Radiol med DOI 10.1007/s11547-013-0376-6
DIAGNOSTIC IMAGING IN ONCOLOGY
The computed tomographic findings of pulmonary epithelioid hemangioendothelioma Kefu Liu • Ping Xie • Weijun Peng Zhengrong Zhou
•
Received: 19 March 2013 / Accepted: 30 July 2013 Ó Italian Society of Medical Radiology 2014
Abstract Purpose The aim of this study is to analyse the computed tomographic (CT) findings of pulmonary epithelioid haemangioendothelioma (EHE). Materials and methods The CT features and clinical presentations of six patients (five women, one man; mean age, 53 years) with pathology-proven pulmonary EHE were reviewed. Noncontrast CT images were available for three patients and enhanced CT images for three patients. The image characteristics included the number of tumours, tumour location and size, tumour margins, the presence of calcification/necrosis/cavity, the presence of perivascular location, the presence of pleural lesions, tumour homogeneity at contrastenhanced CT, tumour enhancement relative to the adjacent muscle and the presence of extrapulmonary lesions. Results Multiple nodules/masses with irregular margin were shown in all cases, and reticulonodular opacities and ground-glass opacities were found in one case. Overall, the six cases showed 178 nodules/masses, 90 % (160/178) of which were \1 cm in diameter. The average size of the largest nodules/masses in each case was 2.7 cm. The
K. Liu (&) P. Xie Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu, China e-mail: [email protected] K. Liu W. Peng Z. Zhou Department of Radiology, Fudan University Shanghai Cancer Center, No.270, Dong An Road, Shanghai 200032, China K. Liu W. Peng Z. Zhou Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
nodules/masses were mostly (93 %, 166/178) located in the subpleural region (\2 cm from the pleura). A total of 48 % (86/178) of nodules/masses showed punctate calcification in four of six cases. All nodules/masses showed perivascular location. Pleural indentation was shown in all cases, as well as pleural-thickening in five cases and pleural effusion in two cases. On contrast-enhanced CT, EHE showed a mildly heterogeneous hyperdense appearance. Conclusions With predilection for subpleural and perivascular location, typical pulmonary EHE appears as multiple irregular nodules with punctate calcification and pleural indentation. Keywords Lung Epithelioid hemangioendothelioma Computed tomography
Introduction Pulmonary epithelioid haemangioendothelioma (EHE) is a rare endothelium-originating tumour of borderline malignancy [1, 2]. EHE can develop in most tissues and the most common sites are soft tissue, bone, liver and lung. EHE was first described as an intravascular bronchioloalveolar tumour (IVBAT) by Dail and Liebow in 1975; however, the angiogenic nature of IVBAT was revealed by later studies showing that IVBAT and epithelioid haemangioendothelioma are different manifestation of the same disease [1, 3–6]. Several studies have reported the CT features of pulmonary EHE [2–5, 7–13], but most of them are case reports, so the total reported sample size is small and the CT features of pulmonary EHE, therefore, need further study. The aim of this retrospective study was to analyse the clinical and CT features of six cases of pulmonary EHE.
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Materials and methods
CT imaging
Patients
In this study noncontrast CT images were available for three patients and contrast-enhanced CT images for three patients. The CT examinations were performed with an MDCT scaner (Somaton Sensation 40 or 64, Siemens, Germany). The CT technical parameters were as follows: tube voltage, 120 kVp; rotation time, 0.5 s; pitch, 1.4 (60 9 0.6 or 40 9 0.6); reconstruction slice thickness, 5 mm (kernel, B70f very sharp and B31f medium smooth?); tube current was adjusted for each subject by using the CARE dose 4D technique. A bolus of nonionic contrast material (300 mg I/ml of iopamidol at 1.5 ml/kg body weight) was injected intravenously at a rate of 2 ml/s using an automated injector. A radiologist evaluated the tumour’s CT features, including (1) the number of tumours, (2) tumour location, (3) tumour size (maximum axial diameter), (4) tumour margin, (5) the presence of calcification, (6) the presence of necrosis and cavity, (7) perivascular location, (8) tumour homogeneity on contrast-enhanced CT and tumour enhancement relative to the adjacent muscle (hypo-, iso-, or hyper attenuating), (9) the presence of pleural lesions
The CT images of six patients with pathologically proved pulmonary EHE were retrospectively reviewed. The clinical diagnosis was confirmed by histology and immunohistochemistry. Institutional review board permission was obtained to review patient medical records, and patient informed consent was not required. The clinical features of the six cases of pulmonary EHEs are shown in Table 1. The tumours were discovered owing to chest pain in two patients, cough in one patient and physical examination in three patients. Mean age was 53 years (range 35–63). Five patients were females and one was male. The serum levels of tumour markers (a-1-fetoprotein, carcinoembryonic antigen, CA19-9, CA125) were normal. Four patients underwent surgical pulmonary lobectomy and two patients underwent CT-guided transthoracic biopsy using an 18-gauge needle. One patient was lost to follow-up immediately after biopsy; the remaining five patients were still alive at the time of writing this paper (36–1,197 post-operative days).
