Schwannoma with Rhabdomyoblastic Differentiation a Unique Variant of Malignant Triton Tumor

Case Report

Schwannoma With Rhabdomyoblastic Differentiation A Unique Variant of Malignant Triton Tumor

Ö Kurtkaya-Yapıcıer, B. W. Scheithauer, J. M. Woodruff, D. D. Wenger, A. M. Cooley, and D. Dominique

A 54-year-old woman presented with intractable perianal, bi- (MPNST). Such lesions are termed malignant Triton tu- lateral buttock, and radiating thigh/calf pain. An MRI scan mors,25,27 referring to the studies of Masson who postu- showed an intradural, contrast-enhancing, ovoid mass in the lated that divergent myoid differentiation could occur in cauda equina region at L1–L2. At laminectomy, the ovoid mass 15,16 arose from a nerve root and, intact, was gross totally resected. neoplastic neuroectodermal cells. In approximately Histologically, the dominant pattern was that of schwannoma. 15% of cases, osseous and/or cartilaginous elements or One year thereafter, the symptoms recurred. An MRI scan dem- even a variety of epithelia may be observed (pluridirec- onstrated an irregular, heterogeneously enhancing tumor recur- tional differentiation).6 The process is not limited to rence. A repeat laminectomy disclosed a large fleshy tumor MPNST. Histologically benign striated muscle differen- involving multiple nerve roots. The lesion was subtotally resected and showed pluridirectional differentiation toward em- tiation has also been reported in a neurofibroma of the 1 bryonal rhabdomyosarcoma, primitive neuroectodermal tumor, vagina. Herein, we report a unique example of and rare malignant epithelial cells. Review of the original tu- schwannoma undergoing transformation to embryonal mor disclosed only foci of embryonal rhabdomyosarcoma and rhabdomyosarcoma in addition to primitive neuroecto- primitive neuroectodermal tumor. Based upon available data dermal tumor (PNET) cells and cells with an epithelial regarding divergent differentiation in peripheral nerve sheath tumors, this is a unique, previously undescribed tumor demon- immunophenotype (pluridirectional differentiation). The strating rhabdomyosarcomatous, primitive neuroectodermal tu- finding underscores the differentiating potential of neo- mor and scant epithelial differentiation in a schwannoma. In plastic Schwann cells and indirectly confirms the essence, it is a variant of malignant Triton tumor because of its schwannian origin of heterologous differentiation in origin in a tumor consisting of well-differentiated Schwann MPNST and rarely neurofibroma.4,30 cells. It supports the contention that the Schwann cell is the source of a variety of heterologous elements in nerve sheath tumors. Key Words: Malignant peripheral nerve sheath tumor— CASE REPORT Primitive neuroectodermal tumor—Schwannoma. The patient, a 54-year-old white woman, presented Am J Surg Pathol 27(6): 848–853, 2003. with a 7-day history of intermittent perirectal and bilat- eral buttocks pain that was sharp in nature and exacer- bated with movement. On the day prior to emergency Divergent differentiation in nerve sheath tumors most admission, the pain became intense and radiated down often takes the form of rhabdomyosarcoma within the both legs to the level of the ankle. The patient was am- substance of a malignant peripheral nerve sheath tumor bulatory at the time of admission. Despite a 10-mg in- jection of intramuscular morphine, no pain relief was From the Department of Laboratory Medicine and Pathology (O.K.-Y., B.W.S.) and Diagnostic Radiology (D.D.W.), Mayo Clinic, Rochester, noted. She remained supine and strictly avoided move- Minnesota; Marmara University School of Medicine (O.K.-Y.), ment. A clinical history indicated she was married, the Institute of Neurological Sciences, Istanbul, Turkey; Memorial Sloan mother of two children, and a nonsmoker. The family Kettering Cancer Center (J.M.W.), New York City, New York; and the Departments of Pathology (A.M.C.) and Surgery (D.D.), Altru history was noncontributory; her mother had died of Hospital, Grand Forks, North Dakota, U.S.A. cancer secondarily involving bone and her father of Address correspondence and reprint requests to B. W. Scheithauer, Parkinson disease. A brother was alive and well. There Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, U.S.A.; e-mail: was no family history of central nervous system neopla- [email protected] sia or of neurofibromatosis types 1 or 2. A general, some-

