EXTRAORDINARY CASE REPORT
Malignant Peripheral Nerve Sheath Tumor With Glandular Differentiation in a Patient With Neurofibromatosis Type 1 Alison A. Galatian, MD,* A. Neil Crowson, MD,†‡ Robert J. Fischer, MD, MPH,§ Edward H. Yob, DO,†¶ and Igor Shendrik, MD†‡
Abstract: The authors report an unusual case of malignant peripheral nerve sheath tumor with malignant differentiation arising as a subcutaneous nodule in the thigh of a 53-year-old woman with a history significant for neurofibromatosis type 1. Peripheral nerve sheath tumors containing a glandular component, commonly referred to as glandular peripheral nerve sheath tumors, are rare neoplasms found largely in patients with neurofibromatosis type 1. These tumors are frequently malignant; recognition of metastatic potential is made based on the atypical spindle-cell component. Rarely, as in our case, the glandular component is also histologically malignant. Only 5 such tumors have been described in the literature to date. Glandular differentiation, particularly with malignant features, can be a potentially misleading feature when found as a component of malignant peripheral nerve sheath tumors and raise a wide spectrum of differential diagnoses, including metastatic Sertoli-Leydig tumors. The patient is free of disease for 22 months after wide tumor reexcision, which contrasts with previously reported devastatingly poor prognosis of these tumors. Key Words: Malignant peripheral nerve sheath tumor, neurofibromatosis type 1, malignant peripheral nerve sheath tumor with glandular differentiation, glandular peripheral nerve sheath tumor (Am J Dermatopathol 2013;35:859–863)
INTRODUCTION Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder with many associated clinical findings and capacity for involvement of nearly every organ system. Cutaneous manifestations include café-au-lait macules, neurofibromas, hamartomas of the iris, and axillary or inguinal freckling. Neurofibromas have been clinically classified as cutaneous, subcutaneous, plexiform, or internal.1 Transformation of neurofibromas into malignant peripheral nerve sheath tumors (MPNSTs) occurs in approximately 10% of NF1 patients during their lifetime2 and represents the major cause of From the *Department of Dermatology, University of Oklahoma, College of Medicine, Oklahoma City, OK; †Oklahoma Department of Dermatology, University of Oklahoma, College of Medicine, Oklahoma City, OK; ‡Dermatopathology Section, Regional Medical Laboratory, Tulsa, OK; §Department of Internal Medicine, University of Oklahoma, College of Medicine, Oklahoma City, OK; and ¶Tulsa Cancer Institute – Skin Cancer Center, Tulsa, OK. The authors declare no conflicts of interest. Reprints: Alison A. Galatian, MD, 619 NE 13th Street, Oklahoma City, OK 73104 (e-mail: [email protected]). © 2013 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 35, Number 8, December 2013
disease-specific death in NF1 patients3–5; MPNSTs are significantly associated with the presence of internal NFs.6,7 Histologically, MPNSTs are spindle-cell tumors arising in conjunction to peripheral nerves. More than half of MPNSTs arise in conjunction with NF1; the others are thought to arise spontaneously. These are aggressive tumors with high rates of local recurrence and metastases. Even with aggressive treatment, 5-year survival rates still range from 35% to 50%.8–11 The prognosis for MPNST arising in association with NF1 seems to be worse than for spontaneous tumors—a recent study of 140 patients found a disease-specific survival of 35% for patients with NF1 and 50% for patients with no history of NF1,11 although this has not been a consistent finding in all studies.8–10,12,13 Other factors that have been found to be associated with a poor prognosis include size .10 cm at diagnosis, metastasis, partial resection of the primary tumor, and lack of S-100 staining.11 Those examples with malignant glandular epithelium may have even higher mortality; all 4 previous cases reported with known follow-up proved to be fatal within 3 years of diagnosis (Table 1).14–17
CASE REPORT A 52-year-old white female with a history significant for NF1 presented to the dermatology clinic with complaints of a subcutaneous nodule of the left lateral thigh of approximately 1-year duration. The tumor had recently increased in size and developed a tingling sensation. On physical examination, she had a 1.5-cm subcutaneous nodule clinically suggestive of a lipoma. Excisional biopsy showed MPNST with glandular differentiation that contained histologically malignant epithelium. Magnetic resonance imaging of the left lower extremity revealed postsurgical enhancing tissue in the lateral thigh with no evidence of deeper involvement. Computed tomography scans of the abdomen and pelvis showed no evidence of previously undiagnosed primary tumor or of metastatic disease. She underwent wide local excision of the left lateral thigh and sentinel lymph node evaluation; surgical margins were free of tumor. Three inguinal sentinel lymph nodes were negative for malignancy. At the time of case submission, she has had no clinical recurrence or signs of metastatic disease at 22 months out from surgical therapy.