Table 1 Clinical and computed tomography (CT) features of pulmonary epithelioid haemangioendothelioma No.
1
2
3
4
5
6
Sex
Female
Female
Female
Female
Female
Male
Age (years)
54
63
57
55
35
54
Symptom
None
Chest pain
None
Chest pain
Cough
None
Multiple/single
Multiple
Multiple
Multiple
Multiple
Multiple
Multiple
Location
Subpleural
Subpleural
Subpleural
Subpleural
Subpleural
Subpleural
Maximum axial diameter (cm)
1.5
5.2
3.0
1.9
3.5
1.5
Margin Calcification
Irregular Yes
Irregular Yes
Irregular Yes
Irregular Yes
Irregular No
Irregular No
Necrosis
No
Yes
No
No
No
No
Cavity
No
No
No
No
No
No
Perivascular location
Yes
Yes
Yes
Yes
Yes
Yes
Non-contrast CT
Heterogeneous
No image
Mild heterogeneous
No image
Homogeneous
No image
Enhanced CT
No image
Heterogeneous and hyperdense
No image
Heterogeneous and hyperdense
No image
Heterogeneous and hyperdense
Pleural indentation
Yes
Yes
Yes
Yes
Yes
Yes
Pleural thickening
Yes
Yes
Yes
Yes
Yes
No
Pleural effusion
No
Yes
No
Yes
No
No
Extrapulmonary lesion
Right frontal bone lesion
Right thyroid mass
Multiple bone lesions
Retroperitoneal mass
Mediastinal mass
Left inguinal mass
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Radiol med Fig. 1 A-54-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest computed tomography (CT) images show multiple irregular subpleural nodules/masses with the pleural indentation sign (b, c, e), perivascular location (a, c, e), as well as punctate calcification in partial nodules/ masses (d, f) and pleural thickening (c, d). Furthermore, the size of the largest nodules/ masses was 1.5 cm in diameter (a). The tumour shows a biphasic pattern with nests of epithelioid cells within a spindle cell stroma. The tubulopapillary pattern can be seen in partial district. The epithelioid tumour cells show large round to oval nuclei with a vesicular chromatin pattern (g, h). The tumour cells were positive for CD34, factor-VIII-related antigen (i, j)
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(pleural indentation, pleural thickening, pleural effusion) and (10) the presence of extrapulmonary lesions.
Results The CT findings of the six EHEs are described in Table 1. Multiple nodules/masses were shown in all cases and reticulonodular opacities and ground-glass opacities were each found in one case. Six cases showed a total of 178 nodules/ masses, 90 % (160/178) of which were \1 cm in diameter. The average size of the largest nodules/masses in each case was 2.7 cm (range 1.5–5.2). The average number of nodules/ masses in each case was 30 (range 11–70). The nodules/ masses were mostly (93 %, 166/178) located in the subpleural region (\2 cm from the pleura) (Figs. 1, 2, 3, 4, 5, 6). All nodules/masses showed irregular margin (Figs. 1, 2, 3, 4, 5, 6). A total of 48 % (86/178) of the nodules/masses showed punctate calcification in four of six cases (Figs. 1, 2, 3, 4). All nodules/masses showed perivascular location (Figs. 1, 2, 3, 4, 5, 6). Pleural indentation was seen in six cases (Figs. 1, 2, 3, 4, 5, 6), pleural thickening in five cases (Figs. 1, 2, 3, 4, 5) and pleural effusion in two cases (Figs. 2, 4). EHE showed a mild-heterogeneous hyperdense appearance on contrast-enhanced CT relative to the adjacent muscle in two cases (Figs. 2, 4); however, the enhancement of the nodules/masses in one case could not be analysed due to small lesion size.
Fig. 2 A 63-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest CT images show multiple irregular subpleural nodules/ masses (a–d) with pleural indentation (a, c), perivascular location (a, c), as well as punctate calcification in partial nodules/masses (b, d), pleuralthickening (c, d) and pleural effusion (a–d). Furthermore, the size of the largest nodules/ masses was 5.2 cm in diameter (b) and the pulmonary epithelioid haemangioendothelioma showed a mild heterogeneous hyperdense appearance relative to muscle on contrast-enhanced CT (b)
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One case had a mediastinal lesion and five cases had extrapulmonary lesions including right frontal bone lesion, right thyroid mass, multiple bone lesions and retroperitoneal mass, but these lesions were not diagnosed by pathology.
