Pathology – Research and Practice 210 (2014) 92–97
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Original Article
Loss of CD34 and high IGF2 are associated with malignant transformation in solitary fibrous tumors Birte Schulz a , Annelore Altendorf-Hofmann b , Thomas Kirchner c , Detlef Katenkamp a , Iver Petersen a , Thomas Knösel a,c,∗ a
Institute of Pathology, Friedrich-Schiller University, Jena, Germany Department of General, Visceral und Vascular Surgery, Friedrich-Schiller University, Jena, Germany c Institute of Pathology, Ludwig-Maximilians-University (LMU), Munich, Germany b
a r t i c l e
i n f o
Article history: Received 17 June 2013 Received in revised form 26 October 2013 Accepted 14 November 2013 Keywords: Solitary fibrous tumors Malignant potential CD34 IGF2 Immunohistochemistry
a b s t r a c t The aim of this study was to characterize the subgroups of solitary fibrous tumor (SFT) and to investigate the expression of different biomarkers including CD34 and IGF2 in malignant transformation. Two hundred and ninety-four (294) SFTs from a single German consultation center of soft tissue tumors were categorized into the new proposal of SFT designation. We found the fibrous variant in 223 (75.9%), the cellular variant in 65 (22.1%), the fat forming variant in 4 (1.4%), and the giant cell-rich variant in 2 (0.6%) cases. Anatomical location, size, mitotic index, necrosis, cellularity, collagenous ropes, and growth pattern of the vessels were recorded. Criteria of malignancy were found in 68 (23%) tumors. Expression of IGF2, IGF1R, CD34, BCL2, CD99, SMA, S100, PanCK, and Ki67 was analyzed immunohistochemically. Low expression of CD34 and high expression of IGF2 were significantly associated with malignant transformation and the metastatic rate. Moreover the presence of necrosis showed the most significant p-value (p < 0.004). Of all SFTs, the fibrous variant is the most common, followed by the cellular variant. The fat-forming and giant cell-rich variants are very rare. Low expression of CD34 and high expression of IGF2 are significantly associated with malignant transformation, and might be an interesting target of individualized therapy. © 2013 Elsevier GmbH. All rights reserved.
Introduction After the first detailed histological description of solitary fibrous tumor (SFT) by Wagner in Leipzig 1870, this tumor group became more popular [21]. Over the years, it appeared that the hemangiopericytoma (HPC)-like growth pattern was a non-specific one, shared by numerous unrelated lesions and that most of these tumors belonged to the SFT family [5,14]. The SFT was described initially in the pleura and was later recognized to arise in almost any extrapleural site [14,19]. The constituent tumor cells of this mesenchymal neoplasm show a fibroblastic phenotype and are arranged in a patternless growth of alternating cellularity and a collagenous stroma with a characteristically so called “staghorn pattern” of the blood vessels. The distinctive histopathological morphology is confirmed with consistent CD34 expression [7,14]. The different morphology of the hypocellular and the hypercellular areas led to the definition of different major subgroups, the
∗ Corresponding author at: Institute of Pathology, Ludwig-MaximiliansUniversity (LMU), Thalkirchnerstr. 36, 80337 Munich, Germany. Tel.: +49 89 2180 73728; fax: +49 89 2180 73742. E-mail address: [email protected] (T. Knösel). 0344-0338/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.prp.2013.11.006