848 SCHWANNOMA WITH RHABDOMYOBLASTIC DIFFERENTIATION 849 what limited physical examination was unrevealing. Vi- the dura, intradural adhesions were evident and required tal signs were normal, and there were no cardiorespira- lysis. The tumor, an ovoid, smooth-surfaced mass, was tory symptoms, organomegaly, adenopathy, or masses seen to arise from a nerve root, which was splayed over involving rectal/perirectal soft tissue. A neurologic ex- its surface. The involved nerve was divided proxi- amination, again limited, revealed no abnormality. The mally and distally. The lesion was delivered intact. Four- MRI examination demonstrated a large, intradural extra- teen months thereafter, the patient presented after a medullary mass in the spinal canal in the region of the 2-week history of severe, intractable, low back pain cauda equina just distal to the conus at L2–L3 (Fig. 1A). worsened by movement. Increasing leg weakness was The mass had nonspecific signal characteristics with low evident, but no abnormalities of bowel or bladder func- signal intensity on T1, primarily high signal on T2, and tion were noted. The follow-up MRI demonstrated a diffuse enhancement with gadolinium. There was a recurrent ovoid mass in the operative bed of the previ- central focus of low signal intensity on the T2 and ously resected lesion (Fig. 1B). The mass had similar gadolinium-enhanced images. The differential diagno- signal characteristics with low signal intensity on T1 and sis for a mass in this anatomic location with these high signal intensity on T2. However, the mass was imaging features would include schwannoma, meningi- slightly larger in size than the previous mass and dem- oma, ependymoma, and metastatic disease. The central onstrated an increase in lesion heterogeneity and margin focus of low signal intensity seen within this hyperin- irregularity on the T2-weighted and gadolinium- tense lesion on the T2-weighted images has been de- enhanced images, features suggestive of a malignant le- scribed as a characteristic MRI feature of neurilemmoma sion or malignant degeneration of a previously benign or neurofibroma, indicating that this could represent a tumor. At surgery, again an L1–L2 laminectomy, a yel- schwannoma. low–gray tumor bulged from the dural incision. A gross At surgery, an L1–L2 laminectomy, no abnormalities total removal of tumor lying between levels L1 and 2 of bone or the epidural space were noted. Upon opening was achieved.

FIG. 1. Sagittal T1-weighted images with fat saturation and gadolinium (A) demonstrate a large well-circumscribed intradural extramedullary mass in the spinal canal just distal to the conus in the region of the cauda equina at L2–L3. There is a small central focus of low signal intensity within the hyperintense lesion on the gadolinium-enhanced image. The recurrence on sagittal T1-weighted images with fat saturation and gadolinium enhancement (B) obtained 14 months following resection of the primary tumor shown in A shows a recurrent mass with similar signal characteristics and anatomic location. The recurrent mass is slightly larger in size and demonstrates an increase in lesion heterogeneity and margin irregularity.

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FIG. 2. (A) Histologically, the primary tumor was in large part a typical schwannoma. (B) At high magnification, nests of rhabdomyoblastic cells are seen to lie in a mucoid stroma. A: hematoxylin and eosin, original magnification ×160; B: hematoxylin and eosin, original magnification ×400.

