
SQ LN 14yrs prior in both biceps; 7yrs prior in R forearm, 4,8x3x1,5, NR Yes - 2 DL; + other SQ LN 10 yrs prior- NR
NA
NA
LN
First tumor with pronounced atypia
Pheochromocytoma
Multiple nevi
Pronounced atypia
66
53/M
R posterior neck
NA
6,8x4,4x4,1
ALT
NA
NA
NA
ALT - atypical lipomatous tumor; DL - dysplastic lipoma; LN - lipomatous neoplasm; NR - not reviewed; SQ – subcutaneous; NA – not available
Table 2
Table 2. Immunohistochemical and molecular genetic features Case S100 p16
p53 IHC
MDM2 CDK4 CD34 IHC IHC
RB1 IHC
CD163
MDM2 FISH
TP53 RB1 FISH count * mutation (cut-off 45%)
NGS
1
NP
1
3
1
NP
Scant
Mostly lost
NP
Neg
NA
28% (28/100)
NA
2
NP
NP
1
Neg.
NP
Substantial
Mostly lost
NP
Neg
Neg
34% (34/100)
NA
3
NP
Neg
2
1
NP
Scattered
Mostly lost
NP
Neg
NA
26% (26/100)
NA
4
NP
NP
3
Neg
NP
Scant
Partially lost
NP
Neg
NA
41% (82/200)
NA
5
NP
NP
1
Neg
NP
NP
Partially lost
NP
Neg
NA
32% (32/100)
NA
6
NP
NP
4
1
Neg
NP
Mostly lost
NP
Neg
Neg
42.5% (85/200)
KMT2D; PAK3
7
NP
NP
2
2
Neg
NP
Mostly lost
NP
Neg
NA
53.5% (107/200)
NA
8
NP
NP
2
Neg.
Neg
NP
Partially lost
NP
Neg
Neg
38.5% (154/400)
NA
9
NP
NP
1
Neg
Neg
NP
Mostly lost
NP
Neg
Neg
66% (66/100)
SETD2; ATM; SUZ12
10
NP
NP
1
Neg.
Neg
NP
Mostly lost
NP
Neg
NA
44% (88/200)
NA
11
NP
NP
1
Neg.
NP
Scattered
Mostly lost
NP
Neg
NA
58.7% (176/300)
PDGFRA; FGFR4
12
NP
2
4
Neg.
NP
Scant
Mostly lost
NP
Neg
NA
31% (31/100)
NA
13
NP
NP
1
1
NP
NP
Mostly lost
NP
NA
NA
NA
NA
14
NP
NP
3
Neg.
NP
NP
Partially lost
NP
NA
Neg
NA
NA
15
NP
3
3
1
NP
NP
Mostly lost
NP
NA
NA
NA
NA
16
NP
4
1
1
NP
NP
Mostly lost
NP
NA
NA
NA
NA
17
NP
NP
2
Neg
NP
NP
Mostly lost
NP
NA
NA
NA
NA
18
NP
NP
2
1
NP
NP
Mostly lost
NP
NA
NA
NA
NA
19
NP
1
3
2
NP
NP
Partially lost
NP
Neg
NA
25% (25/100)
NA
20
NP
NP
NP
Neg.