fibrous and the cellular variant [5]. The histological features of the fibrous variant included a heterogeneous microscopic appearance, an alternating presence of cellular and fibrous areas, hyalinized thick-walled vessels with opened lumina and keloidal collagen. In contrast, the cellular variant showed a monotonous microscopic appearance, moderate to high cellularity, weakly intervening fibrosis, and thin-walled branching vessels. Furthermore, a fat-forming variant and a giant cell-rich variant were described [5,12]. While most solitary fibrous tumors follow a benign clinical course [6], approximately 15–20% of SFT present a more aggressive behavior with tumor recurrences and/or distant metastasis [16]. Some morphological features are known to be associated with aggressive clinical behavior, including more than 4 mitoses/10 HPF, nuclear atypia, hypercellularity, and necrosis [14]. Furthermore, positive surgical margins and tumor size ≥10 cm predict poor survival [6,14]. The treatment of choice for primary tumors is surgical resection with negative margins [2]. However, there are no effective therapies for metastatic or advanced disease. Markers that reliably predict tumor progression and molecular data on the transition from benign to malignant SFTs are needed [7]. The objective of this study was (1) to categorize our cases according to the new proposal of different subgroups, (2) to record the anatomical location, distinct morphological features,
B. Schulz et al. / Pathology – Research and Practice 210 (2014) 92–97
93
Table 1 Antibodies for immunohistochemistry. Antigen
Clone
Firm
Species
Pretreatmenta
Dilution
CD 34 Bcl-2 CD99 Ki67 IGF2 IGF1R MNF ASMA S100
QBEND10 124 O13 MIB-1 Poly 24–31 MNF 116 1A4 Poly
DAKO DAKO Signet DAKO Abcam Zytomed DAKO DAKO DAKO
Mouse Mouse Mouse Mouse Rabbit Mouse Mouse Mouse Rabbit
pH 6.1 pH 6.1 pH 6.1 pH 6.1 pH 6.1 pH 9.0 Proteolytic enzymes pH 9.0 Proteolytic enzymes
1:300 1:200 1:300 1:1000 1:100 1:50 1:200 1:500 1:8000
a
Steaming/humid chamber.
and criteria of malignancy in a well characterized tumor collective, and (3) to evaluate the expression level of IGF2, CD34, and other markers on the protein level in malignant transformation of the different subgroups. Materials and methods Patients Tumor samples Tissue samples of intra- and extrathoracic solitary fibrous tumors were retrieved from the archives of a German consultation and reference center at the Institute of Pathology at FriedrichSchiller-University in Jena. All specimens (n = 294) were referred as consultation cases and, in addition to the original pathology report, microscopic findings (cellularity, blood vessels, collagen bundles, necrosis, mitosis and atypia) were reassessed by two authors (B.S. and T.K). The patient cohort was categorized according to the proposal of Gengler and Guillou [5] into the fibrous, cellular, fatforming, and giant cell-rich variant. We defined the cellular variant as 90% or more cellularity with weakly intervening fibrosis and thin-walled branching vessels. In addition, we recorded patients’ age and gender, anatomical location of the tumors, and criteria of malignant transformation (tumor size, areas of necrosis, mitotic activity, and metastatic spreading of the tumors) similar to precious studies [11,15,17]. This study was performed in accordance with the ethics committee of the Friedrich-Schiller University, Jena.
Immunohistochemistry Commercially available antibodies against IGF2, IGF1R, CD34, BCL2, CD99, SMA, S100, PanCK, and Ki67 were purchased (Table 1), and immunohistochemical staining was performed according to standard procedures to confirm the diagnosis (CD34, BCL2, CD99, SMA, S100, PanCK and Ki67). Briefly, slides were pre-treated as indicated in Table 3 and then incubated with the antibody, followed by antibody detection by a biotinylated antirabbit/antimouse secondary antibody and incubation with Streptavidin Alkaline Phosphatase (Dako Real Detection System, Hamburg Germany). Staining was visualized using a Fast red-type chromogen system (DAKO, Hamburg, Germany). The intensity of the immunostaining in tumor cells was evaluated independently by two pathologists blinded to the clinicopathological data and scored semiquantitatively as negative, weakly, moderately, and strongly positive. The tissue samples were evaluated on standard, full-sized tissue sections.
