583996
research-article2015
IJSXXX10.1177/1066896915583996International Journal of Surgical PathologyThway et al
Case Reports
Malignant Peripheral Nerve Sheath Tumor With Rhabdomyosarcomatous and Glandular Elements: Rare Epithelial Differentiation in a Triton Tumor
International Journal of Surgical Pathology 1–7 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896915583996 ijs.sagepub.com
Khin Thway, FRCPath1, Wael Hamarneh, MRCS1, Aisha B. Miah, PhD, MRCP, FRCR1, and Cyril Fisher, MD, DSc, FRCPath1
Abstract Divergent differentiation occurs in a subset of malignant peripheral nerve sheath tumors (MPNST), but differentiation toward epithelial elements is unusual. MPNST with both heterologous rhabdomyosarcomatous differentiation (malignant Triton tumor), and glandular epithelial differentiation is exceedingly rare, with only 11 cases reported since 1973, and only 1 with histologically proven metastasis. We describe a case occurring in the mediastinum (between the ascending aorta and the main pulmonary artery) of a 40-year-old man with neurofibromatosis type-1. Despite treatment, the tumor metastasized to the right frontal lobe 16 months after diagnosis. Histologically, the primary neoplasm comprised cellular fascicles of atypical spindle cells, with discrete foci of well-formed or more primitive glandular epithelial structures, while the metastases comprised spindle cell sarcoma, including rhabdomyosarcoma, without epithelial elements. We review and discuss the literature on these little characterized neoplasms, including histology and clinical features, adding to the spectrum of documented cases of divergent epithelial differentiation in Triton tumor. Keywords epithelial, glands, glandular, malignant peripheral nerve sheath tumor, neurofibromatosis type 1, rhabdomyosarcoma, Triton tumor
Introduction Malignant peripheral nerve sheath tumors (MPNST) are soft tissue neoplasms that show differentiation toward cells of the nerve sheath. They can arise sporadically or as part of neurofibromatosis type 1 (NF1) (Von Recklinghausen disease), and may arise from peripheral nerves or preexisting benign nerve sheath neoplasms (most frequently neurofibromas). MPNST can show divergent differentiation, usually to mesenchymal elements, particularly skeletal muscle (malignant Triton tumor), but differentiation toward epithelial elements is infrequent. The finding of rhabdomyosarcomatous and glandular differentiation in MPNST remains exceedingly rare. We report a case of malignant Triton tumor with glandular epithelial differentiation, and review the literature on MPNST with this pattern of bi-directional differentiation, with discussion of the clinical and morphologic features, and the pluridirectional differentiation spectrum of peripheral nerve sheath neoplasms.
radiating to the back, associated with lateral ST segment depression on electrocardiography and increased serum troponin. Angiography showed a narrowing of the ostial left main stem coronary artery. He underwent urgent coronary artery bypass graft surgery. Intraoperatively, during preparation for cardiopulmonary bypass, a large, 7-cm mediastinal mass, clinically suggestive of a neurofibroma, was found between the ascending aorta and main pulmonary artery, causing compression of the left main stem of the coronary artery and in keeping with the cause of his acute coronary syndrome (rather than intrinsic coronary artery disease). The lesion was dissected free and coronary artery bypass graft surgery was then performed, which was uneventful. In subsequent staging investigations, magnetic resonance imaging scan and dynamic ultrasound scan demonstrated heterogeneous tissue within the mediastinum, abutting the left atrium, and causing 1
Royal Marsden Hospital, London, UK
Case History A 40-year-old man known to have NF1 presented acutely to the emergency department with central chest pain
Corresponding Author: Khin Thway, Sarcoma Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK. Email: [email protected]
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compression of the pulmonary vasculature and superior vena cava. The features were suggestive of gross active residual disease causing localized symptoms, and in view of this, coupled with the histologically high-grade nature of the tumor and positive margins, the patient was treated with further resection and postoperative radiotherapy to the cardia and pulmonary trunk for control of local disease. The patient remained well until 15 months after presentation, when he suffered a seizure comprising a short episode of loss of consciousness. Magnetic resonance imaging of the brain showed a 1 cm enhancing lesion in the right frontal lobe, consistent with a solitary metastasis. Computed tomography scans of the thorax, abdomen, and pelvis showed no evidence of recurrent disease. The frontal metastatic deposit was then completely resected macroscopically with a cuff of normal tissue. Six months later, the patient presented again, with deteriorating vision and partial seizure activity. Imaging showed a new area of enhancement in the tumor bed, and a further right frontal craniotomy was performed, with excision of all macroscopic tumor. However, repeat brain imaging showed extensive recurrence occurring within a few days after this resection. The patient was transferred to the care of his community palliative team, 24 months after his initial presentation. Grossly, the specimen consisted of a 7 × 4.5 × 4 cm firm, white-gray mass without definite necrosis or hemorrhage. Histologically, this was a pseudo-encapsulated, cellular neoplasm composed of short or longer sweeping fascicles of spindle cells with elongated or ovoid, vesicular or hyperchromatic nuclei and fibrillary cytoplasm (Figure 1A-D). Cellular atypia varied, from mild to marked; giant and bizarre tumor cells were interspersed in areas, and some of these had abundant, brightly eosinophilic cytoplasm (Figure 1E). There was focal necrosis and a mitotic index of up to 14/10 high-power fields. The stroma showed myxoid areas and foci of hyalinization, although no tumoral osteoid formation. Although there were small areas comprising blander cells with tapered or wavy nuclei within fibrous stroma (Figure 1C and D), these were intermixed with atypical spindle cells, and no discrete residual areas of neurofibroma or plexiform neurofibroma were identified. Focally, there were clusters of glands, composed of single layers of cuboidal epithelial cells with ovoid vesicular nuclei showing minimal atypia and moderate amounts of amphophilic or clear cytoplasm, and without mitotic activity (Figures 1F and 2A and B). These glands were largely relatively well formed, although in some areas they had a more primitive, cribriform appearance and often they were difficult to discern from the surrounding spindle cell population. No goblet cells, cellular stratification, papillary formations or mucin pools were present. Immunohistochemically, the spindle cell component showed strong nuclear and cytoplasmic S100 protein
expression in many areas (Figure 2C), and focal CD34 expression. Many cells were strongly positive for desmin, which highlighted markedly atypical “strap-like” cells (Figure 2D), and there was focal nuclear myogenin (Figure 2E). The spindle cells were also focally immunoreactive for CD56 and neuron-specific enolase (NSE), with focal scant positivity for CD99, synaptophysin, p63 and bcl-2. The glandular components were diffusely positive for AE1/AE3, MNF116, CAM5.2 (Figure 2F) and epithelial membrane antigen (EMA), although these markers were negative in the rest of the neoplasm. All elements of the tumor were negative for smooth muscle actin (SMA), h-caldesmon, calponin, CDK4, p16, CK7, CK20, calretinin, CD117, DOG1, TLE1, glial fibrillary acidic protein (GFAP), neurofilament, chromogranin, TTF1, HMB45, Melan-A, prostate-specific antigen (PSA) and CDX2. Reticulin stain showed a nested pattern around the glandular structures but a pericellular distribution in the rest of the tumor. No mucin was seen with periodic acid– Schiff/diastase stains. The features were of high-grade malignant peripheral nerve sheath tumor with heterologous rhabdomyosarcomatous and glandular epithelial differentiation (malignant Triton tumor with epithelial elements), which extended to the surgical margins. The reexcision specimen showed fibroadipose tissue with entrapped remnants of thymus with extensive, chronically inflamed granulation tissue with prominent bacterial infection confirmed on Gram stain, but no residual tumor. The right frontal lobe lesions comprised spindle cell sarcoma with morphology similar to the main specimen and focal expression of myoid markers, consistent with metastatic malignant Triton tumor. No epithelial elements were present.
