Surg Today DOI 10.1007/s00595-015-1176-5
ORIGINAL ARTICLE
Solitary fibrous tumor of the pleura: morphogenesis and progression. A report of 36 cases Tsugumasa Kamata1,2 · Hiroyuki Sakurai1 · Kazuo Nakagawa1 · Shun‑ichi Watanabe1 · Koji Tsuta2 · Hisao Asamura3
Received: 18 January 2015 / Accepted: 19 March 2015 © Springer Japan 2015
Abstract Purpose We attempted to identify the exact point of tumor eruption of a solitary fibrous tumor of the pleura (SFTP). Methods We morphologically classified 36 SFTPs into 5 categories. Type A showed a connection that included a bloodstream with the pleura on both sides. Type B only showed a connection that included a bloodstream with the visceral pleura, and had a non-bloodstream connection with the parietal pleura. Type C only showed a connection that included a bloodstream with the visceral pleura, and had no connection with the parietal pleura. Type D showed a nonbloodstream connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. Finally, type E had no connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. The clinicopathological profiles of the tumors were investigated according to their type. Results The distribution of the 36 SFTPs was as follows: A (19 %), B (6 %), C (67 %), D (0 %) and E (8 %). The tumors categorized as type A tended to be large in size. Conclusions SFTPs commonly arise from the visceral pleura and in accordance with tumor progression they will form a non-bloodstream connection with the parietal * Hiroyuki Sakurai [email protected] 1
Division of Thoracic Surgery, National Cancer Center Hospital, 1‑1 Tsukiji 5‑chome, Chuo‑Ku, Tokyo 104‑0045, Japan
2
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Chuo‑Ku, Tokyo, Japan
3
Department of Surgery, Division of General Thoracic Surgery, School of Medicine, Keio University, Shinjuku‑Ku, Tokyo, Japan
pleura. Finally, a vascular pedicle will arise with the parietal pleura. Keywords Solitary fibrous tumor · Pleura · Morphogenesis
Introduction Solitary fibrous tumor of the pleura (SFTP) was first described as a distinct clinical entity among primary pleural tumors in 1931 by Klemperer and Rabin [1]. After several decades of controversy regarding the histological origin of SFTPs, electron microscopy and immunohistochemistry demonstrated that they have a mesenchymal rather than a mesothelial origin [2–4]. With regard to the morphogenesis of SFTPs, they have been reported to arise more commonly from the visceral pleura than the parietal pleura, and most SFTPs are pedunculated with benign histological features [5]. However, in some cases it is impossible to identify the exact point of tumor eruption because it is connected to both the visceral and parietal pleura. The morphogenic source of such tumors has not been sufficiently discussed in the literature. In this report, we classify SFTPs into 5 categories based on their connection pattern with the visceral and parietal pleura, and investigate the maximum tumor size in each category. We also discuss the morphogenesis and process of the tumor progression of SFTPs.
Methods In the 24-year period from 1990 to 2013, 11,790 general thoracic procedures were performed under general anesthesia at NCCH, Tokyo. Among these, 36 patients (0.3 %)
13
Surg Today
Fig. 1 The morphological classification of SFTP tumors: based on their connection pattern with the visceral and parietal pleura. Type A showed a connection that included a bloodstream with the pleura on both sides. Type B only showed a connection that included a bloodstream connection with the visceral pleura, and showed a non-bloodstream connection with the parietal pleura. Type C only showed a
connection that included a bloodstream with the visceral pleura, and showed no connection with the parietal pleura. Type D showed a nonbloodstream connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. Finally, type E showed no connection with the visceral pleura, and only showed a bloodstream connection with the parietal pleura
underwent surgical treatment for SFTPs. The medical records of each of the patients were reviewed for age, sex, tumor size, signs and symptoms, preoperative evaluations, surgical procedures, pathological features, recurrence patterns, and follow-up period. Informed consent was obtained from all of the patients in this study. According to the texts and figures in the operative notes, we classified each of these 36 tumors into one of 5 categories based on their morphology (types A–E, as shown in Fig. 1). In type A, the tumor showed a connection that included a bloodstream with the pleura on both sides. In type B, the tumor only showed a connection that included a bloodstream with the visceral pleura, and showed a nonbloodstream connection (such as simple adhesion), with the parietal pleura. In type C, the tumor only showed a connection that included a bloodstream with the visceral pleura, and showed no connection with the parietal pleura. In type D, the tumor showed a non-bloodstream connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. In type E, the tumor showed no connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. A bloodstream connection was considered to exist when a vessel ligation was needed in the dissection. The tumors were eventually diagnosed as malignant in a pathological examination when one or more of the criteria reported by England et al. [6] were met: (a) a mitotic count of more than 4 mitoses/10 high-power fields; (b)
the presence of necrosis; (c) hypercellularity as judged by nuclear crowding and overlapping; and (d) the presence of nuclear atypia. Information about the health status of patients was obtained from the clinical records of outpatient clinics.
13
Results Clinical presentation The patient demographics and clinicopathological features are summarized in Table 1. The median age at presentation was 54 years (range 24–81 years). The median maximal diameter of the tumor was 4.2 cm (range 1.0–29.0 cm). The patients’ smoking history and asbestos exposure status were not available. At the time of diagnosis, 6 patients (17 %) Table 1 The patient demographics and clinicopathological features Gender Male Female Age Tumor size Symptoms Yes No
18 (50 %) 18 (50 %) 24–81 (median 54) 1.0–29.0 cm (median 4.2 cm) 6 (17 %) 30 (83 %)
Surg Today
presented symptoms related to the tumor. Three patients suffered from dyspnea and coughing, two patients suffered from chest pain, and one patient suffered from hypoglycemia. Thirty patients (83 %) were totally asymptomatic and the tumor was incidentally found on a chest radiograph or, more rarely, on a CT scan performed for other reasons.
