Case Reports Malignant Peripheral Nerve Sheath Tumor of the Lower Eyelid: Case Presentation and Literature Review Rebecca A. Lindsay, M.D.*, Divakar Gupta, M.D.*, Christopher D. Keene, M.D., Ph.D.†, Amit D. Bhrany, M.D.‡, and Shu-Hong Chang, M.D.* Abstract: Solitary benign neurogenic tumors are common in the orbit, but only rarely arise from peripheral nerves in the eyelids. In contrast, malignant tumors of neural or nerve sheath elements are exceedingly rare in the orbit and, to date, have never been reported in the lower eyelid. The authors report a 55-year-old man with multiple recurrent lower eyelid masses initially treated as chalazia then misdiagnosed as neurotropic malignant melanoma on pathology. Diagnosis of malignant peripheral nerve sheath tumor was ultimately confirmed histopathologically after surgical resection. The patient has since undergone multiple resections and adjuvant radiotherapy. Twenty-two months since the last procedure, the patient remains disease-free.
M
alignant peripheral nerve sheath tumors (MPNST, formerly “neurogenic sarcoma,” “neurofibrosarcoma,” or “malignant schwannoma”) are aggressive neoplasms arising from peripheral nerves in soft tissue. They are typically found in the extremities and have only rarely been reported in the periorbita. Mortality is high, approaching 70%, and the best approach to treatment remains poorly defined to date. Herein, the authors report the first case to their knowledge of an MPNST in the lower eyelid and highlight the importance of careful histologic identification and approach to management.
CASE A 55-year-old male without history of neurofibromatosis, prior malignancy, trauma, or radiation was referred for treatment of biopsy-proven conjunctival malignant melanoma of the right lower eyelid. The patient first noted a painless right lower eyelid lesion in 2010 which was diagnosed as chalazia and for which he underwent 2 incision and drainage procedures. When the lesion reformed within weeks of the second drainage procedure, conjunctival biopsy was performed. Histopathology showed what was thought to be neurotropic malignant melanoma. The patient was then referred to the University of Washington. On examination, vision was intact. External examination was significant for palpable pretarsal and deep nodules in the right lower eyelid (Fig. 1). The remainder of the ocular and orbital examination was unremarkable. Although the prior histopathologic diagnosis was based on a small tissue sample, the authors obtained the slides and verified the diagnosis before proceeding with wide local excision. Intraoperatively, the authors were surprised to find tumor that appeared to infiltrate along peripheral nerves deep into the cheek. Wide margins were Accepted for publication March 31, 2015. *Ophthalmic Plastic & Reconstructive Surgery, Department of Ophthalmology, †Neuropathology, Department of Pathology, and ‡Facial Plastic & Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, Washington, U.S.A. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Shu-Hong Chang, M.D., Box 359608, 325 Ninth Avenue, Seattle, WA 98104. E-mail: shuchang@u. washington.edu DOI: 10.1097/IOP.0000000000000496
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
taken and the defect was reconstructed with tarsoconjunctival and skin advancement flaps, as well as full-thickness skin graft from a right postauricular donor site (Fig. 2). Histopathology from the larger sample revealed normal nerve tissue surrounded by markedly irregular spindle cells with wavy, vesicular nuclei arranged in loose fascicles (Fig. 3). HMB-45, tyrosinase, and melanA immunohistochemical markers were negative. S-100 stained normal nerve in the sections, and tumor cells, having lost S-100 positivity, were identified infiltrating around normal nerves. Tumor was present at the margins of resection. At this time, the tumor was considered to be more consistent with an MPNST. The case was discussed at sarcoma tumor board where, given relatively low-grade features, decision was made to monitor for recurrence. One year after surgery, a recurrence was detected clinically. Magnetic resonance imaging showed involvement of the infraorbital nerve. The patient then underwent combined orbitotomy–maxillectomy for complete excision of the infraorbital nerve, followed by adjuvant radiation totaling 6,600 cGy delivered over 33 fractions (Fig. 4). At last follow-up, 4 years since onset of initial symptoms, the patient is healthy and surveillance magnetic resonance imaging shows no sign of tumor recurrence.