Discussion Pulmonary EHE is a rare tumour, which is characterised histologically by the presence of round or spindle-shaped endothelial cells with abundant cytoplasm embedded in a fibromyxoid stroma; some of the cells may demonstrate intracellular lumina. The diagnosis of pulmonary EHE depends on immunohistochemistry. Definitive diagnosis requires positive immunohistochemical staining for endothelial markers (CD31, CD34, factor VIII and/or FLI-1) [14]. Additional cytogentic studies have revealed chromosome translocation including t(1;3)(p36;25), t(10;14)(p13;q24) and gains and deletions involving chromosomes 11 and 12 [15–17]. Pulmonary EHEs are four times more common in women than in men [1, 11], as seen in our experience (5/6). Pulmonary EHEs are usually asymptomatic and are often detected incidentally [11]; this was also the case in our study where three cases were asymptomatic and three cases showed symptoms (chest pain due to pleural effusion in two cases and cough due to significant pleura adhesion in
Radiol med Fig. 3 A 57-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest CT images show multiple irregular subpleural nodules/ masses (a–d), with pleural indentation sign (a, c), perivascular location (a, c), as well as punctate calcification in partial nodules/masses (d) and pleural thickening (c). Furthermore, the size of the largest nodules/masses was 3.0 cm in diameter (a, b)
Fig. 4 A 55-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest CT images show reticulonodular opacities (a) and multiple irregular subpleural nodules/masses (a–d) with pleural indentation sign (a, b), perivascular location (a, b), as well as punctate calcification in partial nodules/masses (c, d), pleural thickening (a–d) and pleural effusion (a–d). Furthermore, the size of the largest nodules/masses was 1.9 cm in diameter (a, b) and the pulmonary epithelioid haemangioendothelioma showed a mild heterogeneous hyperdense appearance relative to muscle on contrast-enhanced CT (b)
one case). However, in our study the average age was 53 years, in contrast to the findings of previous reports in which most patients were younger than 40 years [1, 6, 18]. Our results showed that all cases had multiple irregular nodules/masses. The average number of nodules/masses in each case was 30 (range 11–70), and most nodules/masses (90 %, 160/178) were \1 cm in diameter. These findings
are similar to those reported in past studies which report that the most characteristic feature of EHE on CT is the presence of multiple perivascular nodules with well- and ill-defined margins in both lungs and nodules up to 2 cm in size, although most are \1 cm in diameter [4, 5, 8, 9, 11, 12, 19]. The feature of irregular margins may be attributed to tumour infiltration of small blood vessels, bronchi/
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Radiol med Fig. 5 A 35-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest CT images show ground-glass opacities (a) and multiple irregular subpleural nodules/ masses (a–f) with pleural indentation sign (a, c, e), perivascular location (a, c) and pleural thickening (c, e). The size of the largest nodules/ masses was 3.5 cm in diameter (a)
bronchioles and lymphatic vessels, especially small arteries, lymphatics and venules of 1 mm or less in diameter within or adjacent to the nodules; less frequently vessels of several millimetres in diameter may be involved [1, 4, 9]. To our knowledge, pulmonary hamartoma, leiomyoma and metastasis usually show nodule/mass with smooth margins; Wegener granulomatosis usually appears as multiple nodules/masses with cavity (size from a few millimetres to over 10 cm) and the number of lesions are often \10 [20– 23], which is not similar to that of EHE. In our study, pulmonary EHE showed predominant subpleural location, which was confirmed by gross pathology revealing an increased number of lesions in the immediate subpleural area [5, 24]. This feature of EHE was different from pneumoconiosis in which the nodules tend to be most numerous in the upper lobe, from metastatic pulmonary nodules which tend to be distributed in the basal portion of the lung, from Wegener granulomatosis which has peribronchovascular, subpleural and angiocentric nodules/masses [20, 23, 25, 26].
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In our study, the pulmonary EHEs showed perivascular location, reflecting the gross pathology finding that tumours are usually found in relation to small and mediumsized vessels and bronchi. Additionally light microscopy shows that tumour vascularity is inapparent, only a rare small capillary can be identified in the tumour itself, and the tumour cells are near vessels and adjacent to alveolar septa, which suggest that EHE has metabolic requirements and its nutrient and oxygen supply is by diffusion [1]. This CT feature is usually not found in pneumoconiosis, metastatic pulmonary nodule, Wegener granulomatosis, pulmonary hamartoma, or benign metastasising leiomyoma [20–23, 25, 26]. In our study, 48 % (86/178) of nodules/masses showed punctate calcification in four of six cases, a feature also reported by other studies [7, 9, 11, 13, 24]. Nodules of pulmonary EHE show an acellular sclerotic central area and the acellular pale pink centres undergo coagulative necrosis, then dystrophic calcification, chondrification, ossification, and rarely positive Congo red staining
Radiol med Fig. 6 A 54-year-old man with pulmonary epithelioid haemangioendothelioma. Chest CT images show multiple irregular subpleural nodules/ masses (a–f) with pleural indentation sign (a, e, f), perivascular location (c, e). However, the size of the largest nodules/masses was too small (1.1 cm in diameter) to analyse the enhancement of lesion (a, b)
reactions can be seen in these necrotic central cores [1]. Punctate calcification can occur in a metastatic sarcoma, but other CT features including smooth margin, tendency to distribute in the basal portion of the lung may be used for the differential diagnosis [26]. In our study, pleural indentation was found in all cases. This corresponds histologically to thickened, fibrotic connective tissue septations with indrawing of the visceral pleura and reflects desmoplastic reaction [27]. Alternatively, the tissue processing shrinkage artefact may be attributed to the fact that the tumour extends into each alveolus from just one focus and a moderate amount of fibrosis [1]. Usually pneumoconiosis, metastasis, Wegener granulomatosis, pulmonary hamartoma and leiomyoma do not show pleural indentation [20–23, 25, 26], unlike pulmonary EHE.