Chest radiography and CT were performed in all the patients and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed in 7 cases. On CT, the density of the tumor was usually quite low and heterogeneous to different extents in large tumors. The FDG-PET scan was negative for FDG accumulation in the tumor.
morphology, into one of 5 categories depending on the connection pattern with the visceral and parietal pleura (Fig. 1, mentioned above). The results are summarized in Table 3. Seven tumors (19 %) were categorized as type A, and had a median size of 20.0 cm (range 7.5–29.0 cm). Two tumors (6 %) were categorized as type B, and had a median size of 5.7 cm (range 5.3–6.0 cm). Twenty-four tumors (67 %) were categorized as type C, and had a median size of 3.3 cm (range 1.0–15.5 cm). None of the tumors was categorized as type D. Finally, 3 tumors (8 %) were categorized as type E, and had a median size of 2.5 cm (range 2.0–6.3 cm). In particular, the tumors that were categorized as type A tended to be larger. Both the cases which required formal lung resection were classified as type C.
Surgical findings
Pathological findings
The operative approach, surgical procedures, and outcomes are summarized in Table 2. The decision to perform surgery and the extent of the resection were decided on a case-bycase basis. An isolated mass excision was performed in 10 cases (28 %) and an en bloc resection of the surrounding structures was carried out in the remaining cases. In two patients, a formal lung resection [lobectomy (n = 1) and segmentectomy (n = 1)] was necessary because of large tumors that extended deep into the lung parenchyma. The surgical approaches included 22 cases (61 %) of thoracotomy and 14 (39 %) cases of video-assisted thoracoscopy (VATS). The resection was complete in all patients.
All of the tumors were determined to be SFTPs based on the pathological findings. In particular, a pattern characterized by a proliferation of uniform elongated spindle cells with a varying amount of connective tissue was detected in most of the cases. In the immunohistochemical analysis, most of the tumors were positive for vimentin and/or CD-34. Twenty-eight tumors (78 %) showed benign features and 8 (22 %) showed distinct features of malignancy. Among the 8 tumors with malignant features, 5 (63 %) were categorized as type A, 2 (25 %) were categorized as type C, and 1 (13 %) was categorized as type E (Table 3). A curative resection was achieved in all of the cases.
Tumors morphology
Clinical outcome
A pedunculated lesion was observed intraoperatively in 27 cases (75 %), while sessile tumors were observed in 9 cases (25 %). Each of the 36 tumors was classified, based on its
No patient died in the perioperative period. Postoperative complications occurred in 3 patients (8 %): gastrointestinal bleeding (n = 1), renal dysfunction (n = 1), and wound disruption (n = 1). The median follow-up period was 68.5 months (range 1–141 months). During the follow-up period, two patients (6 %) experienced tumor recurrence. The morphological features of these 2 tumors at the initial surgery were as follows: one tumor was type A with a size of 26 cm, while the other was type E with a size of 6.3 cm.
Preoperative evaluation
Table 2 The operative approaches, surgical procedures, and outcomes Approach Thoracotomy Video assisted Procedures Wedge resection Tumor resection Lobectomy Segmentectomy Other Operative time Bleeding
22 (61 %) 10 (28 %) 1 (3 %) 1 (3 %) 2 (6 %) 60 min (range 35–350 min) 5 ml (range 0–2684 ml)
Hospitalization
4 days (range 2–33 days)
22 (61 %) 14 (39 %)
Table 3 Tumor morphology Types
A (n = 7) B (n = 2) C (n = 24) D (n = 0) E (n = 3)
Tumor size (cm) Median 20.0 Range 7.5–29.0 Malignant 5/7 cases
5.7 5.3–6.0
3.3 1.0–15.5
NA NA
2.5 2.0–6.3
0/2
2/24
0/0
1/3
NA not applicable
13
In both cases, the recurrence was more than 10 years after the initial surgery. The recurrence pattern was localized, and resection was performed again in both patients. Only one patient (3 %) died during the follow-up period, however, this was not due to the tumor.