DISCUSSION Histologic diagnosis of MPNST can be challenging due to morphologic overlap with other malignant sarcomas and the lack of a specific immunohistochemical or genetic profile. Because diagnosis depends as much on tumor architecture as individual cell appearance, adequate tissue sample is important for accurate histologic diagnosis. Recent genetic work has identified biallelic loss of NF1 on chromosome 17q11 and loss of p53 on chromosome 17q13 as the most frequent gene alterations in these tumors.1 Clinically, MPNSTs are locally aggressive, often poorly differentiated neoplasms arising from elements of neural differentiation such as peripheral nerves or nerve sheath.2 They account for 5% to 10% of soft tissue sarcomas, with an incidence in the general population of only 0.001%.3,4 While exceedingly rare, they are associated with neurofibromatosis in 25% to 50% of cases, arising either de novo or from a pre-existing neurofibroma or schwannoma.1 Current treatment modalities are limited and aimed primarily at total surgical resection, although this is rarely accomplished.2 Adjuvant radiotherapy has also been recommended by the Oncology Consensus Group as a uniform treatment policy for MPNSTs although this seems more to delay local recurrence with little effect on long-term survival. Chemotherapy, to date, has played a minor role in treatment and is typically not offered as firstline therapy.5 Despite their high recurrence rate, combined approach has recently been proposed to increase disease-free survival.6,7 Unlike the more common neurofibroma and schwannoma, comparatively few MPNSTs have been identified in the head and
FIG. 1. Pretarsal nodules along the right lower eyelid (A) and on the conjunctival surface (B).
e1
Copyright © 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
Case Reports
FIG. 2. Intraoperatively, tumor is visible infiltrating peripheral nerves (A). Following wide margin excisions the defect (B) was reconstructed with tarsoconjunctival and local skin advancement flaps as well as a full-thickness skin graft (C).
FIG. 3. H&E histopathologic sections demonstrating at (A) ×20, the nested nature of the tumor in the eyelid, at (B) ×100, the plexiform appearance of the tumor, and at (C) ×400, the hypercellularity and increased mitotic activity.
FIG. 4. The maxillectomy defect was reconstructed with titanium mesh and (A). Photographs before (B) and after (C) maxillectomy + radiation shows cicatricial skin and dry eye changes from radiation treatments.
neck and even fewer in the orbit. Within the National Cancer Institute’s Surveillance, Epidemiology and End Results database of 1,315 cases of MPNSTs from 1973 to 2008, only 14% were identified in the head and neck.3 In their 37 years of experience with this tumor, Greager et al.8 have reported only 2 in the orbit. In Jakobiec’s9 presentation of 8 orbital MPNSTs, all arose from a small branch of V1 in the superonasal orbit. In 2004, Tsuchiya et al.10 presented a case of an epithelioid variant of MPNST in the medial canthal region; and in 2015, Rajabi et al.11 presented a case of MPNST of the lacrimal gland. Finally, Schmidt et al. 12 in 2013 reviewed 36 cases of MPNSTs of the trigeminal nerve and 60% of patients had V2 involvement with a large percentage of patients exhibiting infiltration of multiple nerve branches intracranially or within the orbit. To the best of the authors knowledge, however, this is the first reported case of an MPNST arising
e2
primarily in the lower eyelid. The case highlights the importance of maintaining high clinical suspicion for this rare, but potentially life-threatening entity, careful histopathologic diagnosis using adequate tissue sample, focus on wide resection with tumor-free margins, and vigilant clinical surveillance for tumor recurrence. Clinical care and report of patient described herein were undertaken in a fashion in accordance with the principles of the Declaration of Helsinki and with Health Insurance Portability and Accountability Act regulations.
REFERENCES 1. Thway K, Fisher C. Malignant peripheral nerve sheath tumor: pathology and genetics. Ann Diagn Pathol 2014;18:109–16. 2. Gupta G, Mammis A, Maniker A. Malignant peripheral nerve sheath tumors. Neurosurg Clin N Am 2008;19:533–43, v.
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Copyright © 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
3. Amirian ES, Goodman JC, New P, Scheurer ME. Pediatric and adult malignant peripheral nerve sheath tumors: an analysis of data from the surveillance, epidemiology, and end results program. J Neurooncol 2014;116:609–16. 4. Huang JH, Zhang J, Zager EL. Diagnosis and treatment options for nerve sheath tumors. Expert Rev Neurother 2005;5:515–23. 5. Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis II. Cancer Res 2002;62:1573–77. 6. Basso-Ricci S. Therapy of malignant schwannomas: usefulness of an integrated radiologic. Surgical therapy. J Neurosurg Sci 1989;33:253–7. 7. Doorn PF, Molenaar WM, Buter J, Hoekstra HJ. Malignant peripheral nerve sheath tumors in patients with and without neurofibromatosis. Eur J Surg Oncol 1995;21(1):78–82.
Case Reports
8. Greager JA, Reichard KW, Campana JP, et al. Malignant schwannoma of the head and neck. Am J Surg 1992;163:440–2. 9. Jakobiec FA, Font RL, Zimmerman LE. Malignant peripheral nerve sheath tumors of the orbit: a clinicopathologic study of eight cases. Tr Am Ophth Soc 1985;83:332–66. 10. Tsuchiya D, Hiroshi T, Saito K, Kashiwa H, Maeda K, Yamashita H. Immunohistochemical diagnosis of a rare case of epithelioid malignant peripheral nerve sheath tumor with multiple metastases. Jpn J Ophthalmol. 2004;48:565–9. 11. Rajabi MT, Riazi H, Hosseini SS, et al. Malignant peripheral nerve sheath tumor of lacrimal nerve: a case report. Orbit 2015;34:41–4. 12. Schmidt RF, Yick F, Boghani Z, et al. Malignant peripheral nerve sheath tumors of the trigeminal nerve: a systematic review of 36 cases. Neurosurg Focus 2013;34:E5.