In our study, five cases showed pleural thickening, and two cases showed pleural effusion. The CT findings of pleural EHE are nonspecific and usually demonstrate a pleural effusion with localised or diffuse nodular pleural thickening [2], which typically affects older men, induces chest pain and dyspnoea and is easily mistaken for pleural infections or malignant mesothelioma [3, 4, 28]. Patients with fibrinous pleuritis and extrapleural proliferation of tumour cells or spindle tumour cells generally have a worse prognosis [18, 29]. Due to the small size and non availability of contrastenhanced CT images, the enhancement of EHE could not be analysed. Two cases in our study showed that EHE had a mild-heterogeneous hyperdense appearance on contrastenhanced CT, similar to that described in a case report
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revealing a left hilar mass mimicking central lung cancer [30]. Furthermore, some studies have reported atypical CT manifestations of pulmonary EHE which included diffuse reticulonodular opacities and ground-glass opacities [4, 10]; however, these CT features were each found in one case in our study and are attributed to interstitial infiltration presenting focally in interlobular septa or pleura and around bronchopulmonary rays [1]. Additionally, the extremely long and indolent growth of pulmonary EHE needs to be emphasised. Some authors reported that pulmonary EHE showed little or no growth on serial radiographs [4, 5, 31] and that even partial spontaneous regression [32] and life expectancy may be up to 30 years [4, 5, 31]. Some authors have reported the antitumour effects of interferon, chemotherapy using carboplatin and etoposide [14, 33]. A monoclonal antibody against vascular endothelial growth factor (VEGF) (bevacizumab) together with chemotherapy was recently used for preventing tumour spread in the early period as these tumours express high levels of VEGF [34]. However, there is no established standard treatment of choice [34]. Additionally, the fluorodeoxyglucose positron emission tomography (FDG-PET) scan can provide useful information concerning the malignant potential of each nodule more than 6 mm in diameter. Nodules are negative in PET scans, perhaps being evidence of a more benign character. FDG-PET may be useful to select the more clinically malignant nodules, which worsen the prognosis [31, 35]. Sometimes EHE involves extrapulmonary organs and may be multifocal; the liver and bone are the most frequently affected organs [6]. Hepatic EHE typically appears as multifocal confluent peripheral nodules with adjacent capsular retraction and a low-signal halo; additionally hepatic EHE frequently occurs in older children [36, 37]. Bone EHE typically shows a lytic lesion without matrix mineralisation, even though osseous expansile remodelling may be seen [19]. The present study was limited by a small sample size because pulmonary EHE is rarely encountered. Moreover, none of the cases underwent both unenhanced and contrastenhanced CT imaging. Third, PET and magnetic resonance imaging images were not included in this study. Therefore, further studies with a larger number of cases are needed. In conclusion, with a predilection for subpleural and perivascular location, typical pulmonary EHE appears as multiple irregular nodules with punctate calcification and pleural indentation. Conflict of interest Kefu Liu, Ping Xie, Weijun Peng, Zhengrong Zhou declare no conflict of interest.