PATHOLOGICAL FINDINGS
Grossly, the tumor measured 1.8 · 1.3 · 1.3 cm, and on cut section, the tumor was firm and tan-pink-brown. The lesion appeared to be well circumscribed but not encapsulated and was shelled out with surgical ink identified at the margins. No surrounding normal soft tissue was identified, and no connection to the nerve was seen. Microscopically, it consisted of www.amjdermatopathology.com |
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TABLE 1. Clinical and Pathological Features of Malignant Peripheral Nerve Sheath Tumors with Histologically Malignant Glandular Component Case Number
Age/Sex/NF1
1
Clinical Outcome
Immunohistochemical Studies
Location
Histological Dx
Unknown
Retroperitoneum
MPNST with MGE
Unknown
Unavailable
2
39/Male/No
Superior Mediastinum
MPNST with MGE
Died with disease at 7 mo
3
39/Male/No
Overlying T1–T4
MPNST with MGE and RMD
Died with disease at 15 months
4
29/Male/Yes
Neck
MPNST with MGE
Died with disease at 34 months
5
24/Male/No
Thigh
MPNST with MGE and RMD
Died with disease at 6 months
6
53/Female/Yes
Thigh
MPNST with MGE
Disease free at 22 months from diagnosis
Spindle cells: vimentin+, S-100+, desmin2, GFAP2Glandular cells: EMA+, chromogranin+, keratin+, gastrin+, serotonin+, somatostatin+ Spindle cells: vimentin+, S-100+, NSE+ Glandular cells: EMA+, CEA+, keratin+, chromogranin2, AFP2 Spindle cells: vimentin+, S-100+Glandular cells: Keratin+, EMA+, CAM+, CEA+, chromogranin+, calcitonin+, somatostatin+ Spindle cells: vimentin+, S100+, GFAP+/2Glandular cells: chromogranin+, CK20+/2, CK72 Spindle cells: S-100+, inhibin+, Melan A+Glandular cells: AE1/3+, CK20+, CDX2+, synaptophysin+, chromogranin+
Reference Woodruff and Christensen2 Woodruff and Christensen2
Wong et al3
Nagasaka et al4
Huang et al1
Present case
AFP, alpha-fetoprotein; CEA, carcinoembryonic antigen; EMA, epithelial membrane antigen; GFAP, glial fibrillary acid protein; MGE, malignant glandular epithelium; NSE, neuron-specific enolase; RMD, rhabdomyoblastic differentiation.
a biphasic population on low power view (Fig. 1). The major portion of the tumor was occupied by a dense, monotonous population of spindle cells with a fascicular and trabecular architecture. Cytologically, atypical cells and numerous mitoses were present (Fig. 2A). Some of the trabecular areas mimicked abortive tubular structures resembling primitive neural tube. Trabecular areas were supported by a fibrous stroma. The spindle-cell component transitioned into glandular structures that varied widely in terms of size and appearance—some having a distinctly neuroendocrine in appearance (Fig. 2B), and others showing large intracytoplasmic mucin containing vacuoles with a goblet cell appearance (Fig. 2C). Malignant cytological features, including nuclear pleomorphism and mitoses, were visible in both components.
IMMUNOHISTOCHEMICAL FINDINGS Immunohistochemical (IHC) studies were performed by IHC staining using the Ventana Benchmark automated slide stainer and the biotinylated IgG/streptavidin-peroxidase iView DAB detection kit (Ventana Medical Systems, Tucson, AZ) according to product instructions method using monoclonal or polyclonal antibodies against the following antigens: AE1/3, cytokeratin 5/6, cytokeratin 7, cytokeratin 20, CDX2, synaptophysin, chromogranin, S-100, inhibin, Melan A, neural cell adhesion molecule (NCAM; CD56), WT1, glial fibrillary acid protein (GFAP), TTF-1, and mammoglobin. The spindle-cell
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proliferation was diffusely but weakly immunoreactive for S-100 (Fig. 3A), Inhibin (Fig. 3B), Melan A, and CD56 and focally immunoreactive for WT1 and AE1/3. The glandular epithelial component lining was positive for AE1/3, CK20, CDX2, synaptophysin, and chromogranin (Fig. 3C), with focal positivity for CK5/6 and CK7. No immunoreactivity in either component was found for GFAP, TTF-1, or mammoglobin.
