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© 2003 European Association of Cardio-Thoracic Surgery
Solitary fibrous tumors of the pleura: clinicopathological and immunohistochemical examination
a Department of Surgical Oncology, Hokkaido University Hospital, Kita-15, Nishi-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
* Corresponding author. Tel.: +81-11-716-1161x5932; fax: +81-11-706-7158 Received May 23, 2002; received in revised form October 6, 2002; accepted October 22, 2002
The purpose of this work was to study clinical and biological characteristics of solitary fibrous tumor (SFT) of the pleura. We reviewed the clinicopathological and immunohistochemical features of 12 patients who underwent surgical resection for SFT. Ten cases were histologically defined as benign; two were found to be malignant. CD34 negativity and strong expression of p53 could be observed in a patient with fatal outcome. Ki-67 expression was increased in malignant cases, as compared with benign. We also found that Bcl-2 expression inversely correlated with a tumor diameter. As the development of malignant SFT might be associated with these molecular statuses, immunohistochemical staining should be performed in all cases to identify the biological characteristics of the tumor.
Key Words: Solitary fibrous tumor; CD34; p53; bcl-2
Klemperer and Rabin first categorized solitary fibrous tumor (SFT) of the pleura as primary pleural neoplasms in 1931 [1]. Although still controversial, the histogenesis of SFT is thought to derive from a mesenchymal rather than a mesothelial origin, based on immunohistochemical and ultrastructural examinations [2]. Therefore, this tumor is currently called a localized or solitary fibrous tumor of the pleura. Although most patients have positive clinical outcomes following surgical resection, occasional tumors follow unpredictable clinical courses [3]. As the biological characteristics of SFTs are not well understood, accurate prediction of the clinical course of patients with SFT has remained difficult. Therefore, we sought to identify potential molecules associated with clinical behavior or development of malignant SFT. In the present study, we examined clinical behavior, histopathological and immunohistochemical features of 12 independent cases of pleural SFT.
Surgically resected specimens from 12 patients with SFTs of the pleura were studied. All patients underwent surgical resection between 1993 and 2001 in the Second Department of Surgery at the Hokkaido University School of Medicine and the Department of Thoracic Surgery at Minami-Ichijo Hospital. Following histological review, all slides were re-classified as benign or malignant according to the following criteria: high cellularity, presence of nuclear atypia, mitotic count of more than four mitoses per ten high-power fields (HPF), and presence of necrosis [4]. The pathologists were blinded for the clinical course of the patients. For immunohistochemical analysis, formalin-fixed and paraffin-embedded specimens were stained using an avidin-biotin-peroxidase detection method. This procedure employed an automated immunostainer (Ventana NEXES; Tucson, AZ, USA) following antigen retrieval by pressure-cooking. The immunohistochemical studies of SFT utilized the specified primary antibodies (Table 1). Ten-percent normal goat serum was used as the primary antibody for negative controls. Sections from the p53 or Ki-67 positive colon adenocarcinoma were used as positive controls for p53 or Ki-67, respectively. For bcl-2, tumor infiltrating lymphocytes served as internal positive controls. The mean percentage of cells demonstrating positive immunostaining for p53, Bcl-2, and Ki-67 was determined for at least five areas of 400-fold magnification. Immunohistochemical labeling of all specimens was represented as a median score of three independent evaluations by different investigators, without previous knowledge of the patient background or outcome.
The clinical characteristics of the 12 cases are summarized in Table 2. No patients disclosed previous exposure to asbestos or previous chest trauma. Local resection with free surgical margin was performed in 11 patients by Video-assisted thoracoscopic surgery (VATS). In case 12, a large tumor arising from the left diaphragm was resected along with part of the diaphragm by posterolateral thoracotomy. All tumors were completely resected without lobectomy or pneumonectomy. None of these patients received either radiation or chemotherapy.
Ten patients are currently alive without signs of recurrence after surgery. Six years after resection in case 11, the patient died of multiple recurrent tumors with pleural dissemination (Fig. 1). In case 12, although the primary occurrence was resected, the tumor recurred twice in the following 5 years. Following the resection of the recurrences, the patient is alive without visible tumor retention.
Ten cases (83.3%) were histologically defined as benign, while the remaining two cases (16.7%) were designated malignant. The immunohistochemical features are summarized in Table 2 (see also Fig. 2). All specimens were positive for vimentin, while none showed reactivity for keratin, desmin,  -smooth muscle actin, S100 protein, CD117 or calretinin. Bcl-2 expression demonstrated a significant correlation with tumor diameter (Spearman's rank correlation test;  ). The patients with a larger number of Bcl-2-positive cells showed a smaller tumor size.