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Radiol med 21. Abramson S, Gilkeson RC, Goldstein JD et al (2001) Benign metastasizing leiomyoma: clinical, imaging, and pathologic correlation. AJR Am J Roentgenol 176:1409–1413 22. Siegelman SS, Khouri NF, Scott WW Jr et al (1986) Pulmonary hamartoma: CT findings. Radiology 160:313–317 23. Hirakata K, Nakata H, Nakagawa T (1995) CT of pulmonary metastases with pathological correlation. Semin Ultrasound CT MR 16:379–394 24. Weiss SW, Ishak KG, Dail DH et al (1986) Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 3:259–287 25. Chong S, Lee KS, Chung MJ et al (2006) Pneumoconiosis: comparison of imaging and pathologic findings. Radiographics 26:59–77 26. Seo JB, Im JG, Goo JM et al (2001) Atypical pulmonary metastases: spectrum of radiologic findings. Radiographics 21:403–417 27. Webb WR (1978) The pleural tail sign. Radiology 127:309–313 28. Bahrami A, Allen TC, Cagle PT (2008) Pulmonary epithelioid hemangioendothelioma mimicking mesothelioma. Pathol Int 58:730–734 29. Lau K, Massad M, Pollak C et al (2011) Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: insights from an internet registry in the study of a rare cancer. Chest 140:1312–1318
30. Shang A, Wang X (2009) Pulmonary epithelioid haemangioendothelioma mimicking central lung cancer. Respirology 14:452–455 31. Okamura K, Ohshima T, Nakano R et al (2010) A case of pulmonary epithelioid hemangioendothelioma surviving 10 years without treatment. Ann Thorac Cardiovasc Surg 16:432–435 32. Kitaichi M, Nagai S, Nishimura K et al (1998) Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression. Eur Respir J 12:89–96 33. Calabro L, Di Giacomo AM, Altomonte M et al (2007) Primary hepatic epithelioid hemangioendothelioma progressively responsive to interferon-alpha: is there room for novel anti-angiogenetic treatments? J Exp Clin Cancer Res 26:145–150 34. Kim YH, Mishima M, Miyagawa-Hayashino A (2010) Treatment of pulmonary epithelioid hemangioendothelioma with bevacizumab. J Thorac Oncol 5:1107–1108 35. Watanabe S, Yano F, Kita T et al (2008) 18F-FDG-PET/CT as an indicator for resection of pulmonary epithelioid hemangioendothelioma. Ann Nucl Med 22:521–524 36. Chung EM, Lattin GE Jr, Cube R et al (2011) From the archives of the AFIP: pediatric liver masses: radiologic-pathologic correlation. Part 2. Malignant tumors. Radiographics 31:483–507 37. Miller WJ, Dodd GD 3rd, Federle MP et al (1992) Epithelioid hemangioendothelioma of the liver: imaging findings with pathologic correlation. AJR Am J Roentgenol 159:53–57
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DIAGNOSTIC IMAGING IN ONCOLOGY
The computed tomographic findings of pulmonary epithelioid hemangioendothelioma Kefu Liu • Ping Xie • Weijun Peng Zhengrong Zhou
•
Received: 19 March 2013 / Accepted: 30 July 2013 Ó Italian Society of Medical Radiology 2014
Abstract Purpose The aim of this study is to analyse the computed tomographic (CT) findings of pulmonary epithelioid haemangioendothelioma (EHE). Materials and methods The CT features and clinical presentations of six patients (five women, one man; mean age, 53 years) with pathology-proven pulmonary EHE were reviewed. Noncontrast CT images were available for three patients and enhanced CT images for three patients. The image characteristics included the number of tumours, tumour location and size, tumour margins, the presence of calcification/necrosis/cavity, the presence of perivascular location, the presence of pleural lesions, tumour homogeneity at contrastenhanced CT, tumour enhancement relative to the adjacent muscle and the presence of extrapulmonary lesions. Results Multiple nodules/masses with irregular margin were shown in all cases, and reticulonodular opacities and ground-glass opacities were found in one case. Overall, the six cases showed 178 nodules/masses, 90 % (160/178) of which were \1 cm in diameter. The average size of the largest nodules/masses in each case was 2.7 cm. The
K. Liu (&) P. Xie Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu, China e-mail: [email protected] K. Liu W. Peng Z. Zhou Department of Radiology, Fudan University Shanghai Cancer Center, No.270, Dong An Road, Shanghai 200032, China K. Liu W. Peng Z. Zhou Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
nodules/masses were mostly (93 %, 166/178) located in the subpleural region (\2 cm from the pleura). A total of 48 % (86/178) of nodules/masses showed punctate calcification in four of six cases. All nodules/masses showed perivascular location. Pleural indentation was shown in all cases, as well as pleural-thickening in five cases and pleural effusion in two cases. On contrast-enhanced CT, EHE showed a mildly heterogeneous hyperdense appearance. Conclusions With predilection for subpleural and perivascular location, typical pulmonary EHE appears as multiple irregular nodules with punctate calcification and pleural indentation. Keywords Lung Epithelioid hemangioendothelioma Computed tomography
Introduction Pulmonary epithelioid haemangioendothelioma (EHE) is a rare endothelium-originating tumour of borderline malignancy [1, 2]. EHE can develop in most tissues and the most common sites are soft tissue, bone, liver and lung. EHE was first described as an intravascular bronchioloalveolar tumour (IVBAT) by Dail and Liebow in 1975; however, the angiogenic nature of IVBAT was revealed by later studies showing that IVBAT and epithelioid haemangioendothelioma are different manifestation of the same disease [1, 3–6]. Several studies have reported the CT features of pulmonary EHE [2–5, 7–13], but most of them are case reports, so the total reported sample size is small and the CT features of pulmonary EHE, therefore, need further study. The aim of this retrospective study was to analyse the clinical and CT features of six cases of pulmonary EHE.
