Bone and Soft Tissue Pathology
Neuropathology

High Grade Epithelioid Angiosarcoma Arising in a Schwannoma

Mark A. Edgar
Memorial Sloan Kettering Cancer Center
New York, NY


This case is an example of high grade epithelioid angiosarcoma arising in a schwannoma. Most of the biopsy consisted of angiosarcoma, but in the slide available for review there is a 0.5 cm fragment of convincing schwannoma. This rare occurrence has been well documented in recent years, but it has not been previously reported in the clinical setting of schwannomatosis (possibly present in this patient). This case presents an opportunity to review the topics of malignant degeneration in schwannoma and relationship of angiosarcoma to tumors of the peripheral nervous system and to briefly mention schwannomatosis.


Slide 1
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Figure 1 - Left arm mass. Angiosarcoma displaying rich vascularity. (low-power, H&E)
Figure 2 - Left arm mass. Angiosarcoma. (higher-power, H&E)
Figure 3 - Left arm mass. Spindled cells arranged in fascicles running parallel to blood vessel. (H&E)

Figure 4 - Left arm mass. Angiosarcoma retaining spindled architecture but with plumper, more abundant cytoplasm. (H&E)
Figure 5 - Left arm mass. Angiosarcoma displaying overtly epithelioid morphology. (high-power, H&E)
Figure 6 - Left arm mass. Epithelioid angiosarcoma. Prominent hemosiderin deposition. (high-power, H&E)

Figure 7 - Left arm mass. Spindle cell area with nuclear atypia and hemosiderin deposition. (H&E)
Figure 8 - Left arm mass. Thickened, hyalinized blood vessel. (H&E)
Figure 9 - Left arm mass. Schwannoma (primary tumor of origen of the angiosarcoma). Characteristic morphologic features of schwannoma are seen. (H&E)

Figure 10 - Left arm mass. Area of tumor showing intermingled schwannoma and angiosarcoma tumor cells. (high-power, H&E)
Figure 11 - Vertebral mass. Metastatic epithelioid angiosarcoma (low-power, H&E).
Figure 12 - Vertebral mass. Metastatic epithelioid angiosarcoma (high-power, H&E).


Malignant degeneration is far less common in schwannoma than neurofibroma. In a 1935 study of "neurilemoma" Arthur Purdy Stout reported that "several cases of apparent malignant metamorphosis of a neurilemoma have been reported, and in none of them is the evidence of sufficient weight to permit a positive statement that this change ever occurs [1]". In 1994 Woodruff et al presented two examples of malignant transformation in schwannoma and reviewed seven additional cases from the literature [2]. This paper advised skepticism in assessing purported examples of malignant degeneration in schwannoma and proposed three criteria: 1) Presence of a benign schwannoma of either classic, cellular, or plexiform type; 2) Presence within the schwannoma of a histologically malignant cell population, the malignant potential of which is supported by metastasis or histologic resemblance to a cell population in other schwannomas which has metastasized; and 3) Failure to identify a primary tumor which might have metastasized to the schwannoma. This report drew attention to the two commonest histologic patterns of malignant change in schwannoma, i.e. epithelioid cell type and small cell type. Both cases in that report showed epithelioid malignant cells resembling those in epithelioid malignant peripheral nerve sheath tumor (MPNST) with mitotically active large polyhedral cells possessing abundant eosinophilic cytoplasm and hyperchromatic nuclei with prominent eosinophilic nucleoli. In contrast, small cell malignant change is characterized by an abrupt transition between classic schwannoma and collections of malignant small round or elongated cells which sometimes form neuroepithelial type (pseudo)rosettes. In the most cases, the malignant cells are at least focally immunoreactive for S-100 protein.

In the years following the report of Woodruff et al, scattered reports of malignant degeneration in schwannoma emerged, usually as reports of one or a few cases in patients without known neurofibromatosis. Nayler et al [3] reported an example of epithelioid malignant change in a schwannoma of the median nerve in which the malignant epithelioid cell population strongly labeled for S-100 protein. The first report of angiosarcoma arising in a schwannoma came in 1996 when Trassard et al described a schwannoma of the sciatic nerve in a 65 year old man with associated high grade epithelioid angiosarcoma [4]. The epithelioid cells in this tumor were immunoreactive for vascular markers (CD34, CD31, Factor VIIIR-Ag, and UEA-1 lectin) but not for S-100 protein. In 1999 Mentzel and Katenkamp [5] reported four cases of angiosarcoma arising in peripheral nerve and nerve sheath tumors, one of which was a well differentiated angiosarcoma arising in a longstanding schwannoma. Two other cases represented MPNST with associated angiosarcoma. Heterologous mesenchymal elements commonly seen in association with MPNST include rhabdomyosarcoma (Triton tumor), chondrosarcoma, and osteosarcoma; angiosarcoma is the least common and, as with most other cases of MPNST with heterologous elements, it is most often seen in the setting of type 1 neurofibromatosis (NF1).

In 2001 McMenamin and Fletcher proposed expanding the spectrum of malignancy in schwannomas to include what they called epithelioid malignant change [7]. This was defined as the presence of large epithelioid cells with abundant eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli – cytologic features which typify epithelioid MPNST (either de novo or as a form of malignant degeneration in schwannoma). These cells were usually scattered singly throughout the schwannoma, but in one case they formed a discrete nodule. The authors suggested that epithelioid malignant change might represent a precursor to full-blown epithelioid MPNST, but tumors with this histologic appearance did not show unusual Ki-67 proliferative activity and did not behave in a clinically malignant fashion during the follow up period. The biologic potential of epithelioid malignant change as evidenced by scattered large epithelioid cells in an otherwise typical schwannoma is currently undetermined. In addition, the authors also described four additional cases of epithelioid MPNST and four cases of angiosarcoma arising in schwannoma.