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
e3
Copyright © 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
M
alignant peripheral nerve sheath tumors (MPNST, formerly “neurogenic sarcoma,” “neurofibrosarcoma,” or “malignant schwannoma”) are aggressive neoplasms arising from peripheral nerves in soft tissue. They are typically found in the extremities and have only rarely been reported in the periorbita. Mortality is high, approaching 70%, and the best approach to treatment remains poorly defined to date. Herein, the authors report the first case to their knowledge of an MPNST in the lower eyelid and highlight the importance of careful histologic identification and approach to management.
CASE A 55-year-old male without history of neurofibromatosis, prior malignancy, trauma, or radiation was referred for treatment of biopsy-proven conjunctival malignant melanoma of the right lower eyelid. The patient first noted a painless right lower eyelid lesion in 2010 which was diagnosed as chalazia and for which he underwent 2 incision and drainage procedures. When the lesion reformed within weeks of the second drainage procedure, conjunctival biopsy was performed. Histopathology showed what was thought to be neurotropic malignant melanoma. The patient was then referred to the University of Washington. On examination, vision was intact. External examination was significant for palpable pretarsal and deep nodules in the right lower eyelid (Fig. 1). The remainder of the ocular and orbital examination was unremarkable. Although the prior histopathologic diagnosis was based on a small tissue sample, the authors obtained the slides and verified the diagnosis before proceeding with wide local excision. Intraoperatively, the authors were surprised to find tumor that appeared to infiltrate along peripheral nerves deep into the cheek. Wide margins were Accepted for publication March 31, 2015. *Ophthalmic Plastic & Reconstructive Surgery, Department of Ophthalmology, †Neuropathology, Department of Pathology, and ‡Facial Plastic & Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, Washington, U.S.A. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Shu-Hong Chang, M.D., Box 359608, 325 Ninth Avenue, Seattle, WA 98104. E-mail: shuchang@u. washington.edu DOI: 10.1097/IOP.0000000000000496
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
taken and the defect was reconstructed with tarsoconjunctival and skin advancement flaps, as well as full-thickness skin graft from a right postauricular donor site (Fig. 2). Histopathology from the larger sample revealed normal nerve tissue surrounded by markedly irregular spindle cells with wavy, vesicular nuclei arranged in loose fascicles (Fig. 3). HMB-45, tyrosinase, and melanA immunohistochemical markers were negative. S-100 stained normal nerve in the sections, and tumor cells, having lost S-100 positivity, were identified infiltrating around normal nerves. Tumor was present at the margins of resection. At this time, the tumor was considered to be more consistent with an MPNST. The case was discussed at sarcoma tumor board where, given relatively low-grade features, decision was made to monitor for recurrence. One year after surgery, a recurrence was detected clinically. Magnetic resonance imaging showed involvement of the infraorbital nerve. The patient then underwent combined orbitotomy–maxillectomy for complete excision of the infraorbital nerve, followed by adjuvant radiation totaling 6,600 cGy delivered over 33 fractions (Fig. 4). At last follow-up, 4 years since onset of initial symptoms, the patient is healthy and surveillance magnetic resonance imaging shows no sign of tumor recurrence.
DISCUSSION Histologic diagnosis of MPNST can be challenging due to morphologic overlap with other malignant sarcomas and the lack of a specific immunohistochemical or genetic profile. Because diagnosis depends as much on tumor architecture as individual cell appearance, adequate tissue sample is important for accurate histologic diagnosis. Recent genetic work has identified biallelic loss of NF1 on chromosome 17q11 and loss of p53 on chromosome 17q13 as the most frequent gene alterations in these tumors.1 Clinically, MPNSTs are locally aggressive, often poorly differentiated neoplasms arising from elements of neural differentiation such as peripheral nerves or nerve sheath.2 They account for 5% to 10% of soft tissue sarcomas, with an incidence in the general population of only 0.001%.3,4 While exceedingly rare, they are associated with neurofibromatosis in 25% to 50% of cases, arising either de novo or from a pre-existing neurofibroma or schwannoma.1 Current treatment modalities are limited and aimed primarily at total surgical resection, although this is rarely accomplished.2 Adjuvant radiotherapy has also been recommended by the Oncology Consensus Group as a uniform treatment policy for MPNSTs although this seems more to delay local recurrence with little effect on long-term survival. Chemotherapy, to date, has played a minor role in treatment and is typically not offered as firstline therapy.5 Despite their high recurrence rate, combined approach has recently been proposed to increase disease-free survival.6,7 Unlike the more common neurofibroma and schwannoma, comparatively few MPNSTs have been identified in the head and
FIG. 1. Pretarsal nodules along the right lower eyelid (A) and on the conjunctival surface (B).
e1
Copyright © 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
Case Reports
FIG. 2. Intraoperatively, tumor is visible infiltrating peripheral nerves (A). Following wide margin excisions the defect (B) was reconstructed with tarsoconjunctival and local skin advancement flaps as well as a full-thickness skin graft (C).