Discussion Malignant peripheral nerve sheath tumors showing both rhabdomyosarcomatous and glandular differentiation are exceptionally rare; 11 cases have been reported since 1973, and these are summarized in Table 1.1-10 Only in 1 case has the histology of the metastasis been reported.9 At least half of these have occurred in patients known to have NF1, and these are biologically aggressive neoplasms for which all patients who died did so less than 2 years after initial surgery. MPNST have not been found to have specific or reproducible genetic aberrations; instead they have complex karyotypes, with multiple structural and numeric abnormalities. In both sporadic cases and those of NF1 patients, the most frequent genetic alterations include loss or inactivation of the NF1 tumor suppressor gene on 17q11, and of p53 on 17q13. Divergent differentiation is seen in approximately 15% of MPNST, and is usually toward mesenchymal elements (most commonly skeletal muscle/rhabdomyosarcoma, but
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Figure 1. (A-F) Malignant peripheral nerve sheath tumor with rhabdomyosarcomatous and glandular differentiation. This was a cellular neoplasm composed of short or longer sweeping fascicles of spindle cells with elongated or ovoid, vesicular or hyperchromatic nuclei and fibrillary cytoplasm. Cellular atypia varies from mild to marked. Giant and bizarre tumor cells are present in areas (A, B), some containing abundant, brightly eosinophilic cytoplasm and suggestive of rhabdomyoblastic differentiation (E). In small areas there are blander cells with tapered or wavy nuclei within fibrous stroma, possibly representing foci of residual neurofibroma (C, D), although these are intermixed with atypical spindle cells. Focally, there are clusters of glands distributed within the spindle cells, which can be difficult to discern at low power (F).
also heterologous osteoid, osteosarcoma, chondroid or chondrosarcoma and rarely angiosarcoma) but rarely to epithelial elements;11 the finding of more than one type of heterologous element is rare. Triton tumor refers to any benign or malignant neoplasm showing differentiation toward both neural and skeletal muscle lineages. Malignant Triton tumor comprises MPNST with evidence of skeletal myogenic differentiation, often with variable numbers of spindle, polygonal or bizarre rhabdomyoblasts, and at least focal expression of desmin and myogenic nuclear transcription factors myogenin or MyoD1. More
than 70% of Triton tumors in the series of Brooks et al12 were young patients with NF1, with a marked male preponderance. Malignant Triton tumors are biologically aggressive, with an even worse prognosis than classical MPNST;12 many patients die within 2 years of diagnosis, with 2- and 5-year survivals of 33% and 12%, respectively.5,12 Some large studies have, however, found that metaplastic foci do not alter prognosis.13 Glandular differentiation in MPNST is very rare. It was first reported by Garre in 1892,14 and more often occurs in patients with NF1. Glands can also more rarely be associated
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Figure 2. (A, B) The glandular component comprises single layers of cuboidal epithelial cells with ovoid vesicular nuclei showing minimal atypia and moderate amounts of amphophilic or clear cytoplasm, and without mitotic activity, cellular stratification or papillary formations. The glands are largely well formed, although more focally they have a more primitive, cribriform appearance (A). (C) Immunohistochemically, the spindle cell component shows strong nuclear and cytoplasmic S100 protein expression in many areas. (D) Many cells are strongly positive for desmin, which also highlights markedly atypical “strap-like” cells. (E) Within the desmin-positive areas are cells showing nuclear myogenin expression. (F) The glandular components are diffusely positive for keratins such as CAM5.2.