Though the majority of pleural SFTs have a good clinical outcome following surgical resection, 12–23% of these tumors demonstrate aggressive and malignant clinical courses [2,4,5]. In this study, two cases (16.7%) of SFTs were considered as histopathologically malignant according to the criteria defined by England et al. It was reported that 1.4% of the patients with benign SFT had recurrences and 45% of the patients with malignant SFT were cured after surgery. The most important indicator of clinical outcome, however, was complete excision during the initial surgery [4]. In our study, Ki-67 labeling index was higher in the two malignant cases than in the benign. Moreover, recurrent tumors displayed increased Ki-67 labeling index in comparison to the primary tumors. This finding is consistent with the observations in previous reports suggesting that SFTs might increase their malignant capacity with every recurrence [6]. As Ki-67 labeling index was thought to have strong association with the degree of histopathological malignancy, we suggested that a long and careful follow-up was required for the patient with a strong reactivity to Ki-67. We found that strong expression of p53 and CD34 negativity could be observed in both tumors of a patient with fatal outcome. It was reported that the proportion of cells staining positively for p53 was higher in malignant SFT than in benign [6]. We thought that p53 genetic alteration might then be associated with an additional step in the malignant progression of SFT. Moreover, it was reported that malignant SFTs occasionally exhibited a negative reaction to CD34 immunostaining [6]. In these cases, the loss of CD34 expression may be associated with increased tumor differentiation and the malignant transformation of SFTs.
Bcl-2 was reported to be a highly sensitive marker of SFTs [7]. In our study, all tumors demonstrated positive reactivity for Bcl-2, and we discovered a significant correlation between strong Bcl-2 immunoexpression and a reduced tumor size ( In this study, malignant cases showed different immunohistochemical features from benign cases. As these molecular markers might provide additional information for accurate grasp of the biological status in malignant SFTs, immunohistochemical staining should be performed in all cases. As we reviewed only a small number of cases in this study, further investigation of the biological characteristics of SFT are needed.
ICVTS on-line discussion Author: Dr. Pier Luigi Filosso, Staff Surgeon, University of Torino, Department of Thoracic Surgery, Via Genova 3, Torino, 10126, Italy Date: 10-Jan-2003 11:11 Message: I read with interest and I appreciated the paper of Hiraoka and Colleagues. Solitary fibrous tumours (SFT) of the pleura are a rare entity (no more than 800 cases are described in English Literature) whose clinical course is often unpredictable. Recurrences are possible, especially in so called "malignant SFT", according to England's criteria (hypercellularity, nuclear atypia, high number of mitoses and presence of necrosis). Clinical and radiological features of malignant SFT are:- large size of the tumour - the presence of ipsilateral pleural effusion - the presence of necrotic areas within the mass at thoracic CT scan - the location of the tumour within the pulmonary parenchyma. Strong expression of CD34 and Vimentin is typical in SFT; Ki67 appears an effective marker of the potential malignant form, as confirmed by several Authors. The study of Hiraoka confirms these data. I have some comments about it: (1) Authors report that 11 out of 12 SFT were resected by VATS. I believe that VATS is useful only in the case of small and peduncolated lesions: Cardillo reports SFT' VATS resection in 39 out of 55 patients of his series, while neither de Perrot,nor Suter had experience with this kind of resection. In the series I published in 2001, only in one case (a small and peduncolated SFT) the tumour was resected by VATS. The most important indicator of the clinical outcome in SFT is thecomplete and radical resection of the tumour. I think that in SFT with a large broad base of attachment at the parietal pleura, thoracotomy is mandatory to achieve radicality in resection. (2) The Authors do not indicate the number of SFT arising from the visceral and the parietal pleura, those peduncolated and those with a large base of attachement. (3) The Authors do not indicate if, and in what percentage, extrathoracic symptoms (clubbing, hypoglycaemia and arthritic pain) were present in their patients. These symptoms are generally associated with large SFT; clubbing is an effective and early clinical index of recurrences. 4) Finally, I believe that adjuvant radiation therapy is mandatory in malignant form of SFT, in order to prevent recurrences.
The authors would like to thank Dr. Takashi Minase, Department of Pathology, NTT Higashi Nihon Sapporo Hospital, Japan, and Dr. Tomoo Itoh, Department of Surgical Pathology, Hokkaido University Hospital, Japan, for their help with the histological examinations. doi:10.1016/S1569-9293(02)00091-9
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Abstract
1. Introduction
.