DISCUSSION The MPNSTs are soft tissue sarcomas of ectomesenchymal origin with marked metastatic potential and poor prognosis. Although it is not uncommon for these tumors to show divergent differentiation with heterotopic rhabdoid, chondroid, myoid, epithelial, and osteoid elements, PNSTs containing a glandular component, commonly referred to as glandular PNSTs, are rare tumors found largely in patients with NF1.2 Up to 92% of glandular PNSTs are malignant, consisting of a malignant spindle-cell stroma and benignappearing glands.2 The malignant potential of a glandular PNST is usually determined by the character of the spindlecell component.2 It is especially rare for MPNSTs to contain glandular elements with malignant features, and to our knowledge, only 5 cases with malignant glandular components have been previously described in the literature (Table 1). The clinical behavior of glandular MPNST is aggressive, with 2013 Lippincott Williams & Wilkins
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Malignant Peripheral Nerve Sheath Tumor
FIGURE 1. The tumor specimen shows a biphasic population of spindled cellular areas and glandular spaces on low power view.
all previously reported cases progressing to metastatic disease and death from 6 months to 3 years after diagnosis. The principal differential diagnosis includes benign and malignant soft tissue tumors. The benign tumor most likely to be confused with glandular PNST is the schwannoma with entrapped epithelium.18–20 To make the diagnosis of glandular PNST, evidence supporting a true glandular component may be necessary. The glands should have characteristic components of epithelium21 that are not entrapped or pseudoglandular in appearance.22 The glands of entrapped sweat glands, however, are surrounded by a myoepithelial lining, unlike glandular elements within glandular PNST.2 Biphasic synovial sarcoma with glands is a malignant tumor most readily confused with glandular MPNST; it is stated that the glandular structures of synovial sarcoma should be devoid of neuroendocrine cells with stromal cells rarely expressing S-100 and more frequently keratins.21 A sharp distinction between the spindle and glandular components is lacking, and goblet cells are absent. Our case demonstrates a distinctly biphasic appearance with the spindle areas showing a fascicular and trabecular architecture composed of cytologically malignant spindle cells, admixed with cytologically malignant glandular structures containing goblet cells, thus resembling bowel epithelium. The tumor showed a weak S-100 positivity within the spindle-cell component, whereas the glandular epithelium expressed AE1/AE3, CDX2, synaptophysin, and chromogranin, supporting the diagnosis of glandular MPNST. In addition, the tumor shows a hitherto unreported positivity of spindle cells with Melan-A, Inhibin, WT-1, and CD56, raising the differential diagnosis of metastatic ovarian Sertoli-Leydig cell tumor with heterologous elements. However, the clinical history of NF1, the presence of areas classic for MPNST, and clinical follow-up without presentation of a primary ovarian tumor by clinical imaging criteria are all consistent with the diagnosis of glandular MPNST. The combined expression of Melan A, WT-1, and Inhibin is 2013 Lippincott Williams & Wilkins
FIGURE 2. A, Monotonous population of spindle cells with a fascicular and trabecular architecture. Cells display cytological atypia and numerous mitoses. B, The spindle-cell component transitions to glandular structures, some having a distinctly neuroendocrine appearance. C, Other glandular structures within the tumor display large intracytoplasmic mucin-containing vacuoles with a goblet cell appearance. www.amjdermatopathology.com |
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unusual and is described in the context of sex cord stromal tumors.23 Expression of WT-1 is noted in most MPNST,24 and rare cases of Melan A expression are reported. The latter is considered an indicator of melanocytic differentiation, leading to the proposed appellation of “malignant neuroectodermal tumor with melanocytic differentiation.”25 Inhibin expression is hitherto undescribed in MPNST; we might hypothesize the possibility of adrenal cortical differentiation in this instance. In summary, we report an extraordinarily rare case of glandular MPNST with unusual morphological and IHC findings, raising the differential diagnosis of metastatic ovarian Sertoli-Leydig cell tumor. The morphological and immunohistochemical heterogeneity of the present case supports the general concept of divergent differentiation of MPNSTs and expands the differential diagnosis of these neoplasms. The unremarkable follow-up of the patient, which may be related to the relatively small size of the tumor at presentation, indicates the possibility of long-term disease-free survival despite aggressive behavior of all previously reported glandular MPNSTs. REFERENCES
FIGURE 3. A, The spindle-cell proliferation shows diffuse but weak positivity for S-100. B, The spindle-cell proliferation shows diffuse positivity for inhibin. C, The glandular epithelial component lining shows positivity for chromogranin.
