Virchows Arch DOI 10.1007/s00428-015-1768-x
LETTER TO THE EDITOR
Multifocal cytokeratin expression in pleural and abdominal malignant solitary fibrous tumors: an unusual diagnostic pitfall Evelyne Lecoutere 1 & David Creytens 1
Received: 3 March 2015 / Revised: 17 March 2015 / Accepted: 23 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Dear Editor, Solitary fibrous tumor (SFT) is an uncommon mesenchymal fibroblastic neoplasm usually arising in the pleura, but it can virtually affect any extrapleural site. Conventional SFTs are characterized by short, cytologically bland spindle cells arranged in a patternless architecture, a fibro-collagenous stroma, and a prominent hemangiopericytomatous branching vascular network [1]. The vast majority of SFTs are morphologically and clinically benign. However, 5 to 10 % of SFTs will recur and/or metastasize. Proposed prognostic clinical and morphological criteria for SFT include age at presentation, tumor size, cellularity, mitotic activity (>4 mitoses per 10 high-power fields), the presence of necrosis, and the presence of sharply demarcated anaplastic areas. The vast majority of aggressive SFTs demonstrate these clinical and morphological features of malignancy; however, also morphologically benign-appearing SFTs can metastasize, and therefore, the biological behavior of this tumor type still remains largely unpredictable [1, 2]. Immunohistochemistry is commonly used as a valuable adjunct to diagnosis of SFT, alongside convincing histology. Bcl-2, CD99, and CD34 are often positive in SFT (in nearly 100, 75, and 81–95 % of cases, respectively), but positivity for these markers can also be seen at a high frequency in other soft tissue tumors that can mimic SFT, and they are therefore non-specific [1]. Recent studies have discovered that almost all SFTs harbor a NAB2-STAT6 fusion gene [3]. This fusion gene is considered a driving mutation in
* Evelyne Lecoutere [email protected] 1
Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium
the initiation of SFTs through EGR1 activation and transcriptional deregulation of EGR1-dependent target genes. The resulting overexpression of STAT6 protein has recently been shown to be a highly sensitive and specific marker for these tumors. Hence, STAT6 immunochemistry should lead to a more accurate diagnosis [4, 5]. We describe three cases of a morphological malignant SFT with unexpected strong cytokeratin expression, and we discuss the diagnostic implications thereof. All tumors were primary. The patients were women aged between 42 and 84 years. In two cases, the tumor was located in the pleura, and in one case, the tumor was situated in the abdomen. Histologically, all three cases showed, at least focally, typical histological features of SFT with branching hemangiopericytoma-like vessels and a variable fibro-collagenous background. They all met the proposed criteria of morphologically malignant SFTs, with increased mitotic activity, cytonuclear atypia, and tumoral necrosis (Figs. 1 and 2). Immunohistochemically, the atypical spindle cells in all three cases showed strong and patchy to diffuse expression for CD99 and Bcl-2. However, CD34 expression was heterogenous and loss of CD34 expression was observed in the malignant areas of both pleural tumors (Fig. 3). Staining for cytokeratin AE1/AE3 showed strong multifocal positivity (Fig. 4), but none of the cases was positive for cytokeratin 5, calretinin, and Wilms’ tumor protein 1 (WT1). The unforeseen strong positivity for cytokeratin AE1/AE3 together with the clinical setting of a large pleural or abdominal tumor point to sarcomatoid carcinoma or sarcomatoid mesothelioma as major differential diagnoses. The loss of CD34 reactivity contributes further to this diagnostic dilemma. Nevertheless, a histopathological diagnosis of SFT was made for three reasons. First, characteristic CD34 reactivity can be absent or only focally present in SFT cases [1]. Secondly, a few anecdotal single case reports of cytokeratin
Virchows Arch
Fig. 1 Histomorphologic “patternless pattern” appearance of the tumor with branching vessels, high cellularity, and cytonuclear atypia (hematoxylin & eosin staining, original magnification ×200)
Fig. 4 Multifocal strong cytoplasmic immunoreactivity for cytokeratin AE1/AE3 (original magnification ×200)
Fig. 2 Areas of tumoral necrosis (hematoxylin & eosin staining, original magnification ×400)
positivity in SFTs have been reported in the literature [6, 7]. However, the reported cytokeratin expression in these case reports was more focal and less multifocal compared to our cases. Finally, none of the immunohistochemical mesothelioma markers (cytokeratin 5, calretinin, and WT1) proved to be positive. Based on the recent publications describing the high sensitivity and specificity of nuclear STAT6 expression in distinguishing SFTs from histologic mimics, all three cases were retrospectively reviewed and stained for STAT6. All three cases showed diffuse and strong nuclear positivity for STAT6, confirming the proposed diagnosis of a malignant SFT with an uncommon strong cytokeratin positivity (Fig. 5). In practice, the diagnosis of SFT is usually straightforward. However, SFTs may be diagnostically challenging when the histology is modified by unusual morphological and/or immunophenotypic features, as was the case with the CD34negative and cytokeratin-positive malignant SFTs presented in this study. Presence of strong cytokeratin immunoreactivity in
Fig. 3 Loss of CD34 expression in the malignant tumor areas (original magnification ×100)
Fig. 5 Diffuse strong nuclear expression for STAT6 (original magnification ×400)
Virchows Arch
SFT can be a major diagnostic pitfall in that it can mislead one to interpret such a finding as proof of epithelial differentiation and strengthen the suspicion of a carcinoma or mesothelioma, particularly in the setting of a pleural or abdominal tumoral mass. This study also further supports the utility of STAT6 immunohistochemistry as a valuable ancillary test in the diagnostic work-up of these rare and unconventional cytokeratin positive malignant SFTs.