Neg
NP
Mostly lost
NP
Neg
NA
NA
21
NP
NP
NP
Neg
1
Scattered
NP
NP
Neg
NP
NP
22
NP
NP
NP
Neg
Neg
NP
NP
NP
Neg
NP
NP
23
NP
NP
NP
Neg
Neg
NP
Partially lost
NP
Neg
NP
NP
24
NP
NP
NP
Neg
Neg
NP
Partially lost
NP
Neg
NP
NP
25
NP
NP
NP
Neg
Neg
NP
Partially lost
NP
Neg
NP
NP
26
NP
NP
NP
Neg
Neg
NP
Partially lost
NP
Neg
NP
NP
27
NP
NP
NP
Neg
Neg
NP
NP
NP
Neg
NP
NP
28
NP
NP
NP
Neg
Neg
NP
Mostly lost
NP
Neg
NP
NP
29
NP
NP
NP
Neg
Neg
NP
Partially lost
NP
Neg
NP
NP
30
NP
NP
NP
Neg
Neg
NP
Mostly lost
NP
Neg
NP
NP
31
NP
NP
NP
Neg
Neg
NP
Mostly lost
NP
Neg
NP
NP
32
NP
NP
NP
Neg
Neg
NP
Mostly lost
NP
Neg
NP
NP
33
NP
NP
NP
Neg
Neg
NP
Mostly lost
NP
Neg
NP
NP
34
NP
NP
NP
Neg
Neg
NP
Mostly lost
NP
Neg
NP
NP
35
30
3
2
2
NP
Scattered
NP
Scattered Neg
NP
NP
36
NP
NP
2
NA
NP
NP
NP
NP
Neg
NP
NP
37
NP
NP/5
1
NA
NP
NP
NP
NP
NA/Neg
NP
NP
38
NP
1
1
NA
NP
NP
NP
NP
Neg
NP
NP
NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP
39
NP
3
1
NA
NP
NP
NP
NP
Neg
NP
NP
40
NP
2
4
NA
NP
NP
NP
NP
Neg
NP
NP
41
>50
4
4
NA
NP
Scattered
NP
NP
Neg
NP
NP
42
NP
5
1
NA
NP
NP
NP
NP
Neg
NP
NP
43
NP
5
3
NA
NP
NP
NP
NP
Neg
NP
NP
44
NP
1
2
NA
NP
NP
NP
NP
Neg
NP
NP
45
NP
2
3
NA
NP
Scant
NP
Scattered Neg
NP
NP
46
>50
2
2
NA
NP
Scattered
NP
Scattered Neg
NP
NP
47
NP
3
3
NA
NP
NP
NP
NP
Neg
NP
NP
48
>50
3
2
NA
NP
NP
NP
NP
Neg
NP
NP
49
30
3
2
NA
NP
NP
NP
Scattered Neg
NP
NP
50
NP
4
3
NA
NP
NP
NP
NP
Neg
NP
NP
51
30
5
4
1
NP
Scattered
NP
NP
Neg
NP
NP
52
NP
2
3
Neg
NP
NP
NP
NP
Neg
NP
NP
53
NP
2
1
Neg
NP
NP
NP
NP
Neg
NP
NP
54
NP
2
2
1
NP
NP
NP
NP
Neg
NP
NP
55
>50
2
2
Neg
NP
Scattered
NP
Scattered Neg
NP
NP
56
NP
NP
2
1
NP
NP
NP
NP
Neg
NP
NP
57
>50
NP
1
NA
NP
NP
NP
Scattered Neg
NP
NP
58
NP
3
2
Neg
NP
NP
NP
NP
Neg
NP
NP
59
NP
3
1
1
NP
NP
NP
NP
Neg
NP
NP
60
>50
1
1
1
NP
NP
NP
NP
Neg
NP
NP
61
>50
5
2
1
NP
NP
NP
NP
Neg
NP
NP
62
>50
5
4
2
NP
Substantial
NP
Scattered Neg
NP
NP
63
>50
5
2
1
NP
Substantial
NP
NP
NP
NP
64
>50
5/2
Both Neg 1
NP
Scant/Scattered NP
Scattered Neg/Neg NP for both (both)
NP
65
>50
2
3
1
NP
Substantial
NP
NP
Neg
NP
NP
66
>50
2
1
1
NP
Scattered
NP
NP
Neg
NP
NP
Neg
NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP NP
1: 1-5% positive cells; group 2: 6-10%; group 3:11-15%; group 4:16-20%; group 5: 20-50%; NP – not performed; NA – not analyzable; RB FISH count: *(nuclei with lost signal/nuclei counted)
Figure 1
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Figure 2
Click here to download Figure Figure_2.jpg
Figure 3
Click here to download Figure Figure_3.jpg
Figure 4
Click here to download Figure Figure_4.jpg
Figure 5
Click here to download Figure Figure_5.jpg