Discussion SFTP has been reported to arise more commonly from the visceral pleura than the parietal pleura, with approximately 80 % of SFTPs originating in the visceral pleura and 20 % originating in the parietal pleura [5, 7]. However, with regard to morphogenesis, it is sometimes impossible to identify the exact point of tumor eruption because it is connected to both the visceral and parietal pleura. To elucidate the morphogenesis of SFTPs, we classified each tumor into one of 5 categories depending on the connection pattern with the visceral and parietal pleura, and investigated the maximum tumor size in each category. As a result, most tumors (n = 24) were categorized as type C, which only showed a connection that included a bloodstream with the visceral pleura, and no connection with the parietal pleura. The median size of type C tumors was 3.3 cm. In addition, for the two type B tumors, which only showed a connection that included a bloodstream with the visceral pleura and a non-bloodstream connection (such as in simple adhesion) with the parietal pleura, the median tumor size was 5.7 cm. Additionally, in type A, which showed a connection that included a bloodstream with the pleura on both sides, we observed 7 tumors with a largest median tumor size of 20.0 cm. Based on these results, we can offer a hypothesis regarding the process of tumor progression. SFTPs commonly arise from the visceral pleura. As the tumor progresses and becomes larger, it may form a non-bloodstream connection with the parietal pleura. Therefore, there is connection with the parietal pleura that does not include a blood stream. Finally, a vascular pedicle will arise with the parietal pleura as the tumor becomes larger. Therefore, there is a strong probability that tumors which are found to be large in size in the preoperative evaluation will be categorized as type A. Although the bloodstream of such tumors is supplied from both sides of the pleura, as reported previously, their real origin can be considered to be the visceral side [7–9]. Preoperative angiography and embolization of the feeding arteries might be recommended to decrease the amount of intraoperative bleeding and to improve the safety of the procedure. In contrast, we observed no type D tumors and only three type E tumors, which only showed a connection that included a bloodstream with the parietal pleura. Therefore,
13
Surg Today
tumors that arise from the parietal pleura can be considered to be rare variants. SFTP is an uncommon fibroblastic neoplasm that most often arises in middle-aged adults and which has an equal sex predilection [10]. The incidence of SFTP is 2.8 cases per 100,000 registered hospital patients [11]. More than 900 cases of SFTP were reported in the literature up to 2005 [12]. SFTP presents as smooth masses with a reticulated vasculature and contains spindle-shaped or ovoid cells with round to fusiform nuclei with vacuolated cytoplasm [13]. These tumors were initially thought to originate from the mesothelial layer, but specialized immunohistochemical staining and electron microscopy findings have helped reclassify it as a mesenchymal derivative [2–4]. The expression of vimentin and CD34 and the absence of cytoplasmic keratin expression constitute the evidence for its mesenchymal origins [3, 14]. Recently, the NAB2-STAT6 fusion gene was shown to be present in up to 100 % of SFTPs. It has been hypothesized that NAB2/STAT6 fusion leads to a remarkable nuclear relocation of STAT6; the nuclear localization of STAT6 by immunohistochemistry is a characteristic of SFTPs and may serve as a diagnostic marker that indicates NAB2/STAT6 fusion and helps to discriminate SFTPs from histological mimics [15–17]. SFTP can present with various kinds of symptoms such as intrathoracic symptoms (dyspnea, chest pain, hemoptysis), systemic symptoms (hypoglycemia, hypertrophic osteoarthropathy), or nonspecific symptoms (fever, weight loss, fatigue) [6, 18]. In the present study, 6 patients (17 %) were symptomatic, including one patient with hypoglycemia. Four of the 6 tumors (67 %) of these symptomatic patients were categorized as type A. Presumably a relatively large tumor size may be associated with the development of symptoms. Hypoglycemia, which is observed in up to 2–4 % of cases, is attributed to the production of insulinlike growth factor II (IGF-II), which lowers blood glucose levels and impairs the growth hormone counter-regulatory response to hypoglycemia [19, 20]. This symptom has been noted to resolve after surgical resection of the tumor [21]. This clinical course was confirmed in a patient of the present case series who had suffered from hypoglycemia. Surgery is the first-step treatment of choice for SFTP and complete resection is its primary objective [5, 6, 22]. An extended resection through standard thoracotomy should be performed to promote the completeness of the resection. However, in cases in which a pedunculated appearance is accompanied by the absence of pleural dissemination and/ or clear chest-wall infiltration, it is reasonable to use VATS [23]. In our series, 14 of 36 patients (39 %) underwent a VATS procedure. With regard to the morphological categories, 12 of the 24 (50 %) type C tumors, 1 of the 2 (50 %) type B tumors, and 1 of the 3 (33 %) type E tumors were
Surg Today
managed by VATS, while all of the type A tumors were managed by thoracotomy. If a tumor is found to be rigidly connected to both sides of the pleura in the exploratory thoracoscopy, it would seem difficult to achieve tumor resection using the VATS procedure. England et al. [6] reported 223 cases of SFTs. Histologically, 82 (37 %) of the tumors were considered to be malignant and 141 (63 %) were considered to be benign. In the present study, 8 of 36 tumors (22 %) showed malignant features. In the 7 tumors that were morphologically categorized as type A, 5 (71 %) exhibited malignant features. Thus, when type A tumors are encountered, it is possible for surgeons to interoperatively predict a high possibility of malignancy. The great majority of SFTPs have been reported to have a benign clinical outcome, and around 90 % of the cases enjoy long-term disease-free survival [6, 11, 24]. In our series, local recurrence occurred in 2 of the 36 patients (6 %); at the initial surgery, one tumor was morphologically categorized as type A with malignant histological features, and the other as type E with benign histological features. Previously, Perrot et al. [18] reported significant differences in recurrence and survival among the different morphopathologic subtypes. However, we did not find a significant relationship between the morphopathologic subtype and the risk of recurrence among our morphological categories. A long follow-up period is necessary for these slowgrowing tumors because of the possibility of late recurrence [25]. In our series, we experienced two cases of local late recurrence; each of which occurred more than 10 years after the initial surgery. This is a retrospective analysis and, as such, there are limitations in the extent to which it can be used to clarify the uncertainties regarding SFTPs. However, the relatively large number of observed cases, the homogeneity of the cohort, and the long-term follow-up information support our conclusions. In conclusion, we considered the morphogenesis and the process of tumor progression of SFTPs by classifying them into 5 categories depending on their connection with the visceral and parietal pleura, and investigated the maximum tumor size in each category. SFTPs commonly arise from the visceral pleura. With tumor progression, they will form a non-bloodstream connection with the parietal pleura. Finally, a vascular pedicle will arise with the parietal pleura as the tumor becomes large in size. Tumors that arise from the parietal pleura can be considered to be rare variants. Surgical resection, when technically and medically feasible, is recommended for the treatment of localized SFTP, and long-term survival can be expected. Long-term followup is necessary for these slow-growing tumors due to the possibility of late recurrence.
