Epithelioid angiosarcoma arising in schwannoma: Report ofthree Chinese cases with review of the literaturepin_2827 1..6
Chao Li,1 Ying Chen,2 Hong Zhang,1 Xiongwei Zheng1 and Jian Wang2
1Department of Pathology, Fujian Provincial Cancer Hospital, The Teaching Hospital of Fujian Medical University,Fuzhou, and 2Department of Pathology, Institute of Cancer Research, Cancer Hospital, Fudan University, Departmentof Oncology, Shanghai Medical College, Shanghai, China
Angiosarcoma arising in a schwannoma is extremely rarewith only eleven cases having been reported in the Englishliterature. We describe here three further cases occurring inadult males with a pre-existing longstanding schwannoma.The tumor arose each from the vagus, ischiadic and adren-ergic nerve respectively. None of the patients had vonRecklinghausen’s disease. Microscopically, the tumor wascomposed of a mixture of a benign schwannoma and anepithelioid angiosarcoma. The two components changedabruptly within the tumor. The endothelial cell differentia-tion was confirmed by immunohistochemistry. A review ofpublished reports, including the present cases, suggests apoor prognosis with a high rate of local recurrence, distantmetastasis and mortality.
Angiosarcoma of deep soft tissue is relatively uncommon withone third of cases developing in association with other condi-tions, such as neurofibromatosis, Klippel-Trénaunay syn-drome, Maffucci syndrome, synthetic vascular grafts andother neoplasms.1 Angiosarcomas arising from peripheralnerves and peripheral nerve sheath tumors are extremelyrare. They usually develop in neurofibroma and malignantperipheral nerve sheath tumors (MPNST), especially inpatients with von Recklinghausen’s disease.2–5 In contrast,angiosarcoma arising in a schwannoma is very rare. To thebest of our knowledge, only eleven cases have been reported
in the English literature.3,6–11 We present here three additionalcases of epithelioid angiosarcoma that arose in long-standingschwannoma.
CLINICAL SUMMARY
Case 1
A 55-year-old Chinese man went for further medical attentionbecause of gradual enlargement of an untreated schwan-noma located in the left neck which was diagnosed by fineneedle aspiration 4 years earlier. Over the previous 3 months,the lesion caused mild pain associated with a prickling andtingling sensation on the face and scalp, and ptosis of the lefteye (Horner’s syndrome). Sonography of the neck revealed awell defined 5 ¥ 4 ¥ 3.8 cm low echo area with uneven internalechoes. Contrast-enhanced computed tomography (CT) andmagnetic resonance imaging (MRI) demonstrated a 6 ¥ 5 ¥5 cm round tumor in the left neck with uneven signals (Fig. 1).At surgery the mass was situated at the bifurcation of thecarotid artery and the deep surface of the internal jugular veinwith poorly defined boundaries. It was adherent to the vagusnerve. The patient showed no evidence of local recurrence ormetastases 12 months after surgery and was subsequentlylost to follow up.
Case 2
A 38-year-old Chinese man presented with a long-standing(18 years) mass in the deep soft tissue of the right inguinalregion that had gradually enlarged during recent months. Themass was completely excised. Neither adjuvant radiother-apy nor chemotherapy was administered postoperatively.However, the patient presented with bloody sputum 9 monthslater. Contrast-enhanced CT of the chest demonstrated a
Correspondence: Jian Wang, MD, Department of Pathology, Instituteof Cancer Research, Cancer Hospital, Fudan University, 270 DongAn Street, Shanghai 200032, China. Email: [email protected]
Pathology International 2012 doi:10.1111/j.1440-1827.2012.02827.x
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3.4 ¥ 3.1 cm irregular mass in the left hilum of the lung. Heunderwent left lower lobe resection and mediastinal lymphnode dissection. Histologic examination of surgical specimensshowed metastatic epithelioid angiosarcoma. He receivedchemotherapy shortly after and had signs of no local recur-rence or further metastases 28 months postoperatively.
Case 3
A 67-year-old Chinese man was referred to hospital for evalu-ation of a long-standing (20 years) mass in the right abdomenthat had been recently causing intermittent pain for 2 months.Computed tomography showed a 9 ¥ 6.5 ¥ 8.1 cm mixedsolid and cystic mass in the right iliac fossa of uneven densitywith an intact capsule and scattered calcification deposited inthe periphery of the mass. On operation, an encapsulatedtumor measuring 11 ¥ 8 ¥ 7 cm was removed. The tumor wasadjacent to the right psoas muscle, displacing the ascendingcolon medially. The boundary between the posterior wall ofthe mass and the iliopsoas muscle was poorly demarcated.The patient received no further treatment after surgery. Hewas free of local recurrence or metastases after 32 months offollow up.