with benign neurofibroma.7 The pathogenic basis is not known, although it is hypothesized that neural crest cells are capable of varied differentiation so the glands might arise by metaplasia of neoplastic Schwannian spindle cells of MPNST,7,9 or possibly from autochthonous growth of a separate neural crest ectodermal cell line, which may have migrated along peripheral nerve fibers with the Schwann cells.15 The glands are usually discrete and localized to a few areas, and previous authors have postulated, after only encountering glandular differentiation in the 27th block of a mediastinal MPNST, that glandular differentiation might occur more commonly than realized, if MPNSTs of NF1
patients are exhaustively sampled. Most glands seen in MPNST are histologically benign, but rarely they are malignant, with pleomorphic epithelial cells with hyperchromatic nuclei, mitotic activity and gland-within-gland formations.9,16,17 Malignant glandular elements were present in 2 of the 11 previously reported Triton tumors with glandular differentiation, in accordance with this proportion.5,9 The degree of glandular atypia has not been shown to correlate with the degree of atypia of the spindle cell population. The glands are usually lined by nonciliated cuboidal and/or pseudostratified columnar epithelium, often with clear cytoplasm.18 These often demonstrate mucin production,18 which
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1
52/Male
24/Male
79/Male
40/Male
9. Karpuz et al,8 2000
10. Huang et al,9 2003
11. Guo et al,10 2012
11. Current case
Yes
NA
No
No
Yes
Mediastinum
Thigh
Thigh
Chest wall
Right neck; associated with neurofibroma
Brachial plexus
Thorax, T1-T4
NA
NA
Buttocks
Thigh
Sciatic nerve
Site
Histology, Histochemistry, and Immunohistochemistry
7 cm
9 cm
11 cm
8 cm
10 cm
13 cm
8 cm
NA
NA
NA
Surgery; DOD after 4 months
Surgery; recurred at 13 months; DOD at 19 months Surgery; NA
Treatment and Follow-up
Interlacing spindle cell pattern; RMS; histologically malignant glands Surgery, radiotherapy, with papillary pattern with intraluminal tufting and irregular chemotherapy; recurred at 1 multilayering. S100 and NSE+; glands: CK, EMA, and CEA+, CG and year; DOD at 15 months AFP−; rhabdomyoblasts: desmin, MSA and myoglobin+ Schwannoma pattern; RMS; benign glands Surgery, radiotherapy, chemotherapy; recurred at 7 months; DOD at 18 months Pluridirectional differentiation, with chondrosarcoma, osteosarcoma, Surgery; DOD after 3 months and rhabdomyosarcoma. Muscle-specific actin (HHF-35)+. Glands involving many areas, widely dispersed, discrete, many elongated. Lined by columnar and goblet cells and lumens distended with mucin. Signet ring cells in stroma. Spindle cells S100+; glands CEA, chromogranin, EMA and keratins+ and ACTH, calcitonin, glucagon, PP− Interlacing spindle cell pattern; rhabdomyoblasts; benign glands Surgery; recurred after 5 years S100+; glands: EMA, CK and CEA+; RMS: myoglobin and MSA+, desmin− Interlacing spindle cell pattern; rhabdomyoblasts; histologically Surgery; lung metastasis after 5 malignant glands months; DOD after 6 months S100+, GFAP+/−; glands: CG+, CK7−, CK20+/−, RMS: MSA and desmin+ Bundles and whorls of spindle cells; cells suggestive of Surgery, radiotherapy, rhabdomyoblasts; Also lipoblasts, ganglion cells chemotherapy; recurred after 10 months, without metastasis Fascicular spindle cell pattern; benign, discrete glands Surgery; brain metastasis after Glands: pancytokeratin+; CK7, CK20, CG− 15 months; transferred for RMS: desmin, myogenin+ palliation at 24 months
Rhabdomyosarcoma and osteosarcoma; discrete, well-defined glands
“Huge” Benign glands; RMS Glands: PAS+, AB+ 9.5 cm Fascicles of spindle cells, tapered or blunt ended nuclei and focal herringbone pattern; rhabdomyoblasts; chondroid Glands resembling goblet cells; more primitive glands also present Glands: PAS+, somatostatin+ NA Neurofibroma-like pattern of spindle cells; RMS; benign-looking glands. S100+, myoglobin+ NA RMS; discrete, well defined glands
Maximal Size
Abbreviations: AB, Alcian blue; ACTH, adrenocorticotropic hormone; AFP, α-fetoprotein; CEA, carcinoembryonic antigen; CG, chromogranin; DOD, died of disease; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; MSA, muscle-specific actin; NA, not available/not known; NF1, neurofibromatosis type-1; PAS, periodic acid–Schiff; PP, pancreatic polypeptide; RMS, rhabdomyoblastic/rhabdomyosarcomatous differentiation.
20/Female
No
39/Male
8. Woodruff and Christensen,7 1993
NA
NA
Yes
NA
NA
34/Male
Yes
Yes
29/Male
28/Female
Yes
NF1
38/Female
Age (Years)/ Sex
7. Rose et al,6 1992
3. Daimaru et al,3 1984 4. Christensen et al,4 1988 5. Christensen et al,4 1988 6. Wong et al,5 1991
1. Despres et al, 1973 2. Warner et al,2 1983
Case/Reference/ Year
Table 1. Clinical and Pathologic Features of Malignant Peripheral Nerve Sheath Tumors With Rhabdomyoblastic/Rhabdomyosarcomatous and Glandular Differentiation.