Tissue microarray construction For additional immunohistochemical marker analysis, a tissue microarray (TMA) was constructed from 84 of the 294 cases where paraffin embedded material was available. The SFT TMA was assembled using 0.6 mm punch biopsies from 84 samples according to a standard procedure [9,10] using two cores from each tumor. The TMA also includes normal tissue of the breast, kidney and colon,
Table 2 Histological characteristics of 294 solitary fibrous tumors. Histological feature
Variants of solitary fibrous tumors Fibrous
Cellular
Fat-forming
Giant cell rich
N (%)
Cellularity Low Intermediate High Heterogeneous
18 26 1 178
0 0 59 6
0 0 1 3
1 0 0 1
19 (6.5) 26 (8.8) 61 (20.7) 188 (63.9)
Vessel architecture Thin walled Thick walled
83 140
55 10
1 3
0 2
139 (47.3) 155 (52.7)
Stroma Fibrous Myxoid Pseudocysts Scant fibers
163 46 10 4
9 2 0 54
4 0 0 0
2 0 0 0
178 (60.5) 48 (16.4) 10 (3.4) 58 (19.7)
Collagen bundles None Low Intermediate High
20 102 78 23
16 33 16 0
0 1 3 0
0 1 0 1
36 (12.2) 137 (46.6) 97 (33.0) 24 (8.2)
94
B. Schulz et al. / Pathology – Research and Practice 210 (2014) 92–97
Fig. 1. (A) Solitary fibrous tumor of the fibrous variant with characteristically thick walled vessels (H & E stain: original magnification 100×). (B) Solitary fibrous tumor of the cellular variant with characteristically so called staghorn pattern of the thin walled vessels (H & E stain: original magnification 100×). (C) Solitary fibrous tumor of the fat-forming variant (H & E stain: original magnification 100×). (D) Solitary fibrous tumor of the giant cell rich variant (inlet closer view of the giant cells 200×) (H & E stain: original magnification 100×).
as well as smooth and skeletal muscle, fatty tissue, and connective tissue. In total, 84 specimens of solitary fibrous tumor tissue, including normal controls, were evaluated for IGFR1. Statistical analysis Fisher’s exact test was used to determine the strength of association between the parameters investigated. P values 4/10 HPF) and necrosis. We could not detect the downstream target IGFR1 in our tumor samples with a successful positive control, indicating a signaling pathway via the insulin receptor (IR) rather than IGFR1. Interestingly, Hajdu et al. [7] found a consistent upregulation of IGF2 in SFTs of all anatomical sites with cDNA profiling using the Affymetrix oligonucleotide platform, whereas IGF1R expression was consistently negligible. Our results support the finding by Li et al. [13] that the IGF2-mediated downstream signaling pathway occurs through the insulin receptor rather than IGFR1. In conclusion, we categorized a large tumor collective of solitary fibrous tumors from a single institution in this study, and were able to show that the fibrous variant is the most common, followed by the cellular variant. The fat-forming variant and the giant cell-rich variant are very rare. Malignant transformation occurs more frequently in the cellular variant. Furthermore, we demonstrated that CD34 is the most robust diagnostic marker for SFTs. However, low expression or loss of CD34 is significantly associated with malignant transformation in SFTs. High IGF2 expression on the protein level was found in the majority of SFTs independent of the anatomical location. To the best of our knowledge, this is also the first study to document that gain of IGF2 expression in contrast to the loss of CD34 is associated with malignant transformation. SFTs with high IGF2 and low CD34 showed a higher statistical correlation