PATHOLOGICAL FINDINGS
The excised specimens were foxmalin fixed and paraffinembedded. Sections of 4 mm thickness were prepared andstained with HE. Immunohistochemistry was performed onthe DAKO Autostainer (Dako, Carpinteria, CA, USA) usingthe standard Envision method. The primary antibodies used inthis study include S-100 protein (polyclonal, Dako; dilution1:300), Cytokeratin (AE1/AE3, Dako; dilution 1:400),CAM5.2(CAM5.2, Becton-Dickinson, San Jose, CA, USA;dilution 1:300), factor VIII-related antigen (polyclonal,Thermo-Scientific, Fremont, CA, USA; dilution 1:400),neurone specific enolase (E27, Thermo-Scientific; dilution1:800) and epithelial membrane antigen (E29, Dako;dilution 1:200), Leu7(NK1, Thermo-Scientific; dilution1:100), CD31(JC/70A, Thermo-Scientific; dilution 1:30),CD34(QBEnd/10, Cellmarque; dilution 1:200). Heat-inducedepitope retrieval was carried out by using a steamer. For eachantibody, appropriate positive and negative controls wereincluded.
Macroscopically, the tumor in case 1 was an encapsulatedovoid mass measuring 6 ¥ 5 ¥ 5 cm in size. On cut section,the central areas were gray-yellow whereas the peripheralareas appeared gray-brown (Fig. 2). The excised specimenof case 2 showed a 7 ¥ 6 ¥ 5 cm partially encapsulated masswith attached skin. The lesion penetrated the capsule withextension to the surface of the adjacent skin, forming a1 cm-diameter ulcer. Case 3 was also an encapsulated massmeasuring 11 ¥ 8.5 ¥ 7 cm. It was cystic with a gray toyellowish color. Focal calcification on the capsule and foci ofnecrosis were noted.
On low magnification, the boundaries of cases 1 and 3were intact (Fig. 3), whereas the tumor cells of case 2invaded the fibrous capsule and the adjacent skin. In all threecases the lesion was composed of a mixture of two distinctcomponents: a benign spindled schwannoma and a high-grade epithelioid angiosarcoma (Fig. 4). The spindle cellcomponent displayed typical features of a schwannoma char-acterized by alternating Antoni A and B areas with markednuclear palisading (Fig. 5), xanthomoatous change andhyalinized thick-walled vessels. Degenerative changesincluding enlarged hyperchromatic nuclei, cyst formation,dense fibrosis and calcification were also present. However,nuclear atypia and mitotic figures were absent. The epithe-lioid angiosarcomatous component was present in bothcentral and peripheral areas of the tumor, consisting of nest,tufts or clusters of highly atypical round cells with prominentnuclei. Irregularly anastomosing channels with formation ofpapillae, as well as hemorrhages with hemosiderin deposit,were noted focally (Fig. 6). On high magnification, the epi-thelioid cells had abundant eosinophilic cytoplasm with somecontaining intracytoplasmic lumen. Mitotic figures includingabnormal one were easily encountered with an average of
Figure 1 Magnetic resonance imaging (contrast enhanced T1-WIFSPGR sequence) showing a round tumor in the left neck withinhomogenous enhancement. (arrow) (case 1).
3/10 HPF (Fig. 7). Foci of coagulative necrosis were seen intwo cases.
Immunohistochemistry performed on paraffin embeddedsections revealed that the spindled schwannian cells werediffusely positive for S-100 protein (Fig. 8), whereas theatypical epithelioid cells expressed CD31, CD34 and factorVIII-related antigen, supporting their endothelial differentia-tion (Fig. 9). In addition, the epithelioid cells were alsopositive for AE1/AE3, epithelial membrane antigen andCAM5.2.
DISCUSSION
Schwannomas are benign peripheral nerve sheath tumorsthat occur most frequently in the head and neck, and extremi-ties, followed by the mediastinum and retroperitoneum.Although long-standing schwannomas often undergo degen-eration, it is exceedingly rare for them to manifest malignanttransformation. In more than 1000 cases of schwannoma,Weiss and Goldblum only identified one example of malig-nant transformation.12 In 1994, Woodruff et al. described twocases of schwannoma with malignant transformation whichwere reported as epithelioid MPNST (EMPNST).13 In 2001,McMenamin and Fletcher summarized 17 schwannomas
Figure 2 Macroscopic findings, the mass was enclosed by anintact capsule on cut section, The central areas were gray-yellow(black triangle) and the peripheral areas were gray-brown (blackstar), representing Schwannoma and angiosarcoma respectively.
Figure 3 Microscopic findings: an encapsulated tumor was com-posed of a mixture of a benign schwannoma (black triangle) and anepithelioid angiosarcoma (black star). The two components changedabruptly within the tumor (HE; original magnification ¥ 40).
Figure 4 Microscopy showing the area of benign schwannoma(left) and malignant epithelioid angiosarcoma (right) (HE; originalmagnification ¥ 400).