Acknowledgments None. Conflict of interest The authors have no conflicts of interest to declare.
References 1. Klemperer P, Rabin LB. Primary neoplasms of the pleura. A report of five cases. Arch Pathol. 1931;11:385–412. 2. El-Naggar AK, Ro JY, Ayala AG, Ward R, Ordonez NG. Localized fibrous tumor of the serosal cavities. Immunohistochemical, electron-microscopic, and flow-cytometric DNA study. Am J Clin Pathol. 1989;92:561–5. 3. Flint A, Weiss SW. Cd-34 and keratin expression distinguishes solitary fibrous tumor (fibrous mesothelioma) of pleura from desmoplastic mesothelioma. Hum Pathol. 1995;26:428–31. 4. Al-Izzi M, Thurlow NP, Corrin B. Pleural mesothelioma of connective tissue type, localized fibrous tumour of the pleura, and reactive submesothelial hyperplasia. An immunohistochemical comparison. J Pathol. 1989;158:41–4. 5. Cardillo G, Facciolo F, Cavazzana AO, Capece G, Gasparri R, Martelli M. Localized (solitary) fibrous tumors of the pleura: an analysis of 55 patients. Ann Thorac Surg. 2000;70:1808–12. 6. England DM, Hochholzer L, McCarthy MJ. Localized benign and malignant fibrous tumors of the pleura. A clinicopathologic review of 223 cases. Am J Surg Pathol. 1989;13:640–58. 7. Aydemir B, Celik S, Okay T, Dogusoy I. Intrathoracic giant solitary fibrous tumor. Am J Case Rep. 2013;14:91–3. 8. Miyoshi K, Okumura N, Kokado Y, Matsuoka T, Kameyama K, Nakagawa T. Solitary fibrous tumor of the pleura with a minute malignant component and diaphragmatic vascular supply: report of a case. Surg Today. 2008;38:344–7. 9. Weiss B, Horton DA. Preoperative embolization of a massive solitary fibrous tumor of the pleura. Ann Thorac Surg. 2002;73:983–5. 10. Fletcher CDM, Bridge JA, Hogendoorn PCW. WHO classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013. 11. Okike N, Bernatz PE, Woolner LB. Localized mesothelioma of the pleura: benign and malignant variants. J Thorac Cardiovasc Surg. 1978;75:363–72. 12. Sung SH, Chang JW, Kim J, Lee KS, Han J, Park SI. Solitary fibrous tumors of the pleura: surgical outcome and clinical course. Ann Thorac Surg. 2005;79:303–7. 13. Wu M, Chen RK, Gurung L. Giant solitary fibrous tumor of the pleura. Thorac Cardiovasc Surg. 2005;53:185–8. 14. van de Rijn M, Lombard CM, Rouse RV. Expression of cd34 by solitary fibrous tumors of the pleura, mediastinum, and lung. Am J Surg Pathol. 1994;18:814–20. 15. Koelsche C, Schweizer L, Renner M, Warth A, Jones DT, Sahm F, et al. Nuclear relocation of stat6 reliably predicts NAB2/ STAT6 fusion for the diagnosis of solitary fibrous tumour. Histopathology. 2014;65:613–22. 16. Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol. 2014;27:390–5. 17. Yoshida A, Tsuta K, Ohno M, Yoshida M, Narita Y, Kawai A, et al. STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. Am J Surg Pathol. 2014;38:552–9. 18. de Perrot M, Fischer S, Brundler MA, Sekine Y, Keshavjee S. Solitary fibrous tumors of the pleura. Ann Thorac Surg. 2002;74:285–93. 19. Masson EA, MacFarlane IA, Graham D, Foy P. Spontaneous hypoglycaemia due to a pleural fibroma: role of insulin-like growth factors. Thorax. 1991;46:930–1.
13
20. Zafar H, Takimoto CH, Weiss G. Doege-Potter syndrome: hypoglycemia associated with malignant solitary fibrous tumor. Med Oncol. 2003;20:403–8. 21. Filosso PL, Asioli S, Ruffini E, Rovea P, Macri L, Sapino A, et al. Radical resection of a giant, invasive and symptomatic malignant solitary fibrous tumour (SFT) of the pleura. Lung Cancer. 2009;64:117–20. 22. Watts DM, Jones GP, Bowman GA, Olsen JD. Giant benign mesothelioma. Ann Thorac Surg. 1989;48:590–1. 23. Lococo F, Cesario A, Cardillo G, Filosso P, Galetta D, Carbone L, et al. Malignant solitary fibrous tumors of the pleura:
13
Surg Today retrospective review of a multicenter series. J Thorac Oncol. 2012;7:1698–706. 24. de Perrot M, Kurt AM, Robert JH, Borisch B, Spiliopoulos A. Clinical behavior of solitary fibrous tumors of the pleura. Ann Thorac Surg. 1999;67:1456–9. 2 5. Magdeleinat P, Alifano M, Petino A, Le Rochais JP, Dulmet E, Galateau F, et al. Solitary fibrous tumors of the pleura: clinical characteristics, surgical treatment and outcome. Eur J Cardiothorac Surg. 2002;21:1087–93.