B. Schulz et al. / Pathology – Research and Practice 210 (2014) 92–97
to the metastatic rate than the mitotic index. However, the presence of necrosis showed the most significant p-value for metastatic dissemination. References [1] P. Collini, T. Negri, M. Barisella, E. Palassini, E. Tarantino, U. Pastorino, A. Gronchi, S. Stacchiotti, S. Pilotti, High-grade sarcomatous overgrowth in solitary fibrous tumors: a clinicopathologic study of 10 cases, Am. J. Surg. Pathol. 36 (8 Aug) (2012) 1202–1215. [2] A. Daigeler, M. Lehnhardt, S. Langer, L. Steinstraesser, H.U. Steinau, T. Mentzel, C. Kuhnen, Clinicopathological findings in a case series of extrathoracic solitary fibrous tumors of soft tissues, BMC Surg. 6 (2006) 10. [3] E.G. Demicco, M.S. Park, D.M. Araujo, P.S. Fox, R.L. Bassett, R.E. Pollock, A.J. Lazar, W.L. Wang, Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model, Mod. Pathol. 25 (9 Sep) (2012) 1298–1306. [4] C.D. Fletcher, K.K. Unni, F. Mertens, World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue and Bone, IARC Press, Lyon, 2002. [5] C. Gengler, L. Guillou, Solitary fibrous tumor and haemangiopericytoma: evolution of a concept, Histopathology 48 (2006) 63–74. [6] J.S. Gold, C.R. Antonescu, C. Hajdu, C.R. Ferrone, M. Hussain, J.J. Lewis, M.F. Brennan, D.G. Coit, Clinicopathologic correlates of solitary fibrous tumors, Cancer 94 (2002) 1057–1068. [7] M. Hajdu, S. Singer, R.G. Maki, G.K. Schwartz, M.L. Keohan, C.R. Antonescu, IGF2 over-expression in solitary fibrous tumors is independent of anatomical location and is related to loss of imprinting, J. Pathol. 221 (2010) 300–307. [8] A.Y. Kalebi, M.J. Hale, M.L. Wong, T. Hoffman, J. Murray, Surgically cured hypoglycemia secondary to pleural solitary fibrous tumor: case report and update review on the Doege-Potter syndrome, J. Cardiothorac. Surg. 4 (2009) 45. [9] T. Knösel, A. Emde, K. Schluns, Y. Chen, K. Jurchott, M. Krause, M. Dietel, I. Petersen, Immunoprofiles of 11 biomarkers using tissue microarrays identify prognostic subgroups in colorectal cancer, Neoplasia 7 (2005) 741–747. [10] T. Knösel, V. Emde, K. Schluns, P.M. Schlag, M. Dietel, I. Petersen, Cytokeratin profiles identify diagnostic signatures in colorectal cancer using multiplex analysis of tissue microarrays, Cell Oncol. 28 (2006) 167–175.
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[11] T. Knösel, S. Heretsch, A. Altendorf-Hofmann, P. Richter, K. Katenkamp, D. Katenkamp, A. Berndt, I. Petersen, TLE1 is a robust diagnostic biomarker for synovial sarcomas and correlates with t(X;18): analysis of 319 cases, Eur. J. Cancer 46 (2010) 1170–1176. [12] J.C. Lee, C.D. Fletcher, Malignant fat-forming solitary fibrous tumor (so-called lipomatous hemangiopericytoma): clinicopathologic analysis of 14 cases, Am. J. Surg. Pathol. 35 (2011) 1177–1185. [13] Y. Li, Q. Chang, B.P. Rubin, C.D. Fletcher, T.W. Morgan, S.J. Mentzer, D.J. Sugarbaker, J.A. Fletcher, S. Xiao, Insulin receptor activation in solitary fibrous tumors, J. Pathol. 211 (2007) 550–554. [14] J.M. Mosquera, C.D. Fletcher, Expanding the spectrum of malignant progression in solitary fibrous tumors: a study of 8 cases with a discrete anaplastic component – is this dedifferentiated SFT, Am. J. Surg. Pathol. 33 (2009) 1314–1321. [15] K. Nitsche, B. Gunther, D. Katenkamp, I. Petersen, Thoracic neoplasms at the Jena reference center for soft tissue tumors, J. Cancer Res. Clin. Oncol. 