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Materials and methods
CT imaging
Patients
In this study noncontrast CT images were available for three patients and contrast-enhanced CT images for three patients. The CT examinations were performed with an MDCT scaner (Somaton Sensation 40 or 64, Siemens, Germany). The CT technical parameters were as follows: tube voltage, 120 kVp; rotation time, 0.5 s; pitch, 1.4 (60 9 0.6 or 40 9 0.6); reconstruction slice thickness, 5 mm (kernel, B70f very sharp and B31f medium smooth?); tube current was adjusted for each subject by using the CARE dose 4D technique. A bolus of nonionic contrast material (300 mg I/ml of iopamidol at 1.5 ml/kg body weight) was injected intravenously at a rate of 2 ml/s using an automated injector. A radiologist evaluated the tumour’s CT features, including (1) the number of tumours, (2) tumour location, (3) tumour size (maximum axial diameter), (4) tumour margin, (5) the presence of calcification, (6) the presence of necrosis and cavity, (7) perivascular location, (8) tumour homogeneity on contrast-enhanced CT and tumour enhancement relative to the adjacent muscle (hypo-, iso-, or hyper attenuating), (9) the presence of pleural lesions
The CT images of six patients with pathologically proved pulmonary EHE were retrospectively reviewed. The clinical diagnosis was confirmed by histology and immunohistochemistry. Institutional review board permission was obtained to review patient medical records, and patient informed consent was not required. The clinical features of the six cases of pulmonary EHEs are shown in Table 1. The tumours were discovered owing to chest pain in two patients, cough in one patient and physical examination in three patients. Mean age was 53 years (range 35–63). Five patients were females and one was male. The serum levels of tumour markers (a-1-fetoprotein, carcinoembryonic antigen, CA19-9, CA125) were normal. Four patients underwent surgical pulmonary lobectomy and two patients underwent CT-guided transthoracic biopsy using an 18-gauge needle. One patient was lost to follow-up immediately after biopsy; the remaining five patients were still alive at the time of writing this paper (36–1,197 post-operative days).
Table 1 Clinical and computed tomography (CT) features of pulmonary epithelioid haemangioendothelioma No.
1
2
3
4
5
6
Sex
Female
Female
Female
Female
Female
Male
Age (years)
54
63
57
55
35
54
Symptom
None
Chest pain
None
Chest pain
Cough
None
Multiple/single
Multiple
Multiple
Multiple
Multiple
Multiple
Multiple
Location
Subpleural
Subpleural
Subpleural
Subpleural
Subpleural
Subpleural
Maximum axial diameter (cm)
1.5
5.2
3.0
1.9
3.5
1.5
Margin Calcification
Irregular Yes
Irregular Yes
Irregular Yes
Irregular Yes
Irregular No
Irregular No
Necrosis
No
Yes
No
No
No
No
Cavity
No
No
No
No
No
No
Perivascular location
Yes
Yes
Yes
Yes
Yes
Yes
Non-contrast CT
Heterogeneous
No image
Mild heterogeneous
No image
Homogeneous
No image
Enhanced CT
No image
Heterogeneous and hyperdense
No image
Heterogeneous and hyperdense
No image
Heterogeneous and hyperdense
Pleural indentation
Yes
Yes
Yes
Yes
Yes
Yes
Pleural thickening
Yes
Yes
Yes
Yes
Yes
No
Pleural effusion
No
Yes
No
Yes
No
No
Extrapulmonary lesion
Right frontal bone lesion
Right thyroid mass
Multiple bone lesions
Retroperitoneal mass
Mediastinal mass
Left inguinal mass
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Radiol med Fig. 1 A-54-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest computed tomography (CT) images show multiple irregular subpleural nodules/masses with the pleural indentation sign (b, c, e), perivascular location (a, c, e), as well as punctate calcification in partial nodules/ masses (d, f) and pleural thickening (c, d). Furthermore, the size of the largest nodules/ masses was 1.5 cm in diameter (a). The tumour shows a biphasic pattern with nests of epithelioid cells within a spindle cell stroma. The tubulopapillary pattern can be seen in partial district. The epithelioid tumour cells show large round to oval nuclei with a vesicular chromatin pattern (g, h). The tumour cells were positive for CD34, factor-VIII-related antigen (i, j)
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(pleural indentation, pleural thickening, pleural effusion) and (10) the presence of extrapulmonary lesions.
Results The CT findings of the six EHEs are described in Table 1. Multiple nodules/masses were shown in all cases and reticulonodular opacities and ground-glass opacities were each found in one case. Six cases showed a total of 178 nodules/ masses, 90 % (160/178) of which were \1 cm in diameter. The average size of the largest nodules/masses in each case was 2.7 cm (range 1.5–5.2). The average number of nodules/ masses in each case was 30 (range 11–70). The nodules/ masses were mostly (93 %, 166/178) located in the subpleural region (\2 cm from the pleura) (Figs. 1, 2, 3, 4, 5, 6). All nodules/masses showed irregular margin (Figs. 1, 2, 3, 4, 5, 6). A total of 48 % (86/178) of the nodules/masses showed punctate calcification in four of six cases (Figs. 1, 2, 3, 4). All nodules/masses showed perivascular location (Figs. 1, 2, 3, 4, 5, 6). Pleural indentation was seen in six cases (Figs. 1, 2, 3, 4, 5, 6), pleural thickening in five cases (Figs. 1, 2, 3, 4, 5) and pleural effusion in two cases (Figs. 2, 4). EHE showed a mild-heterogeneous hyperdense appearance on contrast-enhanced CT relative to the adjacent muscle in two cases (Figs. 2, 4); however, the enhancement of the nodules/masses in one case could not be analysed due to small lesion size.