ORIGINAL ARTICLE
Solitary fibrous tumor of the pleura: morphogenesis and progression. A report of 36 cases Tsugumasa Kamata1,2 · Hiroyuki Sakurai1 · Kazuo Nakagawa1 · Shun‑ichi Watanabe1 · Koji Tsuta2 · Hisao Asamura3
Received: 18 January 2015 / Accepted: 19 March 2015 © Springer Japan 2015
Abstract Purpose We attempted to identify the exact point of tumor eruption of a solitary fibrous tumor of the pleura (SFTP). Methods We morphologically classified 36 SFTPs into 5 categories. Type A showed a connection that included a bloodstream with the pleura on both sides. Type B only showed a connection that included a bloodstream with the visceral pleura, and had a non-bloodstream connection with the parietal pleura. Type C only showed a connection that included a bloodstream with the visceral pleura, and had no connection with the parietal pleura. Type D showed a nonbloodstream connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. Finally, type E had no connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. The clinicopathological profiles of the tumors were investigated according to their type. Results The distribution of the 36 SFTPs was as follows: A (19 %), B (6 %), C (67 %), D (0 %) and E (8 %). The tumors categorized as type A tended to be large in size. Conclusions SFTPs commonly arise from the visceral pleura and in accordance with tumor progression they will form a non-bloodstream connection with the parietal * Hiroyuki Sakurai [email protected] 1
Division of Thoracic Surgery, National Cancer Center Hospital, 1‑1 Tsukiji 5‑chome, Chuo‑Ku, Tokyo 104‑0045, Japan
2
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Chuo‑Ku, Tokyo, Japan
3
Department of Surgery, Division of General Thoracic Surgery, School of Medicine, Keio University, Shinjuku‑Ku, Tokyo, Japan
pleura. Finally, a vascular pedicle will arise with the parietal pleura. Keywords Solitary fibrous tumor · Pleura · Morphogenesis
Introduction Solitary fibrous tumor of the pleura (SFTP) was first described as a distinct clinical entity among primary pleural tumors in 1931 by Klemperer and Rabin [1]. After several decades of controversy regarding the histological origin of SFTPs, electron microscopy and immunohistochemistry demonstrated that they have a mesenchymal rather than a mesothelial origin [2–4]. With regard to the morphogenesis of SFTPs, they have been reported to arise more commonly from the visceral pleura than the parietal pleura, and most SFTPs are pedunculated with benign histological features [5]. However, in some cases it is impossible to identify the exact point of tumor eruption because it is connected to both the visceral and parietal pleura. The morphogenic source of such tumors has not been sufficiently discussed in the literature. In this report, we classify SFTPs into 5 categories based on their connection pattern with the visceral and parietal pleura, and investigate the maximum tumor size in each category. We also discuss the morphogenesis and process of the tumor progression of SFTPs.
Methods In the 24-year period from 1990 to 2013, 11,790 general thoracic procedures were performed under general anesthesia at NCCH, Tokyo. Among these, 36 patients (0.3 %)
13
Surg Today
Fig. 1 The morphological classification of SFTP tumors: based on their connection pattern with the visceral and parietal pleura. Type A showed a connection that included a bloodstream with the pleura on both sides. Type B only showed a connection that included a bloodstream connection with the visceral pleura, and showed a non-bloodstream connection with the parietal pleura. Type C only showed a
connection that included a bloodstream with the visceral pleura, and showed no connection with the parietal pleura. Type D showed a nonbloodstream connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. Finally, type E showed no connection with the visceral pleura, and only showed a bloodstream connection with the parietal pleura
underwent surgical treatment for SFTPs. The medical records of each of the patients were reviewed for age, sex, tumor size, signs and symptoms, preoperative evaluations, surgical procedures, pathological features, recurrence patterns, and follow-up period. Informed consent was obtained from all of the patients in this study. According to the texts and figures in the operative notes, we classified each of these 36 tumors into one of 5 categories based on their morphology (types A–E, as shown in Fig. 1). In type A, the tumor showed a connection that included a bloodstream with the pleura on both sides. In type B, the tumor only showed a connection that included a bloodstream with the visceral pleura, and showed a nonbloodstream connection (such as simple adhesion), with the parietal pleura. In type C, the tumor only showed a connection that included a bloodstream with the visceral pleura, and showed no connection with the parietal pleura. In type D, the tumor showed a non-bloodstream connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. In type E, the tumor showed no connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. A bloodstream connection was considered to exist when a vessel ligation was needed in the dissection. The tumors were eventually diagnosed as malignant in a pathological examination when one or more of the criteria reported by England et al. [6] were met: (a) a mitotic count of more than 4 mitoses/10 high-power fields; (b)
the presence of necrosis; (c) hypercellularity as judged by nuclear crowding and overlapping; and (d) the presence of nuclear atypia. Information about the health status of patients was obtained from the clinical records of outpatient clinics.
13
Results Clinical presentation The patient demographics and clinicopathological features are summarized in Table 1. The median age at presentation was 54 years (range 24–81 years). The median maximal diameter of the tumor was 4.2 cm (range 1.0–29.0 cm). The patients’ smoking history and asbestos exposure status were not available. At the time of diagnosis, 6 patients (17 %) Table 1 The patient demographics and clinicopathological features Gender Male Female Age Tumor size Symptoms Yes No
18 (50 %) 18 (50 %) 24–81 (median 54) 1.0–29.0 cm (median 4.2 cm) 6 (17 %) 30 (83 %)
Surg Today
presented symptoms related to the tumor. Three patients suffered from dyspnea and coughing, two patients suffered from chest pain, and one patient suffered from hypoglycemia. Thirty patients (83 %) were totally asymptomatic and the tumor was incidentally found on a chest radiograph or, more rarely, on a CT scan performed for other reasons.