138 (2012) 415–424. [16] M.S. Park, D.M. Araujo, New insights into the hemangiopericytoma/solitary fibrous tumor spectrum of tumors, Curr. Opin. Oncol. 21 (2009) 327–331. [17] I. Petersen, B. Gunther, K. Mildner, F. Subhi, T. Knosel, A. Altendorf-Hofmann, D. Katenkamp, Update from the soft tissue tumor registry in Jena, Pathologe 32 (2011) 40–46. [18] S.E. Steigen, D.F. Schaeffer, R.B. West, T.O. Nielsen, Expression of insulinlike growth factor 2 in mesenchymal neoplasms, Mod. Pathol. 22 (2009) 914–921. [19] A.V. Vallat-Decouvelaere, S.M. Dry, C.D. Fletcher, Atypical and malignant solitary fibrous tumors in extrathoracic locations: evidence of their comparability to intra-thoracic tumors, Am. J. Surg. Pathol. 22 (1998) 1501–1511. [20] M. van de Rijn, C.M. Lombard, R.V. Rouse, Expression of CD34 by solitary fibrous tumors of the pleura, mediastinum, and lung, Am. J. Surg. Pathol. 18 (1994) 814–820. [21] E. Wagner, Das tuberkelähnliche Lymphadenom, in: E. Wagner, C. Wunderlich, W. Roser (Eds.), Archiv der Heilkunde, Wigand, Leipzig, 1870. [22] T. Yokoi, T. Tsuzuki, Y. Yatabe, M. Suzuki, H. Kurumaya, T. Koshikawa, H. Kuhara, M. Kuroda, N. Nakamura, Y. Nakatani, K. Kakudo, Solitary fibrous tumor: significance of p53 and CD34 immunoreactivity in its malignant transformation, Histopathology 32 (1998) 423–432.
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Original Article
Loss of CD34 and high IGF2 are associated with malignant transformation in solitary fibrous tumors Birte Schulz a , Annelore Altendorf-Hofmann b , Thomas Kirchner c , Detlef Katenkamp a , Iver Petersen a , Thomas Knösel a,c,∗ a
Institute of Pathology, Friedrich-Schiller University, Jena, Germany Department of General, Visceral und Vascular Surgery, Friedrich-Schiller University, Jena, Germany c Institute of Pathology, Ludwig-Maximilians-University (LMU), Munich, Germany b
a r t i c l e
i n f o
Article history: Received 17 June 2013 Received in revised form 26 October 2013 Accepted 14 November 2013 Keywords: Solitary fibrous tumors Malignant potential CD34 IGF2 Immunohistochemistry
a b s t r a c t The aim of this study was to characterize the subgroups of solitary fibrous tumor (SFT) and to investigate the expression of different biomarkers including CD34 and IGF2 in malignant transformation. Two hundred and ninety-four (294) SFTs from a single German consultation center of soft tissue tumors were categorized into the new proposal of SFT designation. We found the fibrous variant in 223 (75.9%), the cellular variant in 65 (22.1%), the fat forming variant in 4 (1.4%), and the giant cell-rich variant in 2 (0.6%) cases. Anatomical location, size, mitotic index, necrosis, cellularity, collagenous ropes, and growth pattern of the vessels were recorded. Criteria of malignancy were found in 68 (23%) tumors. Expression of IGF2, IGF1R, CD34, BCL2, CD99, SMA, S100, PanCK, and Ki67 was analyzed immunohistochemically. Low expression of CD34 and high expression of IGF2 were significantly associated with malignant transformation and the metastatic rate. Moreover the presence of necrosis showed the most significant p-value (p < 0.004). Of all SFTs, the fibrous variant is the most common, followed by the cellular variant. The fat-forming and giant cell-rich variants are very rare. Low expression of CD34 and high expression of IGF2 are significantly associated with malignant transformation, and might be an interesting target of individualized therapy. © 2013 Elsevier GmbH. All rights reserved.