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1. Huang L, Espinoza C, Welsh R. Malignant peripheral nerve sheath tumor with divergent differentiation. Arch Pathol Lab Med. 2003;127:e147– e150. 2. Woodruff JM, Christensen WN. Glandular peripheral nerve sheath tumors. Cancer. 1993;72:3618–3628. 3. Wong SY, Teh M, Tan YO, et al. Malignant glandular Triton tumor. Cancer. 1991;67:1076–1083. 4. Nagasaka T, Lai R, Sone M, et al. Glandular malignant peripheral nerve sheath tumor: an unusual case showing histologically malignant glands. Arch Pathol Lab Med. 2000;124:1364–1368 5. Ricardi VM. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Baltimore, MD: John Hopkins University Press; 1992. 6. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumors in neurofibromatosis 1. J Med Genet. 2002;39:311–314. 7. Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet. 2001;68: 1110–1118. 8. Duong TA, Sbidian E, Valeyrie-Allanore L, et al. Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980-2006 in France. Orphanet J Rare Dis. 2011;4:6–18. 9. Evans DG, O’Hara C, Wilding A, et al. Mortality in neurofibromatosis 1 in North West England: an assessment of actual survival in a region of the UK since 1989. Eur J Hum Genet. 2011;19:1187–1191. 10. Tucker T, Wolkenstein P, Revuz J, et al. Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology. 2005;65: 205–211. 11. Zehou O, Bularca S, Bastuji-Garin S, et al. Neurofibromatosis 1 phenotype associated to malignant peripheral nerve sheath tumours: a casecontrol study. J Eur Acad Dermatol Venereol. 2012. DOI: 10.1111/j. 1468–3083.2012.04485.x. 12. Anghileri M, Miceli R, Fiore M, et al. Malignant peripheral nerve sheath tumors: prognostic factors and survival in a series of patients treated at a single institution. Cancer. 2006;107:1065–1074. 13. Carli M, Ferrari A, Mattke A, et al. Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J Clin Oncol. 2005;23:8422–8430. 14. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer. 1986;57:2006–2021. 15. Zou C, Smith KD, Liu J, et al. Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome. Ann Surg. 2009;6:1014–1022. 16. Okada K, Hasegawa T, Tajino T, et al. Clinical relevance of pathological grades of malignant peripheral nerve sheath tumor: a multi-institution TMTS study of 56 cases in Northern Japan. Ann Surg Oncol. 2007;14:597–604.
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17. Hagel C, Zils U, Peiper M, et al. Histopathology and clinical outcome of NF1-associated vs sporadic malignant peripheral nerve sheath tumors. J Neurooncol. 2007;82:187–192. 18. Fletcher CDM, Madziwa D, Heyderman E, et al. Benign dermal schwannoma with glandular elements: true heterology or a local ‘organizer’ effect. Clin Exp Dermatol. 1986;11:475–485. 19. Brooks JJ, Drafen RM. Benign glandular schwannoma. Arch Pathol Lab Med. 1992;116:192–195. 20. Allegranza A, Ferraresi S, Luccarelli G. Malignant glandular schwannoma: a case with favorable prognosis. Histopathology. 1988;12:549–552. 21. Christensen WN, Strong EW, Bains MS, et al. Neuroendocrine differentiation in the glandular peripheral nerve sheath tumor: pathologic
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22. 23. 24. 25.
distinction from the biphasic synovial sarcoma with glands. Am J Surg Pathol. 1988;12:417–426. Ferry JA, Dickerson GR. Pseudoglandular schwannoma. Am J Clin Pathol. 1988;89:546–552. Zhao C, Vinh TN, McManus K, et al. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol. 2009;33:354–366. Schittenhelm J, Thiericke J, Nagel C, et al. WT1 expression in normal and neoplastic cranial and peripheral nerves is independent of grade of malignancy. Cancer Biomark. 2010;7:73–77. Tanas MR, Rubin BP. Malignant neuroectodermal tumor with melanocytic and rhabdomyoblastic differentiation. Rare Tumors. 2009;1:e26.