MATERIALS AND METHODS dilution 1:20), neurofilament protein (Dako Corp; monoclonal 2F11, dilution 1:75), synaptophysin (ICN, Costa Both specimens were fixed in 10% buffered formalin, Mesa, CA, USA; monoclonal 3SY8, dilution 1:40), des- routinely processed, sectioned at 5 ␮m, and stained by min (Dako Corp; monoclonal DER11, dilution 1:100), the hematoxylin and eosin method. Using the avidin bio- MYO D1 (Dako Corp; monoclonal 5.8D, dilution 1:50), tin peroxidase complex method, antisera directed to the myogenin (Dako Corp; polyclonal, dilution 1:4000), following were applied: S-100 protein (Dako Corp, pan-keratin (Zymed; South San Francisco, CA, USA; Carpinteria, CA, USA; polyclonal dilution 1:800), epi- monoclonal AE1-AE3, dilution 1:200); low molecular thelial membrane antigen (Dako Corp; monolconal E29, weight keratin (Becton Dickinson, San Jose, CA, USA;

FIG. 3. The recurrent tumor was composed entirely of poorly differentiated cells (A) with moderate to scant eosin- ophilic cytoplasm (B). A: hematoxylin and eosin, original magnification ×160; B: hematoxylin and eosin, original magnification ×400.

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FIG. 4. The recurrent tumor was immunoreactive for both myoid markers, here seen as myogenin staining (A) and for the neuronal marker synaptophysin (B). A: original magnification ×100; B: original magnification ×160. monoclonal CAM 5.2, dilution 1:50), and p53 (Dako reactivity within the Schwann cells; the same was true of Corp; monoclonal DO-7, dilution 1:200). synaptophysin, keratin (AE1 AE3; CAM5.2), and CD99. In contrast, the scattered cytologically malignant cells RESULTS showed variable but strong reactivity for all three myoid markers, as well as for synaptophysin. No staining was The primary tumor, particularly at low power magni- seen for CAM5.2, keratin (AE1-AE3), epithelial mem- fication, showed all of the characteristic features of brane antigen, S-100 protein, or CD99. p53 staining was schwannoma, including a thick collagenous capsule, an frequently seen in the malignant cells and was moderate attenuated nerve fascicle on its surface, hyalinized ves- to marked in degree. sels, an admixture of compact Antoni A tissue featuring The recurrent tumor consisted entirely of malignant the formation of occasional nodules and Verocay bodies, cells intermediate to small in size (Fig. 3A). Focally, as well as Antoni B tissue (Fig 2A). MIB-1 staining in these were seen to permeate a nerve. Their cytology var- this component was essentially 0. At higher power (Fig. ied from spindle to somewhat epithelioid (Fig. 3B) and 2B), cytologically malignant cells were present singly occasionally multinucleate. Myoid markers (desmin, and in loose clusters often accompanied by a somewhat myogenin, myoD1) showed strong reactivity in large mucoid matrix. Approximately 50% of this tumor com- patches of neoplastic cells (Fig. 4A). Strong, but actually ponent showed MIB-1 immunoreactivity. The cells var- less widespread, synaptophysin staining was also noted ied from uninucleate to multinucleate, were hyperchro- (Fig. 4B). Scant CAM 5.2 and rare AE1–AE3-positive matic and irregular in configuration, and featured fre- cells were seen, as was a single epithelial membrane quent mitoses, some abnormal. Cytoplasm varied in antigen-reactive tumor cell. No recognizable epithelial quantity from scant to moderate, being pale to ampho- structures were noted. A CD99 stain was negative. p53 philic. Myotubes and cross-striations were not observed. immunoreactivity was moderate to strong in scattered The neoplastic Schwann cells of the schwannoma com- neoplastic cells. Approximately 75% of cells were ponent showed strong uniform immunoreactivity for MIB-1 immunopositive. Ultrastructurally, the malignant S-100 protein and membranous staining for collagen 4. cells included rhabdomyoblasts featuring thick and thin Neurofilament protein immunoreactivity was limited to filaments and Z-band formation (Fig. 5A) as well as the nerve fascicle on the tumor surface and to nerve small, poorly differentiated, neuronal cells containing fibers within a minor portion of the tumor. Epithelial scant secretory granules (Fig. 5B). membrane antigen staining was limited to perineurial cells of the fascicle and in the tumor capsule. Scattered DISCUSSION weak to moderately p53-immunoreactive nuclei were noted within the Schwann cell component. Three myoid Divergent differentiation, the very essence of normal markers (desmin, myogenin, and MYO D1) showed no embryologic development, is a genetically determined