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can be intracellular, may distend glands or surround these structures in pools, and can resemble enteric epithelium with goblet cells.4,18 Squamous differentiation is rarely encountered. The glands are lined by keratin-positive epithelium,7 often express carcinoembryonic antigen (CEA), and can express neuroendocrine markers such as chromogranin.4 The mucin is positive for mucicarmine,4 Alcian blue or PAS, with resistance to diastase.2 The presence of glandular elements is not thought to affect the behavior of MPNST, and the outcome of these cases is probably related to the degree of malignant change shown by the neoplastic spindle cell components.18 This appears to be reflected by this current case, in which histology of the brain metastases showed myogenic differentiation, in keeping with the metastatic potential of the Triton element, in contrast to the glandular components, which were not seen in the metastatic tumor. Previous reports have also shown metastasis of the spindle and rhabdomyoblastic component, but not the epithelial component.9 Patients with MPNSTs of the thoracic cavity are often asymptomatic until the tumor causes local symptoms or features of metastasis. The exact origin of this neoplasm, which was an unexpected finding at surgery, was not apparent during the operation, but this could potentially have originated from mediastinal nerves such as the phrenic or cardiac nerves. Although the intraoperative surgical impression was of a neurofibroma, conclusive evidence of a preexisting neurofibroma or plexiform neurofibroma was absent histologically (although there were smaller foci of blander cells with buckled nuclei), but it is conceivable that the patient had a slowly growing neurofibroma at this site for several years which underwent malignant transformation, leading to rapid growth and symptoms and which had overgrown the benign elements. The differential diagnosis is of other neoplasms either showing similar histologic features, or that can occur in similar clinical contexts.19 Synovial sarcoma can arise within a nerve, and the biphasic type can mimic the bland-looking glandular elements of this case. MPNST with glandular elements usually shows a sharp distinction between the spindle and glandular cells,4 in contrast to the complex intermingling seen in synovial sarcoma. Goblet cells are seen only in glandular MPNST and not synovial sarcoma. Cytokeratin or EMA expression is usually seen focally in the spindle areas of biphasic synovial sarcoma, but is usually absent in those of MPNST. Almost all synovial sarcomas show diffuse nuclear expression of TLE120; this is also commonly seen in peripheral nerve sheath tumors, including 30% of MPNSTs,21 but its expression is usually more focal.21-23 While some synovial sarcomas can express myoid markers,24 they do not express myogenin, unlike Triton tumor. CD34 is also only rarely expressed in synovial sarcoma, in contrast to MPNST.25 Sox10 appears to show increased specificity for tumors of neural crest origin compared
with S100 protein,26,27 but expression is absent in most non-Schwannian and nonmelanocytic neoplasms. Finally, MPNST lack the t(X;18) translocation, which fuses SSX1, 2 or 4 with SS18 and which is specific for synovial sarcoma.28-30 Triton tumor with glandular differentiation should also be distinguished from metastatic sarcomatoid carcinoma or carcinosarcoma, but patients with carcinoma may have a history of previous or primary carcinoma, or may harbor dysplastic or in situ changes in the epithelium overlying the neoplasms. Myoepithelial tumors more frequently occur subcutaneously rather than deeply, and, in addition to S100 protein expression, are simultaneously immunoreactive for other myoepithelialassociated markers such as cytokeratins, EMA, SMA, and calponin. Unlike MPNST, myoepithelial neoplasms are often associated with gene fusions involving EWSR1 and a variety of partner genes, including POU5F1, ZNF444, and PBX1.31-34 In the thorax, it is important to exclude mesothelioma, which can show a mixture of spindle and epithelioid cells, but this may show radiologic features of diffuse pleural thickening, as well as diffuse CK5/6 expression and nuclear and cytoplasmic calretinin expression, with most tumors also positive for WT-1 and D240. In summary, we report a rare case of bidirectional differentiation in MPNST showing rhabdomyosarcomatous and glandular elements. The pathogenesis of this phenomenon remains to be understood, but better characterization of the genetic pathways involved may lead to the generation of specific targeted therapies for patients with these highly aggressive neoplasms. Acknowledgments We acknowledge support from the NIHR Royal Marsden/ICR Biomedical Research Centre.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study received support from the NIHR Royal Marsden/ICR Biomedical Research Centre.
References 1. Despres S, Dolivieux P, Laurent M, Nezelof C. Neurofibrosarcome a differentiation glandularire: a propos d’une observation. Arch Anat Pathol. 1973;21:59-62. 2. Warner TF, Louie R, Hafez GR, Chandler E. Malignant nerve sheath tumor containing endocrine cells. Am J Surg Pathol. 1983;7:583-590.
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Thway et al 3. Daimaru Y, Hashimoto H, Enjoji M. Malignant “triton” tumors: a clinicopathologic and immunohistochemical study of nine cases. Hum Pathol. 1984;15:768-778. 4. Christensen WN, Strong EW, Bains MS, Woodruff JM. Neuroendocrine differentiation in the glandular peripheral nerve sheath tumor. Pathologic distinction from the biphasic synovial sarcoma with glands. Am J Surg Pathol. 1988;12:417-426. 5. Wong SY, Teh M, Tan YO, Best PV. Malignant glandular triton tumor. Cancer. 1991;67:1076-1083. 6. Rose DS, Wilkins MJ, Birch R, Evans DJ. Malignant peripheral nerve sheath tumour with rhabdomyoblastic and glandular differentiation: immunohistochemical features. Histopathology. 1992;21:287-290. 7. Woodruff JM, Christensen WN. Glandular peripheral nerve sheath tumors. Cancer. 1993;72:3618-3628. 8. Karpuz V, Letovanec N, Von Hochstetter A, Joris F. Malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation and glandular component [in French]. Ann Pathol. 2000;20:62-65. 9. Huang L, Espinoza C, Welsh R. Malignant peripheral nerve sheath tumor with divergent differentiation. Arch Pathol Lab Med. 2003;127:e147-e150. 10. Guo A, Liu A, Wei L, Song X. Malignant peripheral nerve sheath tumors: differentiation patterns and immunohistochemical features—a mini-review and our new findings. J Cancer. 2012;3:303-309. 11. Ducatman BS, Scheithauer BW. Malignant peripheral nerve sheath tumors with divergent differentiation. Cancer. 1984;54:1049-1057. 