2.
3.
4.
5.
Conflict of interest The authors declare no conflict of interest. 6.
References 1.
Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F (2013) World Health Organization classification of tumours. Pathology and genetics. Tumours of soft tissue and bone. IARC, Lyon
7.
Demicco E, Park M, Araujo D et al (2012) Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model. Mod Pathol 25:1298–1306 Chmielecki C, Crago AM, Rosenberg M et al (2013) Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 45:131–132 Doyle LA, Vivero M, Fletcher CD et al (2014) Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol 27:390–395 Yoshida A, Tsuta K, Ohno M et al (2014) STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. Am J Surg Pathol 38:552–559 Yan B, Raju GC, Salto-Tellez M (2008) Epithelioid, cytokeratin expressing malignant solitary fibrous tumour of the pleura. Pathology 40:98–99 Cavazza A, Rossi G, Agostini L et al (2003) Cytokeratin-positive malignant solitary fibrous tumour of the pleura: an unusual pitfall in the diagnosis of pleural spindle cell neoplasms. Histopathology 43: 606–608
LETTER TO THE EDITOR
Multifocal cytokeratin expression in pleural and abdominal malignant solitary fibrous tumors: an unusual diagnostic pitfall Evelyne Lecoutere 1 & David Creytens 1
Received: 3 March 2015 / Revised: 17 March 2015 / Accepted: 23 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Dear Editor, Solitary fibrous tumor (SFT) is an uncommon mesenchymal fibroblastic neoplasm usually arising in the pleura, but it can virtually affect any extrapleural site. Conventional SFTs are characterized by short, cytologically bland spindle cells arranged in a patternless architecture, a fibro-collagenous stroma, and a prominent hemangiopericytomatous branching vascular network [1]. The vast majority of SFTs are morphologically and clinically benign. However, 5 to 10 % of SFTs will recur and/or metastasize. Proposed prognostic clinical and morphological criteria for SFT include age at presentation, tumor size, cellularity, mitotic activity (>4 mitoses per 10 high-power fields), the presence of necrosis, and the presence of sharply demarcated anaplastic areas. The vast majority of aggressive SFTs demonstrate these clinical and morphological features of malignancy; however, also morphologically benign-appearing SFTs can metastasize, and therefore, the biological behavior of this tumor type still remains largely unpredictable [1, 2]. Immunohistochemistry is commonly used as a valuable adjunct to diagnosis of SFT, alongside convincing histology. Bcl-2, CD99, and CD34 are often positive in SFT (in nearly 100, 75, and 81–95 % of cases, respectively), but positivity for these markers can also be seen at a high frequency in other soft tissue tumors that can mimic SFT, and they are therefore non-specific [1]. Recent studies have discovered that almost all SFTs harbor a NAB2-STAT6 fusion gene [3]. This fusion gene is considered a driving mutation in
* Evelyne Lecoutere [email protected] 1
Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium
the initiation of SFTs through EGR1 activation and transcriptional deregulation of EGR1-dependent target genes. The resulting overexpression of STAT6 protein has recently been shown to be a highly sensitive and specific marker for these tumors. Hence, STAT6 immunochemistry should lead to a more accurate diagnosis [4, 5]. We describe three cases of a morphological malignant SFT with unexpected strong cytokeratin expression, and we discuss the diagnostic implications thereof. All tumors were primary. The patients were women aged between 42 and 84 years. In two cases, the tumor was located in the pleura, and in one case, the tumor was situated in the abdomen. Histologically, all three cases showed, at least focally, typical histological features of SFT with branching hemangiopericytoma-like vessels and a variable fibro-collagenous background. They all met the proposed criteria of morphologically malignant SFTs, with increased mitotic activity, cytonuclear atypia, and tumoral necrosis (Figs. 1 and 2). Immunohistochemically, the atypical spindle cells in all three