Figure 5 The schwannoma components displayed prominentAntoni A character with marked palisadde spindle cells (HE; originalmagnification ¥ 400).
with evidence of malignant transformation, all of which hadan epithelioid morphology.8 Of the 17 cases, four were purelyEMPNSTs, whereas another four cases were angiosarcomasof predominantly epitheloid type. The remaining ten caseswere described as with epithelioid malignant change (EMC),including one case coexistant with EMPNST.
Compared with EMPNST and EMC, angiosarcoma arisingin a schwannoma represents a rare event. To the best of ourknowledge, only 11 convincing cases have been reportedsince the first case described by Trassard et al. in 1996.6 Theclinicopathological features of these 11 cases together withthe present three cases are summarized in Table 1. Briefly,all cases occurred in adults, ranging in age from 17 to
74 years (median 65 years). Ten were over 50 years old(71%). There were eight males and six females with a M : Fratio of 1.3:1. Six of the lesions were located in the neck,three in the upper leg, and one each in the buttock, chest,intracranial, abdominal cavity and right inguinal region. Fourtumors arose from the ischiadic, five from vagus nerve, oneeach from the intracranial vestibular, phrenic and adrenergicnerve. Half of the patients presented with pain and gradualenlargement of a preexisting longstanding lesion (range, 10to 30 years). None of the patients had evidence of von Reck-linghausen’s disease.
The lesions ranged from 2.5 to 30 cm in size with a mediandiameter of 6 cm. On cut section, six tumors were confinedwithin their capsules, while six showed partial capsular inva-sion and five penetrated the capsules with involvement of
Figure 6 Epithelioid angiosarcoma cells were arranged in solidsheet, papillae patterns and irregularly anastomosing channels(HE; original magnification ¥ 200).
Figure 7 The epithelioid tumor cells displayed obvious atypia andmitotic figures (HE; original magnification ¥ 400).
Figure 8 The spindled schwannian cells were diffusely positive forS-100 protein (original magnification ¥ 200).
Figure 9 The atypical epithelioid cells showed strong membranousimmunoreactivity for CD31 (original magnification ¥ 400).
adjacent soft tissues or skin. Microscopically, all cases werecomposed of a mixture of schwannoma and angiosarcomawhich changed abruptly in the tumor. With regard to theschwannoma component, twelve cases were of classicaltype, one case was degenerative and one was a plexiformsubtype. The angiosarcoma component in all 11 cases hadepithelioid morphology, most of them were moderately differ-entiated and a few were poorly differentiated.6 Immunohis-tochemically, the epithelioid angiosarcoma components werenot only strongly positive for CD31, CD34 and factor VIII-related antigen, but also positive for a few epithelial markers.
The differential diagnosis of epithelioid angiosarcomaincludes EMPNST, EMC and carcinoma. It is not difficult todiagnose correctly on light microscopy by distinctive morpho-logic patterns. Occasionally, extensive hemorrhage andnecrosis can make diagnosis difficult. Immunochemistry ishelpful. The atypical epithelioid cells of EMC and up to 80%of EMPNST have been reported to be diffusely positive forS-100 protein.8,14 While carcinomas are positive for epithelialmarkers. Stains for endothelial markers (CD31 and CD34)are negative in these cells.
Predisposing factors for angiosarcoma arising in a schw-annoma have not been identified.4,5,15,16 Trassard et al. foundWeibel-Palade bodies in the cytoplasm of epithelioid tumorcells by electron microscopy and suggested that angiosar-coma possibly arose from pre-existing vascular tissue ofschwannoma.6 Rückert et al. proposed that chronic vascularstasis and edema may contribute to the development ofangiosarcoma in a long-standing schwannoma, similar tolymphedema-associated angiosarcomas.7 The positiveimmunoreactivity for vascular endothelial cell growth factor(VEGF) in two cases of epithelioid angiosarcoma and onecase of schwannoma made Mentzel and Katenkamp con-sider that this angiogenic factor might play a role in thepathogenesis of angiosarcoma arising in neural tissue andbenign and malignant peripheral nerve sheath tumors.3
However, the hypothesis needs to be confirmed by furthermolecular studies.
It is worthy of note that the angiosarcomatous componentin all 14 cases had an epithelioid morphology which wasassociated with a poor prognosis. In the series of epithelioidangiosarcoma of deep soft tissue reported by Fletcher et al.,three of five patients died of the disease and two developeddistant metastasis, with a mean survival of 12 months.17 Theclinical course of the reported 14 angiosarcomas arising inschwannoma was also not good. The follow up data showedthat two recurred locally, four developed distant metastasesand two died of the disease. We noted that incompleteresection, penetration of the capsule with invasion of adja-cent tissue and large tumor size were associated with pooroutcomes.
In conclusion, angiosarcoma arising in schwannoma rep-resents a rare event. Similar to angiosarcoma of deep softTa
tissue, the majority have an epithelioid morphology which isassociated with a poor prognosis.
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