12. Brooks JS, Freeman M, Enterline HT. Malignant “Triton” tumors. Natural history and immunohistochemistry of nine new cases with literature review. Cancer. 1985;55:2543-2549. 13. Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer. 1986;57: 2006-2021. 14. Garre C. Uber sekundar malige neurome. Beitr Klin Chir. 1892;9:465-495. 15. Krumerman MS, Stingle W. Synchronous malignant glandular schwannomas in congenital neurofibromatosis. Cancer. 1978;41:2444-2451. 16. Galatian AA, Crowson AN, Fischer RJ, Yob EH, Shendrik I. Malignant peripheral nerve sheath tumor with glandular differentiation in a patient with neurofibromatosis type 1. Am J Dermatopathol. 2013;35:859-863. 17. Nagasaka T, Lai R, Sone M, Nakashima T, Nakashima N. Glandular malignant peripheral nerve sheath tumor: an unusual case showing histologically malignant glands. Arch Pathol Lab Med. 2000;124:1364-1368. 18. Woodruff JM. Peripheral nerve tumors showing glan dular differentiation (glandular schwannomas). Cancer. 1976;37:2399-2413. 19. Thway K, Fisher C. Malignant peripheral nerve sheath tumor: pathology and genetics. Ann Diagn Pathol. 2014;18: 109-116. 20. Terry J, Saito T, Subramanian S, et al. TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma
emerging from gene expression profiling studies. Am J Surg Pathol. 2007;31:240-246. 21. Kosemehmetoglu K, Vrana JA, Folpe AL. TLE1 expression is not specific for synovial sarcoma: a whole section study of 163 soft tissue and bone neoplasms. Mod Pathol. 2009;22:872-878. 22. Foo WC, Cruise MW, Wick MR, Hornick JL. Immunohistochemical staining for TLE1 distinguishes synovial sarcoma from histologic mimics. Am J Clin Pathol. 2011;135:839-844. 23. Thway K, Fisher C. Synovial sarcoma: defining features and diagnostic evolution. Ann Diagn Pathol. 2014;18:369-380. 24. Fisher C, Montgomery E, Healy V. Calponin and h-caldesmon expression in synovial sarcoma; the use of calponin in diagnosis. Histopathology. 2003;42:588-593. 25. Pelmus M, Guillou L, Hostein I, Sierankowski G, Lussan C, Coindre JM. Monophasic fibrous and poorly differentiated synovial sarcoma: immunohistochemical reassessment of 60 t(X;18)(SYT-SSX)-positive cases. Am J Surg Pathol. 2002;26:1434-1440. 26. Karamchandani JR, Nielsen TO, van de Rijn M, West RB. Sox10 and S100 in the diagnosis of soft-tissue neoplasms. Appl Immunohistochem Mol Morphol. 2012;20:445-450. 27. Nonaka D, Chiriboga L, Rubin BP. Sox10: a pan-schwannian and melanocytic marker. Am J Surg Pathol. 2008;32: 1291-1298. 28. van de Rijn M, Barr FG, Collins MH, Xiong QB, Fisher C. Absence of SYT-SSX fusion products in soft tissue tumors other than synovial sarcoma. Am J Clin Pathol. 1999;112: 43-49. 29. Ladanyi M, Woodruff JM, Scheithauer BW, et al.Reply to O’Sullivan MJ, Kyriakos M, Zhu X, Wick MR, Swanson PE, Dehner LP, Humphrey PA, Pfeifer JD: malignant peripheral nerve sheath tumors with t(X;18). A pathologic and molecular genetic study. Mod Pathol. 2000;13:1336-46. Mod Pathol. 2001;14:733-737. 30. Coindre JM, Hostein I, Benhattar J, Lussan C, Rivel J, Guillou L. Malignant peripheral nerve sheath tumors are t(X;18)-negative sarcomas. Molecular analysis of 25 cases occurring in neurofibromatosis type 1 patients, using two different RT-PCR-based methods of detection. Mod Pathol. 2002;15:589-592. 31. Antonescu CR, Zhang L, Chang NE, et al. EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosomes Cancer. 2010;49:1114-1124. 32. Balogh Z, Deak L, Sapi Z. Malignant myoepithelioma of soft tissue: a case report with cytogenetic findings. Cancer Genet Cytogenet. 2008;183:121-124. 33. Brandal P, Panagopoulos I, Bjerkehagen B, et al. Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1PBX1 fusion gene in a myoepithelioma. Genes Chromosomes Cancer. 2008;47:558-564. 34. Brandal P, Panagopoulos I, Bjerkehagen B, Heim S. t(19;22) (q13;q12) Translocation leading to the novel fusion gene EWSR1-ZNF444 in soft tissue myoepithelial carcinoma. Genes Chromosomes Cancer. 2009;48:1051-1056.
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research-article2015
IJSXXX10.1177/1066896915583996International Journal of Surgical PathologyThway et al
Case Reports
Malignant Peripheral Nerve Sheath Tumor With Rhabdomyosarcomatous and Glandular Elements: Rare Epithelial Differentiation in a Triton Tumor
International Journal of Surgical Pathology 1–7 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896915583996 ijs.sagepub.com
Khin Thway, FRCPath1, Wael Hamarneh, MRCS1, Aisha B. Miah, PhD, MRCP, FRCR1, and Cyril Fisher, MD, DSc, FRCPath1
Abstract Divergent differentiation occurs in a subset of malignant peripheral nerve sheath tumors (MPNST), but differentiation toward epithelial elements is unusual. MPNST with both heterologous rhabdomyosarcomatous differentiation (malignant Triton tumor), and glandular epithelial differentiation is exceedingly rare, with only 11 cases reported since 1973, and only 1 with histologically proven metastasis. We describe a case occurring in the mediastinum (between the ascending aorta and the main pulmonary artery) of a 40-year-old man with neurofibromatosis type-1. Despite treatment, the tumor metastasized to the right frontal lobe 16 months after diagnosis. Histologically, the primary neoplasm comprised cellular fascicles of atypical spindle cells, with discrete foci of well-formed or more primitive glandular epithelial structures, while the metastases comprised spindle cell sarcoma, including rhabdomyosarcoma, without epithelial elements. We review and discuss the literature on these little characterized neoplasms, including histology and clinical features, adding to the spectrum of documented cases of divergent epithelial differentiation in Triton tumor. Keywords epithelial, glands, glandular, malignant peripheral nerve sheath tumor, neurofibromatosis type 1, rhabdomyosarcoma, Triton tumor
Introduction Malignant peripheral nerve sheath tumors (MPNST) are soft tissue neoplasms that show differentiation toward cells of the nerve sheath. They can arise sporadically or as part of neurofibromatosis type 1 (NF1) (Von Recklinghausen disease), and may arise from peripheral nerves or preexisting benign nerve sheath neoplasms (most frequently neurofibromas). MPNST can show divergent differentiation, usually to mesenchymal elements, particularly skeletal muscle (malignant Triton tumor), but differentiation toward epithelial elements is infrequent. The finding of rhabdomyosarcomatous and glandular differentiation in MPNST remains exceedingly rare. We report a case of malignant Triton tumor with glandular epithelial differentiation, and review the literature on MPNST with this pattern of bi-directional differentiation, with discussion of the clinical and morphologic features, and the pluridirectional differentiation spectrum of peripheral nerve sheath neoplasms.