Chest radiography and CT were performed in all the patients and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed in 7 cases. On CT, the density of the tumor was usually quite low and heterogeneous to different extents in large tumors. The FDG-PET scan was negative for FDG accumulation in the tumor.
morphology, into one of 5 categories depending on the connection pattern with the visceral and parietal pleura (Fig. 1, mentioned above). The results are summarized in Table 3. Seven tumors (19 %) were categorized as type A, and had a median size of 20.0 cm (range 7.5–29.0 cm). Two tumors (6 %) were categorized as type B, and had a median size of 5.7 cm (range 5.3–6.0 cm). Twenty-four tumors (67 %) were categorized as type C, and had a median size of 3.3 cm (range 1.0–15.5 cm). None of the tumors was categorized as type D. Finally, 3 tumors (8 %) were categorized as type E, and had a median size of 2.5 cm (range 2.0–6.3 cm). In particular, the tumors that were categorized as type A tended to be larger. Both the cases which required formal lung resection were classified as type C.
Surgical findings
Pathological findings
The operative approach, surgical procedures, and outcomes are summarized in Table 2. The decision to perform surgery and the extent of the resection were decided on a case-bycase basis. An isolated mass excision was performed in 10 cases (28 %) and an en bloc resection of the surrounding structures was carried out in the remaining cases. In two patients, a formal lung resection [lobectomy (n = 1) and segmentectomy (n = 1)] was necessary because of large tumors that extended deep into the lung parenchyma. The surgical approaches included 22 cases (61 %) of thoracotomy and 14 (39 %) cases of video-assisted thoracoscopy (VATS). The resection was complete in all patients.
All of the tumors were determined to be SFTPs based on the pathological findings. In particular, a pattern characterized by a proliferation of uniform elongated spindle cells with a varying amount of connective tissue was detected in most of the cases. In the immunohistochemical analysis, most of the tumors were positive for vimentin and/or CD-34. Twenty-eight tumors (78 %) showed benign features and 8 (22 %) showed distinct features of malignancy. Among the 8 tumors with malignant features, 5 (63 %) were categorized as type A, 2 (25 %) were categorized as type C, and 1 (13 %) was categorized as type E (Table 3). A curative resection was achieved in all of the cases.
Tumors morphology
Clinical outcome
A pedunculated lesion was observed intraoperatively in 27 cases (75 %), while sessile tumors were observed in 9 cases (25 %). Each of the 36 tumors was classified, based on its
No patient died in the perioperative period. Postoperative complications occurred in 3 patients (8 %): gastrointestinal bleeding (n = 1), renal dysfunction (n = 1), and wound disruption (n = 1). The median follow-up period was 68.5 months (range 1–141 months). During the follow-up period, two patients (6 %) experienced tumor recurrence. The morphological features of these 2 tumors at the initial surgery were as follows: one tumor was type A with a size of 26 cm, while the other was type E with a size of 6.3 cm.
Preoperative evaluation
Table 2 The operative approaches, surgical procedures, and outcomes Approach Thoracotomy Video assisted Procedures Wedge resection Tumor resection Lobectomy Segmentectomy Other Operative time Bleeding
22 (61 %) 10 (28 %) 1 (3 %) 1 (3 %) 2 (6 %) 60 min (range 35–350 min) 5 ml (range 0–2684 ml)
Hospitalization
4 days (range 2–33 days)
22 (61 %) 14 (39 %)
Table 3 Tumor morphology Types
A (n = 7) B (n = 2) C (n = 24) D (n = 0) E (n = 3)
Tumor size (cm) Median 20.0 Range 7.5–29.0 Malignant 5/7 cases
5.7 5.3–6.0
3.3 1.0–15.5
NA NA
2.5 2.0–6.3
0/2
2/24
0/0
1/3
NA not applicable
13
In both cases, the recurrence was more than 10 years after the initial surgery. The recurrence pattern was localized, and resection was performed again in both patients. Only one patient (3 %) died during the follow-up period, however, this was not due to the tumor.