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Malignant Peripheral Nerve Sheath Tumor With Glandular Differentiation in a Patient With Neurofibromatosis Type 1 Alison A. Galatian, MD,* A. Neil Crowson, MD,†‡ Robert J. Fischer, MD, MPH,§ Edward H. Yob, DO,†¶ and Igor Shendrik, MD†‡
Abstract: The authors report an unusual case of malignant peripheral nerve sheath tumor with malignant differentiation arising as a subcutaneous nodule in the thigh of a 53-year-old woman with a history significant for neurofibromatosis type 1. Peripheral nerve sheath tumors containing a glandular component, commonly referred to as glandular peripheral nerve sheath tumors, are rare neoplasms found largely in patients with neurofibromatosis type 1. These tumors are frequently malignant; recognition of metastatic potential is made based on the atypical spindle-cell component. Rarely, as in our case, the glandular component is also histologically malignant. Only 5 such tumors have been described in the literature to date. Glandular differentiation, particularly with malignant features, can be a potentially misleading feature when found as a component of malignant peripheral nerve sheath tumors and raise a wide spectrum of differential diagnoses, including metastatic Sertoli-Leydig tumors. The patient is free of disease for 22 months after wide tumor reexcision, which contrasts with previously reported devastatingly poor prognosis of these tumors. Key Words: Malignant peripheral nerve sheath tumor, neurofibromatosis type 1, malignant peripheral nerve sheath tumor with glandular differentiation, glandular peripheral nerve sheath tumor (Am J Dermatopathol 2013;35:859–863)
INTRODUCTION Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder with many associated clinical findings and capacity for involvement of nearly every organ system. Cutaneous manifestations include café-au-lait macules, neurofibromas, hamartomas of the iris, and axillary or inguinal freckling. Neurofibromas have been clinically classified as cutaneous, subcutaneous, plexiform, or internal.1 Transformation of neurofibromas into malignant peripheral nerve sheath tumors (MPNSTs) occurs in approximately 10% of NF1 patients during their lifetime2 and represents the major cause of From the *Department of Dermatology, University of Oklahoma, College of Medicine, Oklahoma City, OK; †Oklahoma Department of Dermatology, University of Oklahoma, College of Medicine, Oklahoma City, OK; ‡Dermatopathology Section, Regional Medical Laboratory, Tulsa, OK; §Department of Internal Medicine, University of Oklahoma, College of Medicine, Oklahoma City, OK; and ¶Tulsa Cancer Institute – Skin Cancer Center, Tulsa, OK. The authors declare no conflicts of interest. Reprints: Alison A. Galatian, MD, 619 NE 13th Street, Oklahoma City, OK 73104 (e-mail: [email protected]). © 2013 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 35, Number 8, December 2013
disease-specific death in NF1 patients3–5; MPNSTs are significantly associated with the presence of internal NFs.6,7 Histologically, MPNSTs are spindle-cell tumors arising in conjunction to peripheral nerves. More than half of MPNSTs arise in conjunction with NF1; the others are thought to arise spontaneously. These are aggressive tumors with high rates of local recurrence and metastases. Even with aggressive treatment, 5-year survival rates still range from 35% to 50%.8–11 The prognosis for MPNST arising in association with NF1 seems to be worse than for spontaneous tumors—a recent study of 140 patients found a disease-specific survival of 35% for patients with NF1 and 50% for patients with no history of NF1,11 although this has not been a consistent finding in all studies.8–10,12,13 Other factors that have been found to be associated with a poor prognosis include size .10 cm at diagnosis, metastasis, partial resection of the primary tumor, and lack of S-100 staining.11 Those examples with malignant glandular epithelium may have even higher mortality; all 4 previous cases reported with known follow-up proved to be fatal within 3 years of diagnosis (Table 1).14–17
CASE REPORT A 52-year-old white female with a history significant for NF1 presented to the dermatology clinic with complaints of a subcutaneous nodule of the left lateral thigh of approximately 1-year duration. The tumor had recently increased in size and developed a tingling sensation. On physical examination, she had a 1.5-cm subcutaneous nodule clinically suggestive of a lipoma. Excisional biopsy showed MPNST with glandular differentiation that contained histologically malignant epithelium. Magnetic resonance imaging of the left lower extremity revealed postsurgical enhancing tissue in the lateral thigh with no evidence of deeper involvement. Computed tomography scans of the abdomen and pelvis showed no evidence of previously undiagnosed primary tumor or of metastatic disease. She underwent wide local excision of the left lateral thigh and sentinel lymph node evaluation; surgical margins were free of tumor. Three inguinal sentinel lymph nodes were negative for malignancy. At the time of case submission, she has had no clinical recurrence or signs of metastatic disease at 22 months out from surgical therapy.