radiating to the back, associated with lateral ST segment depression on electrocardiography and increased serum troponin. Angiography showed a narrowing of the ostial left main stem coronary artery. He underwent urgent coronary artery bypass graft surgery. Intraoperatively, during preparation for cardiopulmonary bypass, a large, 7-cm mediastinal mass, clinically suggestive of a neurofibroma, was found between the ascending aorta and main pulmonary artery, causing compression of the left main stem of the coronary artery and in keeping with the cause of his acute coronary syndrome (rather than intrinsic coronary artery disease). The lesion was dissected free and coronary artery bypass graft surgery was then performed, which was uneventful. In subsequent staging investigations, magnetic resonance imaging scan and dynamic ultrasound scan demonstrated heterogeneous tissue within the mediastinum, abutting the left atrium, and causing 1
Royal Marsden Hospital, London, UK
Case History A 40-year-old man known to have NF1 presented acutely to the emergency department with central chest pain
Corresponding Author: Khin Thway, Sarcoma Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK. Email: [email protected]
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compression of the pulmonary vasculature and superior vena cava. The features were suggestive of gross active residual disease causing localized symptoms, and in view of this, coupled with the histologically high-grade nature of the tumor and positive margins, the patient was treated with further resection and postoperative radiotherapy to the cardia and pulmonary trunk for control of local disease. The patient remained well until 15 months after presentation, when he suffered a seizure comprising a short episode of loss of consciousness. Magnetic resonance imaging of the brain showed a 1 cm enhancing lesion in the right frontal lobe, consistent with a solitary metastasis. Computed tomography scans of the thorax, abdomen, and pelvis showed no evidence of recurrent disease. The frontal metastatic deposit was then completely resected macroscopically with a cuff of normal tissue. Six months later, the patient presented again, with deteriorating vision and partial seizure activity. Imaging showed a new area of enhancement in the tumor bed, and a further right frontal craniotomy was performed, with excision of all macroscopic tumor. However, repeat brain imaging showed extensive recurrence occurring within a few days after this resection. The patient was transferred to the care of his community palliative team, 24 months after his initial presentation. Grossly, the specimen consisted of a 7 × 4.5 × 4 cm firm, white-gray mass without definite necrosis or hemorrhage. Histologically, this was a pseudo-encapsulated, cellular neoplasm composed of short or longer sweeping fascicles of spindle cells with elongated or ovoid, vesicular or hyperchromatic nuclei and fibrillary cytoplasm (Figure 1A-D). Cellular atypia varied, from mild to marked; giant and bizarre tumor cells were interspersed in areas, and some of these had abundant, brightly eosinophilic cytoplasm (Figure 1E). There was focal necrosis and a mitotic index of up to 14/10 high-power fields. The stroma showed myxoid areas and foci of hyalinization, although no tumoral osteoid formation. Although there were small areas comprising blander cells with tapered or wavy nuclei within fibrous stroma (Figure 1C and D), these were intermixed with atypical spindle cells, and no discrete residual areas of neurofibroma or plexiform neurofibroma were identified. Focally, there were clusters of glands, composed of single layers of cuboidal epithelial cells with ovoid vesicular nuclei showing minimal atypia and moderate amounts of amphophilic or clear cytoplasm, and without mitotic activity (Figures 1F and 2A and B). These glands were largely relatively well formed, although in some areas they had a more primitive, cribriform appearance and often they were difficult to discern from the surrounding spindle cell population. No goblet cells, cellular stratification, papillary formations or mucin pools were present. Immunohistochemically, the spindle cell component showed strong nuclear and cytoplasmic S100 protein
expression in many areas (Figure 2C), and focal CD34 expression. Many cells were strongly positive for desmin, which highlighted markedly atypical “strap-like” cells (Figure 2D), and there was focal nuclear myogenin (Figure 2E). The spindle cells were also focally immunoreactive for CD56 and neuron-specific enolase (NSE), with focal scant positivity for CD99, synaptophysin, p63 and bcl-2. The glandular components were diffusely positive for AE1/AE3, MNF116, CAM5.2 (Figure 2F) and epithelial membrane antigen (EMA), although these markers were negative in the rest of the neoplasm. All elements of the tumor were negative for smooth muscle actin (SMA), h-caldesmon, calponin, CDK4, p16, CK7, CK20, calretinin, CD117, DOG1, TLE1, glial fibrillary acidic protein (GFAP), neurofilament, chromogranin, TTF1, HMB45, Melan-A, prostate-specific antigen (PSA) and CDX2. Reticulin stain showed a nested pattern around the glandular structures but a pericellular distribution in the rest of the tumor. No mucin was seen with periodic acid– Schiff/diastase stains. The features were of high-grade malignant peripheral nerve sheath tumor with heterologous rhabdomyosarcomatous and glandular epithelial differentiation (malignant Triton tumor with epithelial elements), which extended to the surgical margins. The reexcision specimen showed fibroadipose tissue with entrapped remnants of thymus with extensive, chronically inflamed granulation tissue with prominent bacterial infection confirmed on Gram stain, but no residual tumor. The right frontal lobe lesions comprised spindle cell sarcoma with morphology similar to the main specimen and focal expression of myoid markers, consistent with metastatic malignant Triton tumor. No epithelial elements were present.
Discussion Malignant peripheral nerve sheath tumors showing both rhabdomyosarcomatous and glandular differentiation are exceptionally rare; 11 cases have been reported since 1973, and these are summarized in Table 1.1-10 Only in 1 case has the histology of the metastasis been reported.9 At least half of these have occurred in patients known to have NF1, and these are biologically aggressive neoplasms for which all patients who died did so less than 2 years after initial surgery. MPNST have not been found to have specific or reproducible genetic aberrations; instead they have complex karyotypes, with multiple structural and numeric abnormalities. In both sporadic cases and those of NF1 patients, the most frequent genetic alterations include loss or inactivation of the NF1 tumor suppressor gene on 17q11, and of p53 on 17q13. Divergent differentiation is seen in approximately 15% of MPNST, and is usually toward mesenchymal elements (most commonly skeletal muscle/rhabdomyosarcoma, but
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Figure 1. (A-F) Malignant peripheral nerve sheath tumor with rhabdomyosarcomatous and glandular differentiation. This was a cellular neoplasm composed of short or longer sweeping fascicles of spindle cells with elongated or ovoid, vesicular or hyperchromatic nuclei and fibrillary cytoplasm. Cellular atypia varies from mild to marked. Giant and bizarre tumor cells are present in areas (A, B), some containing abundant, brightly eosinophilic cytoplasm and suggestive of rhabdomyoblastic differentiation (E). In small areas there are blander cells with tapered or wavy nuclei within fibrous stroma, possibly representing foci of residual neurofibroma (C, D), although these are intermixed with atypical spindle cells. Focally, there are clusters of glands distributed within the spindle cells, which can be difficult to discern at low power (F).