Fig. 2 A 63-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest CT images show multiple irregular subpleural nodules/ masses (a–d) with pleural indentation (a, c), perivascular location (a, c), as well as punctate calcification in partial nodules/masses (b, d), pleuralthickening (c, d) and pleural effusion (a–d). Furthermore, the size of the largest nodules/ masses was 5.2 cm in diameter (b) and the pulmonary epithelioid haemangioendothelioma showed a mild heterogeneous hyperdense appearance relative to muscle on contrast-enhanced CT (b)
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One case had a mediastinal lesion and five cases had extrapulmonary lesions including right frontal bone lesion, right thyroid mass, multiple bone lesions and retroperitoneal mass, but these lesions were not diagnosed by pathology.
Discussion Pulmonary EHE is a rare tumour, which is characterised histologically by the presence of round or spindle-shaped endothelial cells with abundant cytoplasm embedded in a fibromyxoid stroma; some of the cells may demonstrate intracellular lumina. The diagnosis of pulmonary EHE depends on immunohistochemistry. Definitive diagnosis requires positive immunohistochemical staining for endothelial markers (CD31, CD34, factor VIII and/or FLI-1) [14]. Additional cytogentic studies have revealed chromosome translocation including t(1;3)(p36;25), t(10;14)(p13;q24) and gains and deletions involving chromosomes 11 and 12 [15–17]. Pulmonary EHEs are four times more common in women than in men [1, 11], as seen in our experience (5/6). Pulmonary EHEs are usually asymptomatic and are often detected incidentally [11]; this was also the case in our study where three cases were asymptomatic and three cases showed symptoms (chest pain due to pleural effusion in two cases and cough due to significant pleura adhesion in
Radiol med Fig. 3 A 57-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest CT images show multiple irregular subpleural nodules/ masses (a–d), with pleural indentation sign (a, c), perivascular location (a, c), as well as punctate calcification in partial nodules/masses (d) and pleural thickening (c). Furthermore, the size of the largest nodules/masses was 3.0 cm in diameter (a, b)
Fig. 4 A 55-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest CT images show reticulonodular opacities (a) and multiple irregular subpleural nodules/masses (a–d) with pleural indentation sign (a, b), perivascular location (a, b), as well as punctate calcification in partial nodules/masses (c, d), pleural thickening (a–d) and pleural effusion (a–d). Furthermore, the size of the largest nodules/masses was 1.9 cm in diameter (a, b) and the pulmonary epithelioid haemangioendothelioma showed a mild heterogeneous hyperdense appearance relative to muscle on contrast-enhanced CT (b)
one case). However, in our study the average age was 53 years, in contrast to the findings of previous reports in which most patients were younger than 40 years [1, 6, 18]. Our results showed that all cases had multiple irregular nodules/masses. The average number of nodules/masses in each case was 30 (range 11–70), and most nodules/masses (90 %, 160/178) were \1 cm in diameter. These findings
are similar to those reported in past studies which report that the most characteristic feature of EHE on CT is the presence of multiple perivascular nodules with well- and ill-defined margins in both lungs and nodules up to 2 cm in size, although most are \1 cm in diameter [4, 5, 8, 9, 11, 12, 19]. The feature of irregular margins may be attributed to tumour infiltration of small blood vessels, bronchi/
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Radiol med Fig. 5 A 35-year-old woman with pulmonary epithelioid haemangioendothelioma. Chest CT images show ground-glass opacities (a) and multiple irregular subpleural nodules/ masses (a–f) with pleural indentation sign (a, c, e), perivascular location (a, c) and pleural thickening (c, e). The size of the largest nodules/ masses was 3.5 cm in diameter (a)
bronchioles and lymphatic vessels, especially small arteries, lymphatics and venules of 1 mm or less in diameter within or adjacent to the nodules; less frequently vessels of several millimetres in diameter may be involved [1, 4, 9]. To our knowledge, pulmonary hamartoma, leiomyoma and metastasis usually show nodule/mass with smooth margins; Wegener granulomatosis usually appears as multiple nodules/masses with cavity (size from a few millimetres to over 10 cm) and the number of lesions are often \10 [20– 23], which is not similar to that of EHE. In our study, pulmonary EHE showed predominant subpleural location, which was confirmed by gross pathology revealing an increased number of lesions in the immediate subpleural area [5, 24]. This feature of EHE was different from pneumoconiosis in which the nodules tend to be most numerous in the upper lobe, from metastatic pulmonary nodules which tend to be distributed in the basal portion of the lung, from Wegener granulomatosis which has peribronchovascular, subpleural and angiocentric nodules/masses [20, 23, 25, 26].