cases showed strong and patchy to diffuse expression for CD99 and Bcl-2. However, CD34 expression was heterogenous and loss of CD34 expression was observed in the malignant areas of both pleural tumors (Fig. 3). Staining for cytokeratin AE1/AE3 showed strong multifocal positivity (Fig. 4), but none of the cases was positive for cytokeratin 5, calretinin, and Wilms’ tumor protein 1 (WT1). The unforeseen strong positivity for cytokeratin AE1/AE3 together with the clinical setting of a large pleural or abdominal tumor point to sarcomatoid carcinoma or sarcomatoid mesothelioma as major differential diagnoses. The loss of CD34 reactivity contributes further to this diagnostic dilemma. Nevertheless, a histopathological diagnosis of SFT was made for three reasons. First, characteristic CD34 reactivity can be absent or only focally present in SFT cases [1]. Secondly, a few anecdotal single case reports of cytokeratin
Virchows Arch
Fig. 1 Histomorphologic “patternless pattern” appearance of the tumor with branching vessels, high cellularity, and cytonuclear atypia (hematoxylin & eosin staining, original magnification ×200)
Fig. 4 Multifocal strong cytoplasmic immunoreactivity for cytokeratin AE1/AE3 (original magnification ×200)
Fig. 2 Areas of tumoral necrosis (hematoxylin & eosin staining, original magnification ×400)
positivity in SFTs have been reported in the literature [6, 7]. However, the reported cytokeratin expression in these case reports was more focal and less multifocal compared to our cases. Finally, none of the immunohistochemical mesothelioma markers (cytokeratin 5, calretinin, and WT1) proved to be positive. Based on the recent publications describing the high sensitivity and specificity of nuclear STAT6 expression in distinguishing SFTs from histologic mimics, all three cases were retrospectively reviewed and stained for STAT6. All three cases showed diffuse and strong nuclear positivity for STAT6, confirming the proposed diagnosis of a malignant SFT with an uncommon strong cytokeratin positivity (Fig. 5). In practice, the diagnosis of SFT is usually straightforward. However, SFTs may be diagnostically challenging when the histology is modified by unusual morphological and/or immunophenotypic features, as was the case with the CD34negative and cytokeratin-positive malignant SFTs presented in this study. Presence of strong cytokeratin immunoreactivity in
Fig. 3 Loss of CD34 expression in the malignant tumor areas (original magnification ×100)
Fig. 5 Diffuse strong nuclear expression for STAT6 (original magnification ×400)
Virchows Arch
SFT can be a major diagnostic pitfall in that it can mislead one to interpret such a finding as proof of epithelial differentiation and strengthen the suspicion of a carcinoma or mesothelioma, particularly in the setting of a pleural or abdominal tumoral mass. This study also further supports the utility of STAT6 immunohistochemistry as a valuable ancillary test in the diagnostic work-up of these rare and unconventional cytokeratin positive malignant SFTs.
2.
3.
4.
5.
Conflict of interest The authors declare no conflict of interest. 6.
References 1.
Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F (2013) World Health Organization classification of tumours. Pathology and genetics. Tumours of soft tissue and bone. IARC, Lyon
7.
Demicco E, Park M, Araujo D et al (2012) Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model. Mod Pathol 25:1298–1306 Chmielecki C, Crago AM, Rosenberg M et al (2013) Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 45:131–132 Doyle LA, Vivero M, Fletcher CD et al (2014) Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol 27:390–395 Yoshida A, Tsuta K, Ohno M et al (2014) STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. Am J Surg Pathol 38:552–559 Yan B, Raju GC, Salto-Tellez M (2008) Epithelioid, cytokeratin expressing malignant solitary fibrous tumour of the pleura. Pathology 40:98–99 Cavazza A, Rossi G, Agostini L et al (2003) Cytokeratin-positive malignant solitary fibrous tumour of the pleura: an unusual pitfall in the diagnosis of pleural spindle cell neoplasms. Histopathology 43: 606–608