Introduction After the first detailed histological description of solitary fibrous tumor (SFT) by Wagner in Leipzig 1870, this tumor group became more popular [21]. Over the years, it appeared that the hemangiopericytoma (HPC)-like growth pattern was a non-specific one, shared by numerous unrelated lesions and that most of these tumors belonged to the SFT family [5,14]. The SFT was described initially in the pleura and was later recognized to arise in almost any extrapleural site [14,19]. The constituent tumor cells of this mesenchymal neoplasm show a fibroblastic phenotype and are arranged in a patternless growth of alternating cellularity and a collagenous stroma with a characteristically so called “staghorn pattern” of the blood vessels. The distinctive histopathological morphology is confirmed with consistent CD34 expression [7,14]. The different morphology of the hypocellular and the hypercellular areas led to the definition of different major subgroups, the
∗ Corresponding author at: Institute of Pathology, Ludwig-MaximiliansUniversity (LMU), Thalkirchnerstr. 36, 80337 Munich, Germany. Tel.: +49 89 2180 73728; fax: +49 89 2180 73742. E-mail address: [email protected] (T. Knösel). 0344-0338/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.prp.2013.11.006
fibrous and the cellular variant [5]. The histological features of the fibrous variant included a heterogeneous microscopic appearance, an alternating presence of cellular and fibrous areas, hyalinized thick-walled vessels with opened lumina and keloidal collagen. In contrast, the cellular variant showed a monotonous microscopic appearance, moderate to high cellularity, weakly intervening fibrosis, and thin-walled branching vessels. Furthermore, a fat-forming variant and a giant cell-rich variant were described [5,12]. While most solitary fibrous tumors follow a benign clinical course [6], approximately 15–20% of SFT present a more aggressive behavior with tumor recurrences and/or distant metastasis [16]. Some morphological features are known to be associated with aggressive clinical behavior, including more than 4 mitoses/10 HPF, nuclear atypia, hypercellularity, and necrosis [14]. Furthermore, positive surgical margins and tumor size ≥10 cm predict poor survival [6,14]. The treatment of choice for primary tumors is surgical resection with negative margins [2]. However, there are no effective therapies for metastatic or advanced disease. Markers that reliably predict tumor progression and molecular data on the transition from benign to malignant SFTs are needed [7]. The objective of this study was (1) to categorize our cases according to the new proposal of different subgroups, (2) to record the anatomical location, distinct morphological features,
B. Schulz et al. / Pathology – Research and Practice 210 (2014) 92–97
93
Table 1 Antibodies for immunohistochemistry. Antigen
Clone
Firm
Species
Pretreatmenta
Dilution
CD 34 Bcl-2 CD99 Ki67 IGF2 IGF1R MNF ASMA S100
QBEND10 124 O13 MIB-1 Poly 24–31 MNF 116 1A4 Poly
DAKO DAKO Signet DAKO Abcam Zytomed DAKO DAKO DAKO
Mouse Mouse Mouse Mouse Rabbit Mouse Mouse Mouse Rabbit
pH 6.1 pH 6.1 pH 6.1 pH 6.1 pH 6.1 pH 9.0 Proteolytic enzymes pH 9.0 Proteolytic enzymes
1:300 1:200 1:300 1:1000 1:100 1:50 1:200 1:500 1:8000
a
Steaming/humid chamber.
and criteria of malignancy in a well characterized tumor collective, and (3) to evaluate the expression level of IGF2, CD34, and other markers on the protein level in malignant transformation of the different subgroups. Materials and methods Patients Tumor samples Tissue samples of intra- and extrathoracic solitary fibrous tumors were retrieved from the archives of a German consultation and reference center at the Institute of Pathology at FriedrichSchiller-University in Jena. All specimens (n = 294) were referred as consultation cases and, in addition to the original pathology report, microscopic findings (cellularity, blood vessels, collagen bundles, necrosis, mitosis and atypia) were reassessed by two authors (B.S. and T.K). The patient cohort was categorized according to the proposal of Gengler and Guillou [5] into the fibrous, cellular, fatforming, and giant cell-rich variant. We defined the cellular variant as 90% or more cellularity with weakly intervening fibrosis and thin-walled branching vessels. In addition, we recorded patients’ age and gender, anatomical location of the tumors, and criteria of malignant transformation (tumor size, areas of necrosis, mitotic activity, and metastatic spreading of the tumors) similar to precious studies [11,15,17]. This study was performed in accordance with the ethics committee of the Friedrich-Schiller University, Jena.