The preceding examples of angiosarcoma arising in schwannoma all involved peripheral nerves; there is also one recent (2006) report of intracranial angiosarcoma arising from a vestibular schwannoma [6]. This case concerns a 66 year old man who developed angiosarcoma ten years following apparently complete resection of a vestibular schwannoma. Although histology from the recurrence is said to show "proliferating schwannoma" and angiosarcoma, convincing histologic documentation of schwannoma is lacking in this case.

The histogenesis of malignant change in schwannomas is unsettled. Nayler et al suggest that epithelioid malignant change arises in Antoni A areas and later invades Antoni B tissue and ultimately extends through the tumor capsule (a view shared by Dr. James Woodruff). On the other hand, it has been suggested that angiosarcoma arises not from neoplastic Schwann cells but from tumor vasculature, possibly as a complication of chronic vascular stasis as appears to occur in those angiosarcomas arising in the setting of chronic lymphedema. To date, no molecular genetic evidence has been published to support this hypothesis.

Finally, this case concerns a patient with multiple schwannomas who meets criteria for possible schwannomatosis. Schwannomatosis has recently been recognized as a third form of neurofibromatosis which, in contrast to NF1 and NF2, is rarely familial. Schwannomatosis presents as multiple (usually painful) non-vestibular schwannomas which often affect a single anatomic region such as a single limb, multiple contiguous spinal segments, or one half of the body. The absence of vestibular schwannomas excludes patients with NF2 from the groups of definite and possible schwannomatosis as specified in the following proposed criteria for schwannomatosis [8]:

Definite Schwannomatosis:
  • Age >30 AND two or more non-intradermal schwannomas, at least 1 with histologic confirmation AND no evidence of vestibular tumor on high-quality MRI scan AND no known constitutional NF2 mutation OR

  • One pathologically confirmed non-vestibular schwannoma plus a first-degree relative who meets above criteria

Possible Schwannomatosis
  • Age <30 years AND two or more non-intradermal schwannomas, at least 1 with histologic confirmation AND no evidence of vestibular tumor on high quality MRI scan AND no known constitutional NF2 mutation OR

  • Age >45 years AND two or more non-intradermal schwannomas, at least 1 with histologic confirmation AND no symptoms of 8th nerve dysfunction AND no known constitutional NF2 mutation OR

  • Radiographic evidence of a non-vestibular schwannoma and first-degree relative meeting criteria for definite schwannomatosis

In our patient, a head CT scan showed no evidence of vestibular schwannomas, but cranial MRI has not been performed. It is important to note that standard CT and MRI protocols may sometimes miss small vestibular schwannomas and that patients with schwannomatosis may develop vestibular tumors late in life (as sporadic tumors); this naturally raises interest in identifying the genetic locus for schwannomatosis as a definitive diagnostic marker. One study employing NF2 locus mutation analysis, chromosome 22 loss of heterozygosity analysis and linkage study excluded NF2 as the genetic locus of schwannomatosis, but showed linkage to a nearby locus on chromosome 22 [9]. If our patient ultimately meets criteria for definite schwannomatosis he could be the first; perhaps because experience with schwannomatosis is limited, to date no examples of malignant degeneration in schwannomatosis have been reported.

References
  1. Stout AP. The peripheral manifestations of the specific nerve sheath tumor (neurilemmoma). Am J Cancer 1935;24:751-96.

  2. Woodruff JM, Selig AM, Crowley K, Allen PW. Schwannoma (neurilemmoma) with malignant transformation. A rare, distinctive peripheral nerve sheath tumor. Am J Surg Pathol 1994;18:882-895.

  3. Nayler SJ, Leiman G, Omar T, Cooper K. Malignant transformation in a schwannoma. Histopathol 1996;29:189-192.

  4. Trassard M, Le Doussal V, Bui BN, Coindre J-M. Angiosarcoma arising in a solitary schwannoma (neurilemmoma) of the sciatic nerve. Am J Surg Pathol 1996;20:1412-17.

  5. Mentzel T and Katenkamp D. Intraneural angiosarcoma and angiosarcoma arising in benign and malignant peripheral nerve sheath tumors: clinicopathological and immunohistochemical analysis of four cases. Histopathol 1999;35:114-120.

  6. Ito T, Tsutsumi T, Ohno K, Takizawa T, Kitamura K. Intracranial angiosarcoma arising from a schwannoma. J Laryngol Otol 2006;Sept 25:1-4.

  7. McMenamin ME, Fletcher CD. Expanding the spectrum of malignant change in schwannomas: epithelioid malignant change, epithelioid malignant nerve sheath tumor, and epithelioid angiosarcoma: a study of 17 cases. Am J Surg Pathol 2001;25:13-25.

  8. MacCollin M, Chiocca EA, Evans DG et al. Diagnostic criteria for schwannomatosis. Neurology 2005;64:1838-1845.

  9. MacCollin M, Willett C, Heinrich B, Jacoby LB, Acierno JS, Perry A. Familial schwannomatosis: Exclusion of the NF2 locus as the germline event. Neurology 2003;60:1968-1974.