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FIG. 5. Ultrastructurally, the recurrent tumor consisted of cells showing either rhabdomyoblastic (A) or neuronal differentiation (B). This consisted of thick and thin filaments in association with Z-bands (A) and of sparse neurosecretory granules (B). A: original magnification ×12,000; B: original magnification ×18,000. process also seen in neoplasia. With reference to central lignant mesenchymal tissues noted above, glandular nervous system tumors, it manifests as a subtle shift in components are, with rare exception, benign in appear- differentiation to closely related cell types. Examples in- ance.27 Of MPNSTs showing any form of divergent dif- clude mixed glioma (oligoastrocytoma),14 tumors show- ferentiation, an association with neurofibromatosis type ing more substantial divergence, e.g., glioneuronal neo- 1 is seen in the majority.6,27,28 plasms (ganglioglioma),12 and truly heterologous differ- Divergent differentiation in conventional schwanno- entiation, such as gliomas exhibiting skeletal muscle, mas is a rare event.21 Osseous metaplasia is often con- chondro-osseous, or even true epithelial differentiation.18 sidered a secondary phenomenon superimposed upon Similar transitions occur in peripheral nerve tumors, both dystrophic calcification related to hyalinized vasculature benign and malignant. Benign examples include 1) ordi- and tumor ischemia. Nonetheless, true osseous as well as nary neurofibromas in which perineurial-like cells ap- cartilaginous, and even adipose, differentiation does oc- pear to arise from Schwann cells, which, based on recent cur in schwannomas10,13,19; the latter is best seen as a genetic evidence,20 appear to be the principle if not the component of psammomatous melanotic schwannoma in only neoplastic cell, and 2) rare examples of neurofi- Carney complex.3 Melanin production as seen in mela- broma with more obvious divergent differentiation. The notic schwannomas, more often benign than malignant, latter include a vaginal neurofibroma containing benign is accepted as being within the repertoire of schwannian skeletal muscle (benign Triton tumor),1 an example of cells and is not considered divergent differentiation. The plexiform neurofibroma with extensive glandular differ- same is true of glial fibrillary acidic protein expression.17 entiation,22 and angiosarcomas arising from neurofibro- Although once thought to be a manifestation of glandular mas.23 Far more often, the underlying lesion is an differentiation,2,5,7,8,31 the finding of glands within su- MPNST6 in which embryonal rhabdomyosarcoma is the perficially situated schwannomas is now attributed to most frequently occurring element (malignant Triton tu- entrapment of normal cutaneous adnexae (sweat glands mor).6,25,28 In approximately 15% of cases, the latter also replete with myoepithelial cells).27 Thus, the spectrum of feature other mesenchymal or even epithelial compo- differentiation in schwannomas is largely limited to be- nents (MPNST with pluridirectional differentiation).5 nign mesenchymal tissues. Those rare examples of an- Among the other mesenchymal components are chondro- giosarcoma supervening upon schwannoma23,24 are sarcoma, osteosarcoma, and even rare examples of an- thought not to represent divergent differentiation. In- giosarcomatous elements.23 Far less frequent than stead, it is considered a manifestation of intratumoral MPNST with divergent mesenchymal differentiation are vascular stasis and malignant transformation of resident examples in which epithelium of glandular, squamous, or endothelial cells.24 This interpretation is supported in neuroendocrine types are also present or occur alone part by the immunophenotypes of the two components, (glandular MPNST).6,9,26,27 Interestingly, unlike the ma- which differ entirely, and lack of transitional cells.23,24