Immunohistochemistry Commercially available antibodies against IGF2, IGF1R, CD34, BCL2, CD99, SMA, S100, PanCK, and Ki67 were purchased (Table 1), and immunohistochemical staining was performed according to standard procedures to confirm the diagnosis (CD34, BCL2, CD99, SMA, S100, PanCK and Ki67). Briefly, slides were pre-treated as indicated in Table 3 and then incubated with the antibody, followed by antibody detection by a biotinylated antirabbit/antimouse secondary antibody and incubation with Streptavidin Alkaline Phosphatase (Dako Real Detection System, Hamburg Germany). Staining was visualized using a Fast red-type chromogen system (DAKO, Hamburg, Germany). The intensity of the immunostaining in tumor cells was evaluated independently by two pathologists blinded to the clinicopathological data and scored semiquantitatively as negative, weakly, moderately, and strongly positive. The tissue samples were evaluated on standard, full-sized tissue sections.
Tissue microarray construction For additional immunohistochemical marker analysis, a tissue microarray (TMA) was constructed from 84 of the 294 cases where paraffin embedded material was available. The SFT TMA was assembled using 0.6 mm punch biopsies from 84 samples according to a standard procedure [9,10] using two cores from each tumor. The TMA also includes normal tissue of the breast, kidney and colon,
Table 2 Histological characteristics of 294 solitary fibrous tumors. Histological feature
Variants of solitary fibrous tumors Fibrous
Cellular
Fat-forming
Giant cell rich
N (%)
Cellularity Low Intermediate High Heterogeneous
18 26 1 178
0 0 59 6
0 0 1 3
1 0 0 1
19 (6.5) 26 (8.8) 61 (20.7) 188 (63.9)
Vessel architecture Thin walled Thick walled
83 140
55 10
1 3
0 2
139 (47.3) 155 (52.7)
Stroma Fibrous Myxoid Pseudocysts Scant fibers
163 46 10 4
9 2 0 54
4 0 0 0
2 0 0 0
178 (60.5) 48 (16.4) 10 (3.4) 58 (19.7)
Collagen bundles None Low Intermediate High
20 102 78 23
16 33 16 0
0 1 3 0
0 1 0 1
36 (12.2) 137 (46.6) 97 (33.0) 24 (8.2)
94
B. Schulz et al. / Pathology – Research and Practice 210 (2014) 92–97
Fig. 1. (A) Solitary fibrous tumor of the fibrous variant with characteristically thick walled vessels (H & E stain: original magnification 100×). (B) Solitary fibrous tumor of the cellular variant with characteristically so called staghorn pattern of the thin walled vessels (H & E stain: original magnification 100×). (C) Solitary fibrous tumor of the fat-forming variant (H & E stain: original magnification 100×). (D) Solitary fibrous tumor of the giant cell rich variant (inlet closer view of the giant cells 200×) (H & E stain: original magnification 100×).