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In our study, the pulmonary EHEs showed perivascular location, reflecting the gross pathology finding that tumours are usually found in relation to small and mediumsized vessels and bronchi. Additionally light microscopy shows that tumour vascularity is inapparent, only a rare small capillary can be identified in the tumour itself, and the tumour cells are near vessels and adjacent to alveolar septa, which suggest that EHE has metabolic requirements and its nutrient and oxygen supply is by diffusion [1]. This CT feature is usually not found in pneumoconiosis, metastatic pulmonary nodule, Wegener granulomatosis, pulmonary hamartoma, or benign metastasising leiomyoma [20–23, 25, 26]. In our study, 48 % (86/178) of nodules/masses showed punctate calcification in four of six cases, a feature also reported by other studies [7, 9, 11, 13, 24]. Nodules of pulmonary EHE show an acellular sclerotic central area and the acellular pale pink centres undergo coagulative necrosis, then dystrophic calcification, chondrification, ossification, and rarely positive Congo red staining
Radiol med Fig. 6 A 54-year-old man with pulmonary epithelioid haemangioendothelioma. Chest CT images show multiple irregular subpleural nodules/ masses (a–f) with pleural indentation sign (a, e, f), perivascular location (c, e). However, the size of the largest nodules/masses was too small (1.1 cm in diameter) to analyse the enhancement of lesion (a, b)
reactions can be seen in these necrotic central cores [1]. Punctate calcification can occur in a metastatic sarcoma, but other CT features including smooth margin, tendency to distribute in the basal portion of the lung may be used for the differential diagnosis [26]. In our study, pleural indentation was found in all cases. This corresponds histologically to thickened, fibrotic connective tissue septations with indrawing of the visceral pleura and reflects desmoplastic reaction [27]. Alternatively, the tissue processing shrinkage artefact may be attributed to the fact that the tumour extends into each alveolus from just one focus and a moderate amount of fibrosis [1]. Usually pneumoconiosis, metastasis, Wegener granulomatosis, pulmonary hamartoma and leiomyoma do not show pleural indentation [20–23, 25, 26], unlike pulmonary EHE.
In our study, five cases showed pleural thickening, and two cases showed pleural effusion. The CT findings of pleural EHE are nonspecific and usually demonstrate a pleural effusion with localised or diffuse nodular pleural thickening [2], which typically affects older men, induces chest pain and dyspnoea and is easily mistaken for pleural infections or malignant mesothelioma [3, 4, 28]. Patients with fibrinous pleuritis and extrapleural proliferation of tumour cells or spindle tumour cells generally have a worse prognosis [18, 29]. Due to the small size and non availability of contrastenhanced CT images, the enhancement of EHE could not be analysed. Two cases in our study showed that EHE had a mild-heterogeneous hyperdense appearance on contrastenhanced CT, similar to that described in a case report
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revealing a left hilar mass mimicking central lung cancer [30]. Furthermore, some studies have reported atypical CT manifestations of pulmonary EHE which included diffuse reticulonodular opacities and ground-glass opacities [4, 10]; however, these CT features were each found in one case in our study and are attributed to interstitial infiltration presenting focally in interlobular septa or pleura and around bronchopulmonary rays [1]. Additionally, the extremely long and indolent growth of pulmonary EHE needs to be emphasised. Some authors reported that pulmonary EHE showed little or no growth on serial radiographs [4, 5, 31] and that even partial spontaneous regression [32] and life expectancy may be up to 30 years [4, 5, 31]. Some authors have reported the antitumour effects of interferon, chemotherapy using carboplatin and etoposide [14, 33]. A monoclonal antibody against vascular endothelial growth factor (VEGF) (bevacizumab) together with chemotherapy was recently used for preventing tumour spread in the early period as these tumours express high levels of VEGF [34]. However, there is no established standard treatment of choice [34]. Additionally, the fluorodeoxyglucose positron emission tomography (FDG-PET) scan can provide useful information concerning the malignant potential of each nodule more than 6 mm in diameter. Nodules are negative in PET scans, perhaps being evidence of a more benign character. FDG-PET may be useful to select the more clinically malignant nodules, which worsen the prognosis [31, 35]. Sometimes EHE involves extrapulmonary organs and may be multifocal; the liver and bone are the most frequently affected organs [6]. Hepatic EHE typically appears as multifocal confluent peripheral nodules with adjacent capsular retraction and a low-signal halo; additionally hepatic EHE frequently occurs in older children [36, 37]. Bone EHE typically shows a lytic lesion without matrix mineralisation, even though osseous expansile remodelling may be seen [19]. The present study was limited by a small sample size because pulmonary EHE is rarely encountered. Moreover, none of the cases underwent both unenhanced and contrastenhanced CT imaging. Third, PET and magnetic resonance imaging images were not included in this study. Therefore, further studies with a larger number of cases are needed. In conclusion, with a predilection for subpleural and perivascular location, typical pulmonary EHE appears as multiple irregular nodules with punctate calcification and pleural indentation. Conflict of interest Kefu Liu, Ping Xie, Weijun Peng, Zhengrong Zhou declare no conflict of interest.
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