Discussion SFTP has been reported to arise more commonly from the visceral pleura than the parietal pleura, with approximately 80 % of SFTPs originating in the visceral pleura and 20 % originating in the parietal pleura [5, 7]. However, with regard to morphogenesis, it is sometimes impossible to identify the exact point of tumor eruption because it is connected to both the visceral and parietal pleura. To elucidate the morphogenesis of SFTPs, we classified each tumor into one of 5 categories depending on the connection pattern with the visceral and parietal pleura, and investigated the maximum tumor size in each category. As a result, most tumors (n = 24) were categorized as type C, which only showed a connection that included a bloodstream with the visceral pleura, and no connection with the parietal pleura. The median size of type C tumors was 3.3 cm. In addition, for the two type B tumors, which only showed a connection that included a bloodstream with the visceral pleura and a non-bloodstream connection (such as in simple adhesion) with the parietal pleura, the median tumor size was 5.7 cm. Additionally, in type A, which showed a connection that included a bloodstream with the pleura on both sides, we observed 7 tumors with a largest median tumor size of 20.0 cm. Based on these results, we can offer a hypothesis regarding the process of tumor progression. SFTPs commonly arise from the visceral pleura. As the tumor progresses and becomes larger, it may form a non-bloodstream connection with the parietal pleura. Therefore, there is connection with the parietal pleura that does not include a blood stream. Finally, a vascular pedicle will arise with the parietal pleura as the tumor becomes larger. Therefore, there is a strong probability that tumors which are found to be large in size in the preoperative evaluation will be categorized as type A. Although the bloodstream of such tumors is supplied from both sides of the pleura, as reported previously, their real origin can be considered to be the visceral side [7–9]. Preoperative angiography and embolization of the feeding arteries might be recommended to decrease the amount of intraoperative bleeding and to improve the safety of the procedure. In contrast, we observed no type D tumors and only three type E tumors, which only showed a connection that included a bloodstream with the parietal pleura. Therefore,
13
Surg Today
tumors that arise from the parietal pleura can be considered to be rare variants. SFTP is an uncommon fibroblastic neoplasm that most often arises in middle-aged adults and which has an equal sex predilection [10]. The incidence of SFTP is 2.8 cases per 100,000 registered hospital patients [11]. More than 900 cases of SFTP were reported in the literature up to 2005 [12]. SFTP presents as smooth masses with a reticulated vasculature and contains spindle-shaped or ovoid cells with round to fusiform nuclei with vacuolated cytoplasm [13]. These tumors were initially thought to originate from the mesothelial layer, but specialized immunohistochemical staining and electron microscopy findings have helped reclassify it as a mesenchymal derivative [2–4]. The expression of vimentin and CD34 and the absence of cytoplasmic keratin expression constitute the evidence for its mesenchymal origins [3, 14]. Recently, the NAB2-STAT6 fusion gene was shown to be present in up to 100 % of SFTPs. It has been hypothesized that NAB2/STAT6 fusion leads to a remarkable nuclear relocation of STAT6; the nuclear localization of STAT6 by immunohistochemistry is a characteristic of SFTPs and may serve as a diagnostic marker that indicates NAB2/STAT6 fusion and helps to discriminate SFTPs from histological mimics [15–17]. SFTP can present with various kinds of symptoms such as intrathoracic symptoms (dyspnea, chest pain, hemoptysis), systemic symptoms (hypoglycemia, hypertrophic osteoarthropathy), or nonspecific symptoms (fever, weight loss, fatigue) [6, 18]. In the present study, 6 patients (17 %) were symptomatic, including one patient with hypoglycemia. Four of the 6 tumors (67 %) of these symptomatic patients were categorized as type A. Presumably a relatively large tumor size may be associated with the development of symptoms. Hypoglycemia, which is observed in up to 2–4 % of cases, is attributed to the production of insulinlike growth factor II (IGF-II), which lowers blood glucose levels and impairs the growth hormone counter-regulatory response to hypoglycemia [19, 20]. This symptom has been noted to resolve after surgical resection of the tumor [21]. This clinical course was confirmed in a patient of the present case series who had suffered from hypoglycemia. Surgery is the first-step treatment of choice for SFTP and complete resection is its primary objective [5, 6, 22]. An extended resection through standard thoracotomy should be performed to promote the completeness of the resection. However, in cases in which a pedunculated appearance is accompanied by the absence of pleural dissemination and/ or clear chest-wall infiltration, it is reasonable to use VATS [23]. In our series, 14 of 36 patients (39 %) underwent a VATS procedure. With regard to the morphological categories, 12 of the 24 (50 %) type C tumors, 1 of the 2 (50 %) type B tumors, and 1 of the 3 (33 %) type E tumors were
Surg Today
managed by VATS, while all of the type A tumors were managed by thoracotomy. If a tumor is found to be rigidly connected to both sides of the pleura in the exploratory thoracoscopy, it would seem difficult to achieve tumor resection using the VATS procedure. England et al. [6] reported 223 cases of SFTs. Histologically, 82 (37 %) of the tumors were considered to be malignant and 141 (63 %) were considered to be benign. In the present study, 8 of 36 tumors (22 %) showed malignant features. In the 7 tumors that were morphologically categorized as type A, 5 (71 %) exhibited malignant features. Thus, when type A tumors are encountered, it is possible for surgeons to interoperatively predict a high possibility of malignancy. The great majority of SFTPs have been reported to have a benign clinical outcome, and around 90 % of the cases enjoy long-term disease-free survival [6, 11, 24]. In our series, local recurrence occurred in 2 of the 36 patients (6 %); at the initial surgery, one tumor was morphologically categorized as type A with malignant histological features, and the other as type E with benign histological features. Previously, Perrot et al. [18] reported significant differences in recurrence and survival among the different morphopathologic subtypes. However, we did not find a significant relationship between the morphopathologic subtype and the risk of recurrence among our morphological categories. A long follow-up period is necessary for these slowgrowing tumors because of the possibility of late recurrence [25]. In our series, we experienced two cases of local late recurrence; each of which occurred more than 10 years after the initial surgery. This is a retrospective analysis and, as such, there are limitations in the extent to which it can be used to clarify the uncertainties regarding SFTPs. However, the relatively large number of observed cases, the homogeneity of the cohort, and the long-term follow-up information support our conclusions. In conclusion, we considered the morphogenesis and the process of tumor progression of SFTPs by classifying them into 5 categories depending on their connection with the visceral and parietal pleura, and investigated the maximum tumor size in each category. SFTPs commonly arise from the visceral pleura. With tumor progression, they will form a non-bloodstream connection with the parietal pleura. Finally, a vascular pedicle will arise with the parietal pleura as the tumor becomes large in size. Tumors that arise from the parietal pleura can be considered to be rare variants. Surgical resection, when technically and medically feasible, is recommended for the treatment of localized SFTP, and long-term survival can be expected. Long-term followup is necessary for these slow-growing tumors due to the possibility of late recurrence.