as well as smooth and skeletal muscle, fatty tissue, and connective tissue. In total, 84 specimens of solitary fibrous tumor tissue, including normal controls, were evaluated for IGFR1. Statistical analysis Fisher’s exact test was used to determine the strength of association between the parameters investigated. P values 4/10 HPF) and necrosis. We could not detect the downstream target IGFR1 in our tumor samples with a successful positive control, indicating a signaling pathway via the insulin receptor (IR) rather than IGFR1. Interestingly, Hajdu et al. [7] found a consistent upregulation of IGF2 in SFTs of all anatomical sites with cDNA profiling using the Affymetrix oligonucleotide platform, whereas IGF1R expression was consistently negligible. Our results support the finding by Li et al. [13] that the IGF2-mediated downstream signaling pathway occurs through the insulin receptor rather than IGFR1. In conclusion, we categorized a large tumor collective of solitary fibrous tumors from a single institution in this study, and were able to show that the fibrous variant is the most common, followed by the cellular variant. The fat-forming variant and the giant cell-rich variant are very rare. Malignant transformation occurs more frequently in the cellular variant. Furthermore, we demonstrated that CD34 is the most robust diagnostic marker for SFTs. However, low expression or loss of CD34 is significantly associated with malignant transformation in SFTs. High IGF2 expression on the protein level was found in the majority of SFTs independent of the anatomical location. To the best of our knowledge, this is also the first study to document that gain of IGF2 expression in contrast to the loss of CD34 is associated with malignant transformation. SFTs with high IGF2 and low CD34 showed a higher statistical correlation
B. Schulz et al. / Pathology – Research and Practice 210 (2014) 92–97
to the metastatic rate than the mitotic index. However, the presence of necrosis showed the most significant p-value for metastatic dissemination. References [1] P. Collini, T. Negri, M. Barisella, E. Palassini, E. Tarantino, U. Pastorino, A. Gronchi, S. Stacchiotti, S. Pilotti, High-grade sarcomatous overgrowth in solitary fibrous tumors: a clinicopathologic study of 10 cases, Am. J. Surg. Pathol. 36 (8 Aug) (2012) 1202–1215. [2] A. Daigeler, M. Lehnhardt, S. Langer, L. Steinstraesser, H.U. Steinau, T. Mentzel, C. Kuhnen, Clinicopathological findings in a case series of extrathoracic solitary fibrous tumors of soft tissues, BMC Surg. 6 (2006) 10. [3] E.G. Demicco, M.S. Park, D.M. Araujo, P.S. Fox, R.L. Bassett, R.E. Pollock, A.J. Lazar, W.L. Wang, Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model, Mod. Pathol. 25 (9 Sep) (2012) 1298–1306. [4] C.D. Fletcher, K.K. Unni, F. Mertens, World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue and Bone, IARC Press, Lyon, 2002. [5] C. Gengler, L. Guillou, Solitary fibrous tumor and haemangiopericytoma: evolution of a concept, Histopathology 48 (2006) 63–74. [6] J.S. Gold, C.R. Antonescu, C. Hajdu, C.R. Ferrone, M. Hussain, J.J. Lewis, M.F. Brennan, D.G. Coit, Clinicopathologic correlates of solitary fibrous tumors, Cancer 94 (2002) 1057–1068. [7] M. Hajdu, S. Singer, R.G. Maki, G.K. Schwartz, M.L. Keohan, C.R. Antonescu, IGF2 over-expression in solitary fibrous tumors is independent of anatomical location and is related to loss of imprinting, J. Pathol. 221 (2010) 300–307. [8] A.Y. Kalebi, M.J. Hale, M.L. Wong, T. Hoffman, J. Murray, Surgically cured hypoglycemia secondary to pleural solitary fibrous tumor: case report and update review on the Doege-Potter syndrome, J. Cardiothorac. Surg. 4 (2009) 45. [9] T. Knösel, A. Emde, K. Schluns, Y. Chen, K. Jurchott, M. Krause, M. Dietel, I. Petersen, Immunoprofiles of 11 biomarkers using tissue microarrays identify prognostic subgroups in colorectal cancer, Neoplasia 7 (2005) 741–747. [10] T. Knösel, V. Emde, K. Schluns, P.M. Schlag, M. Dietel, I. Petersen, Cytokeratin profiles identify diagnostic signatures in colorectal cancer using multiplex analysis of tissue microarrays, Cell Oncol. 28 (2006) 167–175.
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