also heterologous osteoid, osteosarcoma, chondroid or chondrosarcoma and rarely angiosarcoma) but rarely to epithelial elements;11 the finding of more than one type of heterologous element is rare. Triton tumor refers to any benign or malignant neoplasm showing differentiation toward both neural and skeletal muscle lineages. Malignant Triton tumor comprises MPNST with evidence of skeletal myogenic differentiation, often with variable numbers of spindle, polygonal or bizarre rhabdomyoblasts, and at least focal expression of desmin and myogenic nuclear transcription factors myogenin or MyoD1. More
than 70% of Triton tumors in the series of Brooks et al12 were young patients with NF1, with a marked male preponderance. Malignant Triton tumors are biologically aggressive, with an even worse prognosis than classical MPNST;12 many patients die within 2 years of diagnosis, with 2- and 5-year survivals of 33% and 12%, respectively.5,12 Some large studies have, however, found that metaplastic foci do not alter prognosis.13 Glandular differentiation in MPNST is very rare. It was first reported by Garre in 1892,14 and more often occurs in patients with NF1. Glands can also more rarely be associated
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Figure 2. (A, B) The glandular component comprises single layers of cuboidal epithelial cells with ovoid vesicular nuclei showing minimal atypia and moderate amounts of amphophilic or clear cytoplasm, and without mitotic activity, cellular stratification or papillary formations. The glands are largely well formed, although more focally they have a more primitive, cribriform appearance (A). (C) Immunohistochemically, the spindle cell component shows strong nuclear and cytoplasmic S100 protein expression in many areas. (D) Many cells are strongly positive for desmin, which also highlights markedly atypical “strap-like” cells. (E) Within the desmin-positive areas are cells showing nuclear myogenin expression. (F) The glandular components are diffusely positive for keratins such as CAM5.2.
with benign neurofibroma.7 The pathogenic basis is not known, although it is hypothesized that neural crest cells are capable of varied differentiation so the glands might arise by metaplasia of neoplastic Schwannian spindle cells of MPNST,7,9 or possibly from autochthonous growth of a separate neural crest ectodermal cell line, which may have migrated along peripheral nerve fibers with the Schwann cells.15 The glands are usually discrete and localized to a few areas, and previous authors have postulated, after only encountering glandular differentiation in the 27th block of a mediastinal MPNST, that glandular differentiation might occur more commonly than realized, if MPNSTs of NF1
patients are exhaustively sampled. Most glands seen in MPNST are histologically benign, but rarely they are malignant, with pleomorphic epithelial cells with hyperchromatic nuclei, mitotic activity and gland-within-gland formations.9,16,17 Malignant glandular elements were present in 2 of the 11 previously reported Triton tumors with glandular differentiation, in accordance with this proportion.5,9 The degree of glandular atypia has not been shown to correlate with the degree of atypia of the spindle cell population. The glands are usually lined by nonciliated cuboidal and/or pseudostratified columnar epithelium, often with clear cytoplasm.18 These often demonstrate mucin production,18 which
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1
52/Male
24/Male
79/Male
40/Male
9. Karpuz et al,8 2000
10. Huang et al,9 2003
11. Guo et al,10 2012
11. Current case
Yes
NA
No
No
Yes
Mediastinum
Thigh
Thigh
Chest wall
Right neck; associated with neurofibroma
Brachial plexus
Thorax, T1-T4
NA
NA
Buttocks
Thigh
Sciatic nerve
Site
Histology, Histochemistry, and Immunohistochemistry
7 cm
9 cm
11 cm
8 cm
10 cm
13 cm
8 cm
NA
NA
NA
Surgery; DOD after 4 months
Surgery; recurred at 13 months; DOD at 19 months Surgery; NA
Treatment and Follow-up
Interlacing spindle cell pattern; RMS; histologically malignant glands Surgery, radiotherapy, with papillary pattern with intraluminal tufting and irregular chemotherapy; recurred at 1 multilayering. S100 and NSE+; glands: CK, EMA, and CEA+, CG and year; DOD at 15 months AFP−; rhabdomyoblasts: desmin, MSA and myoglobin+ Schwannoma pattern; RMS; benign glands Surgery, radiotherapy, chemotherapy; recurred at 7 months; DOD at 18 months Pluridirectional differentiation, with chondrosarcoma, osteosarcoma, Surgery; DOD after 3 months and rhabdomyosarcoma. Muscle-specific actin (HHF-35)+. Glands involving many areas, widely dispersed, discrete, many elongated. Lined by columnar and goblet cells and lumens distended with mucin. Signet ring cells in stroma. Spindle cells S100+; glands CEA, chromogranin, EMA and keratins+ and ACTH, calcitonin, glucagon, PP− Interlacing spindle cell pattern; rhabdomyoblasts; benign glands Surgery; recurred after 5 years S100+; glands: EMA, CK and CEA+; RMS: myoglobin and MSA+, desmin− Interlacing spindle cell pattern; rhabdomyoblasts; histologically Surgery; lung metastasis after 5 malignant glands months; DOD after 6 months S100+, GFAP+/−; glands: CG+, CK7−, CK20+/−, RMS: MSA and desmin+ Bundles and whorls of spindle cells; cells suggestive of Surgery, radiotherapy, rhabdomyoblasts; Also lipoblasts, ganglion cells chemotherapy; recurred after 10 months, without metastasis Fascicular spindle cell pattern; benign, discrete glands Surgery; brain metastasis after Glands: pancytokeratin+; CK7, CK20, CG− 15 months; transferred for RMS: desmin, myogenin+ palliation at 24 months
Rhabdomyosarcoma and osteosarcoma; discrete, well-defined glands
“Huge” Benign glands; RMS Glands: PAS+, AB+ 9.5 cm Fascicles of spindle cells, tapered or blunt ended nuclei and focal herringbone pattern; rhabdomyoblasts; chondroid Glands resembling goblet cells; more primitive glands also present Glands: PAS+, somatostatin+ NA Neurofibroma-like pattern of spindle cells; RMS; benign-looking glands. S100+, myoglobin+ NA RMS; discrete, well defined glands
Maximal Size
Abbreviations: AB, Alcian blue; ACTH, adrenocorticotropic hormone; AFP, α-fetoprotein; CEA, carcinoembryonic antigen; CG, chromogranin; DOD, died of disease; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; MSA, muscle-specific actin; NA, not available/not known; NF1, neurofibromatosis type-1; PAS, periodic acid–Schiff; PP, pancreatic polypeptide; RMS, rhabdomyoblastic/rhabdomyosarcomatous differentiation.