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Myoid differentiation has not heretofore been described 7. Elston DM, Bergfeld WF, Biscotti CV, et al. Schwannoma with in schwannoma. The same is true of bona fide neuronal sweat duct differentiation. J Cutan Pathol 1993;20:254–8. 8. Fletcher CD, Madziwa D, Heyderman E, et al. Benign dermal transition to small cell differentiation. Although small schwannoma with glandular elements: true heterology or a local “neuroectodermal” tumor has twice been reported,11,29 “organizer” effect. Clin Exp Dermatol 1986;11:475–85. neither immunohistochemical (neuronal marker) staining 9. Garre C. Uber Sekunder Maligne Neuroma. Beitr Z Klin Chir Z 1932;9:465–95. nor diagnostic ultrastructural features (processes, micro- 10. Graham DI, Bond MR. Intradural spinal ossifying schwannoma: tubules, secretory granules) have been documented. Our case report. J Neurosurg 1972;36:487–9. case illustrates both. Thus, the range of differentiation, 11. Hanada M, Tanaka T, Kanayama S, et al. Malignant transformation of intrathoracic ancient neurilemoma in a patient without von which included scant true epithelium, is truly unique. Recklinghausen’s disease. Acta Pathol Jpn 1982;32:527–36. In that conventional schwannoma differs from neuro- 12. Hirose T, Scheithauer BW, Lopes MB, et al. Ganglioglioma: an fibroma and MPNST with their varied cytologic makeup, ultrastructural and immunohistochemical study. Cancer 1997;79: 989–1003. our case brings focus upon the well-differentiated 13. Kasantikul V, Brown WJ, Netsky MG. Mesenchymal differentia- Schwann cell as the element undergoing the process of tion in trigeminal neurilemmoma. Cancer 1982;50:1568–71. divergent differentiation. Reflecting back upon neurofi- 14. Kraus JA, Koopermann J, Kaskel P, et al. Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligoden- broma, the lesion underlying over half of MPNST, it may droglioma and oligoastrocytoma. J Neuropathol Exp Neurol 1995; be that their so-called “perineurial-like cells” with fea- 54:91–5. tures intermediate between Schwann and perineurial 15. Masson P, Martin J. Rhabdomyomes des nerfs. Bull Assoc Fr Cancer 1938;27:751–67. cells, having already undergone subtle divergent differ- 16. Masson P. Human Tumors. Detroit, Michigan: Wayne State Uni- entiation along perineurial lines, may be those prone to versity Press, 1970:1107–9. undergo further differentiation along mesenchymal and 17. Memoli V, Brown EF, Could VE. Glial fibrillary acidic protein (GFAP) immunoreactivity in peripheral nerve sheath tumors. Ul- rarely glandular lines. Recent work has recognized the trastruct Pathol 1984;7:267–75. potential of schwannoma cells to undergo anaplasia and 18. Mork SJ, Rubinstein LJ, Kepes JJ. Patterns of epithelial metaplasia to form malignant epithelioid cell tumors.29 Until now it in malignant gliomas: II. Squamous differentiation of epithelial- like formations in gliosarcomas and glioblastomas. J Neuropathol was thought that, unlike neurofibromas, the lack of re- Exp Neurol 1988;47:101–18. ports of metaplasia to malignant mesenchymal tissues in 19. Ou YC, Yang DY, Chang CG. Ossification within a thoracic neu- schwannoma reflected a basic limitation of the metaplas- rilemmoma: a case report. Chin Med J 1988;42:143–6. 20. Perry A, Roth KA, Banerjee R, et al. NF1 Deletions in S-100 tic potential of highly differentiated Schwann cells com- protein-positive and negative cells of sporadic and neurofibroma- prising this tumor. This would also explain why meta- tosis 1 (NF-1)-associated plexiform neurofibromas and malignant plastic changes in MPNST are far more frequent in those peripheral nerve sheath tumors. Am J Pathol 2001;159:57–61. 21. Scheithauer BW, Woodruff JM, Erlandson RA. Schwannoma, arising from neurofibromas or in patients with neurofi- chapter 7. 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