Acknowledgments None. Conflict of interest The authors have no conflicts of interest to declare.
References 1. Klemperer P, Rabin LB. Primary neoplasms of the pleura. A report of five cases. Arch Pathol. 1931;11:385–412. 2. El-Naggar AK, Ro JY, Ayala AG, Ward R, Ordonez NG. Localized fibrous tumor of the serosal cavities. Immunohistochemical, electron-microscopic, and flow-cytometric DNA study. Am J Clin Pathol. 1989;92:561–5. 3. Flint A, Weiss SW. Cd-34 and keratin expression distinguishes solitary fibrous tumor (fibrous mesothelioma) of pleura from desmoplastic mesothelioma. Hum Pathol. 1995;26:428–31. 4. Al-Izzi M, Thurlow NP, Corrin B. Pleural mesothelioma of connective tissue type, localized fibrous tumour of the pleura, and reactive submesothelial hyperplasia. An immunohistochemical comparison. J Pathol. 1989;158:41–4. 5. Cardillo G, Facciolo F, Cavazzana AO, Capece G, Gasparri R, Martelli M. Localized (solitary) fibrous tumors of the pleura: an analysis of 55 patients. Ann Thorac Surg. 2000;70:1808–12. 6. England DM, Hochholzer L, McCarthy MJ. Localized benign and malignant fibrous tumors of the pleura. A clinicopathologic review of 223 cases. Am J Surg Pathol. 1989;13:640–58. 7. Aydemir B, Celik S, Okay T, Dogusoy I. Intrathoracic giant solitary fibrous tumor. Am J Case Rep. 2013;14:91–3. 8. Miyoshi K, Okumura N, Kokado Y, Matsuoka T, Kameyama K, Nakagawa T. Solitary fibrous tumor of the pleura with a minute malignant component and diaphragmatic vascular supply: report of a case. Surg Today. 2008;38:344–7. 9. Weiss B, Horton DA. Preoperative embolization of a massive solitary fibrous tumor of the pleura. Ann Thorac Surg. 2002;73:983–5. 10. Fletcher CDM, Bridge JA, Hogendoorn PCW. WHO classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013. 11. Okike N, Bernatz PE, Woolner LB. Localized mesothelioma of the pleura: benign and malignant variants. J Thorac Cardiovasc Surg. 1978;75:363–72. 12. Sung SH, Chang JW, Kim J, Lee KS, Han J, Park SI. Solitary fibrous tumors of the pleura: surgical outcome and clinical course. Ann Thorac Surg. 2005;79:303–7. 13. Wu M, Chen RK, Gurung L. Giant solitary fibrous tumor of the pleura. Thorac Cardiovasc Surg. 2005;53:185–8. 14. van de Rijn M, Lombard CM, Rouse RV. Expression of cd34 by solitary fibrous tumors of the pleura, mediastinum, and lung. Am J Surg Pathol. 1994;18:814–20. 15. Koelsche C, Schweizer L, Renner M, Warth A, Jones DT, Sahm F, et al. Nuclear relocation of stat6 reliably predicts NAB2/ STAT6 fusion for the diagnosis of solitary fibrous tumour. Histopathology. 2014;65:613–22. 16. Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol. 2014;27:390–5. 17. Yoshida A, Tsuta K, Ohno M, Yoshida M, Narita Y, Kawai A, et al. STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. Am J Surg Pathol. 2014;38:552–9. 18. de Perrot M, Fischer S, Brundler MA, Sekine Y, Keshavjee S. Solitary fibrous tumors of the pleura. Ann Thorac Surg. 2002;74:285–93. 19. Masson EA, MacFarlane IA, Graham D, Foy P. Spontaneous hypoglycaemia due to a pleural fibroma: role of insulin-like growth factors. Thorax. 1991;46:930–1.
13
20. Zafar H, Takimoto CH, Weiss G. Doege-Potter syndrome: hypoglycemia associated with malignant solitary fibrous tumor. Med Oncol. 2003;20:403–8. 21. Filosso PL, Asioli S, Ruffini E, Rovea P, Macri L, Sapino A, et al. Radical resection of a giant, invasive and symptomatic malignant solitary fibrous tumour (SFT) of the pleura. Lung Cancer. 2009;64:117–20. 22. Watts DM, Jones GP, Bowman GA, Olsen JD. Giant benign mesothelioma. Ann Thorac Surg. 1989;48:590–1. 23. Lococo F, Cesario A, Cardillo G, Filosso P, Galetta D, Carbone L, et al. Malignant solitary fibrous tumors of the pleura:
13
Surg Today retrospective review of a multicenter series. J Thorac Oncol. 2012;7:1698–706. 24. de Perrot M, Kurt AM, Robert JH, Borisch B, Spiliopoulos A. Clinical behavior of solitary fibrous tumors of the pleura. Ann Thorac Surg. 1999;67:1456–9. 2 5. Magdeleinat P, Alifano M, Petino A, Le Rochais JP, Dulmet E, Galateau F, et al. Solitary fibrous tumors of the pleura: clinical characteristics, surgical treatment and outcome. Eur J Cardiothorac Surg. 2002;21:1087–93.