FIG. 3. H&E histopathologic sections demonstrating at (A) ×20, the nested nature of the tumor in the eyelid, at (B) ×100, the plexiform appearance of the tumor, and at (C) ×400, the hypercellularity and increased mitotic activity.
FIG. 4. The maxillectomy defect was reconstructed with titanium mesh and (A). Photographs before (B) and after (C) maxillectomy + radiation shows cicatricial skin and dry eye changes from radiation treatments.
neck and even fewer in the orbit. Within the National Cancer Institute’s Surveillance, Epidemiology and End Results database of 1,315 cases of MPNSTs from 1973 to 2008, only 14% were identified in the head and neck.3 In their 37 years of experience with this tumor, Greager et al.8 have reported only 2 in the orbit. In Jakobiec’s9 presentation of 8 orbital MPNSTs, all arose from a small branch of V1 in the superonasal orbit. In 2004, Tsuchiya et al.10 presented a case of an epithelioid variant of MPNST in the medial canthal region; and in 2015, Rajabi et al.11 presented a case of MPNST of the lacrimal gland. Finally, Schmidt et al. 12 in 2013 reviewed 36 cases of MPNSTs of the trigeminal nerve and 60% of patients had V2 involvement with a large percentage of patients exhibiting infiltration of multiple nerve branches intracranially or within the orbit. To the best of the authors knowledge, however, this is the first reported case of an MPNST arising
e2
primarily in the lower eyelid. The case highlights the importance of maintaining high clinical suspicion for this rare, but potentially life-threatening entity, careful histopathologic diagnosis using adequate tissue sample, focus on wide resection with tumor-free margins, and vigilant clinical surveillance for tumor recurrence. Clinical care and report of patient described herein were undertaken in a fashion in accordance with the principles of the Declaration of Helsinki and with Health Insurance Portability and Accountability Act regulations.
REFERENCES 1. Thway K, Fisher C. Malignant peripheral nerve sheath tumor: pathology and genetics. Ann Diagn Pathol 2014;18:109–16. 2. Gupta G, Mammis A, Maniker A. Malignant peripheral nerve sheath tumors. Neurosurg Clin N Am 2008;19:533–43, v.
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Copyright © 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
3. Amirian ES, Goodman JC, New P, Scheurer ME. Pediatric and adult malignant peripheral nerve sheath tumors: an analysis of data from the surveillance, epidemiology, and end results program. J Neurooncol 2014;116:609–16. 4. Huang JH, Zhang J, Zager EL. Diagnosis and treatment options for nerve sheath tumors. Expert Rev Neurother 2005;5:515–23. 5. Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis II. Cancer Res 2002;62:1573–77. 6. Basso-Ricci S. Therapy of malignant schwannomas: usefulness of an integrated radiologic. Surgical therapy. J Neurosurg Sci 1989;33:253–7. 7. Doorn PF, Molenaar WM, Buter J, Hoekstra HJ. Malignant peripheral nerve sheath tumors in patients with and without neurofibromatosis. Eur J Surg Oncol 1995;21(1):78–82.
Case Reports
8. Greager JA, Reichard KW, Campana JP, et al. Malignant schwannoma of the head and neck. Am J Surg 1992;163:440–2. 9. Jakobiec FA, Font RL, Zimmerman LE. Malignant peripheral nerve sheath tumors of the orbit: a clinicopathologic study of eight cases. Tr Am Ophth Soc 1985;83:332–66. 10. Tsuchiya D, Hiroshi T, Saito K, Kashiwa H, Maeda K, Yamashita H. Immunohistochemical diagnosis of a rare case of epithelioid malignant peripheral nerve sheath tumor with multiple metastases. Jpn J Ophthalmol. 2004;48:565–9. 11. Rajabi MT, Riazi H, Hosseini SS, et al. Malignant peripheral nerve sheath tumor of lacrimal nerve: a case report. Orbit 2015;34:41–4. 12. Schmidt RF, Yick F, Boghani Z, et al. Malignant peripheral nerve sheath tumors of the trigeminal nerve: a systematic review of 36 cases. Neurosurg Focus 2013;34:E5.
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
e3
Copyright © 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