20/Female
No
39/Male
8. Woodruff and Christensen,7 1993
NA
NA
Yes
NA
NA
34/Male
Yes
Yes
29/Male
28/Female
Yes
NF1
38/Female
Age (Years)/ Sex
7. Rose et al,6 1992
3. Daimaru et al,3 1984 4. Christensen et al,4 1988 5. Christensen et al,4 1988 6. Wong et al,5 1991
1. Despres et al, 1973 2. Warner et al,2 1983
Case/Reference/ Year
Table 1. Clinical and Pathologic Features of Malignant Peripheral Nerve Sheath Tumors With Rhabdomyoblastic/Rhabdomyosarcomatous and Glandular Differentiation.
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can be intracellular, may distend glands or surround these structures in pools, and can resemble enteric epithelium with goblet cells.4,18 Squamous differentiation is rarely encountered. The glands are lined by keratin-positive epithelium,7 often express carcinoembryonic antigen (CEA), and can express neuroendocrine markers such as chromogranin.4 The mucin is positive for mucicarmine,4 Alcian blue or PAS, with resistance to diastase.2 The presence of glandular elements is not thought to affect the behavior of MPNST, and the outcome of these cases is probably related to the degree of malignant change shown by the neoplastic spindle cell components.18 This appears to be reflected by this current case, in which histology of the brain metastases showed myogenic differentiation, in keeping with the metastatic potential of the Triton element, in contrast to the glandular components, which were not seen in the metastatic tumor. Previous reports have also shown metastasis of the spindle and rhabdomyoblastic component, but not the epithelial component.9 Patients with MPNSTs of the thoracic cavity are often asymptomatic until the tumor causes local symptoms or features of metastasis. The exact origin of this neoplasm, which was an unexpected finding at surgery, was not apparent during the operation, but this could potentially have originated from mediastinal nerves such as the phrenic or cardiac nerves. Although the intraoperative surgical impression was of a neurofibroma, conclusive evidence of a preexisting neurofibroma or plexiform neurofibroma was absent histologically (although there were smaller foci of blander cells with buckled nuclei), but it is conceivable that the patient had a slowly growing neurofibroma at this site for several years which underwent malignant transformation, leading to rapid growth and symptoms and which had overgrown the benign elements. The differential diagnosis is of other neoplasms either showing similar histologic features, or that can occur in similar clinical contexts.19 Synovial sarcoma can arise within a nerve, and the biphasic type can mimic the bland-looking glandular elements of this case. MPNST with glandular elements usually shows a sharp distinction between the spindle and glandular cells,4 in contrast to the complex intermingling seen in synovial sarcoma. Goblet cells are seen only in glandular MPNST and not synovial sarcoma. Cytokeratin or EMA expression is usually seen focally in the spindle areas of biphasic synovial sarcoma, but is usually absent in those of MPNST. Almost all synovial sarcomas show diffuse nuclear expression of TLE120; this is also commonly seen in peripheral nerve sheath tumors, including 30% of MPNSTs,21 but its expression is usually more focal.21-23 While some synovial sarcomas can express myoid markers,24 they do not express myogenin, unlike Triton tumor. CD34 is also only rarely expressed in synovial sarcoma, in contrast to MPNST.25 Sox10 appears to show increased specificity for tumors of neural crest origin compared
with S100 protein,26,27 but expression is absent in most non-Schwannian and nonmelanocytic neoplasms. Finally, MPNST lack the t(X;18) translocation, which fuses SSX1, 2 or 4 with SS18 and which is specific for synovial sarcoma.28-30 Triton tumor with glandular differentiation should also be distinguished from metastatic sarcomatoid carcinoma or carcinosarcoma, but patients with carcinoma may have a history of previous or primary carcinoma, or may harbor dysplastic or in situ changes in the epithelium overlying the neoplasms. Myoepithelial tumors more frequently occur subcutaneously rather than deeply, and, in addition to S100 protein expression, are simultaneously immunoreactive for other myoepithelialassociated markers such as cytokeratins, EMA, SMA, and calponin. Unlike MPNST, myoepithelial neoplasms are often associated with gene fusions involving EWSR1 and a variety of partner genes, including POU5F1, ZNF444, and PBX1.31-34 In the thorax, it is important to exclude mesothelioma, which can show a mixture of spindle and epithelioid cells, but this may show radiologic features of diffuse pleural thickening, as well as diffuse CK5/6 expression and nuclear and cytoplasmic calretinin expression, with most tumors also positive for WT-1 and D240. In summary, we report a rare case of bidirectional differentiation in MPNST showing rhabdomyosarcomatous and glandular elements. The pathogenesis of this phenomenon remains to be understood, but better characterization of the genetic pathways involved may lead to the generation of specific targeted therapies for patients with these highly aggressive neoplasms. Acknowledgments We acknowledge support from the NIHR Royal Marsden/ICR Biomedical Research Centre.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study received support from the NIHR Royal Marsden/ICR Biomedical Research Centre.
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