PATHOLOGICAL FINDINGS
Grossly, the tumor measured 1.8 · 1.3 · 1.3 cm, and on cut section, the tumor was firm and tan-pink-brown. The lesion appeared to be well circumscribed but not encapsulated and was shelled out with surgical ink identified at the margins. No surrounding normal soft tissue was identified, and no connection to the nerve was seen. Microscopically, it consisted of www.amjdermatopathology.com |
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TABLE 1. Clinical and Pathological Features of Malignant Peripheral Nerve Sheath Tumors with Histologically Malignant Glandular Component Case Number
Age/Sex/NF1
1
Clinical Outcome
Immunohistochemical Studies
Location
Histological Dx
Unknown
Retroperitoneum
MPNST with MGE
Unknown
Unavailable
2
39/Male/No
Superior Mediastinum
MPNST with MGE
Died with disease at 7 mo
3
39/Male/No
Overlying T1–T4
MPNST with MGE and RMD
Died with disease at 15 months
4
29/Male/Yes
Neck
MPNST with MGE
Died with disease at 34 months
5
24/Male/No
Thigh
MPNST with MGE and RMD
Died with disease at 6 months
6
53/Female/Yes
Thigh
MPNST with MGE
Disease free at 22 months from diagnosis
Spindle cells: vimentin+, S-100+, desmin2, GFAP2Glandular cells: EMA+, chromogranin+, keratin+, gastrin+, serotonin+, somatostatin+ Spindle cells: vimentin+, S-100+, NSE+ Glandular cells: EMA+, CEA+, keratin+, chromogranin2, AFP2 Spindle cells: vimentin+, S-100+Glandular cells: Keratin+, EMA+, CAM+, CEA+, chromogranin+, calcitonin+, somatostatin+ Spindle cells: vimentin+, S100+, GFAP+/2Glandular cells: chromogranin+, CK20+/2, CK72 Spindle cells: S-100+, inhibin+, Melan A+Glandular cells: AE1/3+, CK20+, CDX2+, synaptophysin+, chromogranin+
Reference Woodruff and Christensen2 Woodruff and Christensen2
Wong et al3
Nagasaka et al4
Huang et al1
Present case
AFP, alpha-fetoprotein; CEA, carcinoembryonic antigen; EMA, epithelial membrane antigen; GFAP, glial fibrillary acid protein; MGE, malignant glandular epithelium; NSE, neuron-specific enolase; RMD, rhabdomyoblastic differentiation.
a biphasic population on low power view (Fig. 1). The major portion of the tumor was occupied by a dense, monotonous population of spindle cells with a fascicular and trabecular architecture. Cytologically, atypical cells and numerous mitoses were present (Fig. 2A). Some of the trabecular areas mimicked abortive tubular structures resembling primitive neural tube. Trabecular areas were supported by a fibrous stroma. The spindle-cell component transitioned into glandular structures that varied widely in terms of size and appearance—some having a distinctly neuroendocrine in appearance (Fig. 2B), and others showing large intracytoplasmic mucin containing vacuoles with a goblet cell appearance (Fig. 2C). Malignant cytological features, including nuclear pleomorphism and mitoses, were visible in both components.
IMMUNOHISTOCHEMICAL FINDINGS Immunohistochemical (IHC) studies were performed by IHC staining using the Ventana Benchmark automated slide stainer and the biotinylated IgG/streptavidin-peroxidase iView DAB detection kit (Ventana Medical Systems, Tucson, AZ) according to product instructions method using monoclonal or polyclonal antibodies against the following antigens: AE1/3, cytokeratin 5/6, cytokeratin 7, cytokeratin 20, CDX2, synaptophysin, chromogranin, S-100, inhibin, Melan A, neural cell adhesion molecule (NCAM; CD56), WT1, glial fibrillary acid protein (GFAP), TTF-1, and mammoglobin. The spindle-cell
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proliferation was diffusely but weakly immunoreactive for S-100 (Fig. 3A), Inhibin (Fig. 3B), Melan A, and CD56 and focally immunoreactive for WT1 and AE1/3. The glandular epithelial component lining was positive for AE1/3, CK20, CDX2, synaptophysin, and chromogranin (Fig. 3C), with focal positivity for CK5/6 and CK7. No immunoreactivity in either component was found for GFAP, TTF-1, or mammoglobin.
DISCUSSION The MPNSTs are soft tissue sarcomas of ectomesenchymal origin with marked metastatic potential and poor prognosis. Although it is not uncommon for these tumors to show divergent differentiation with heterotopic rhabdoid, chondroid, myoid, epithelial, and osteoid elements, PNSTs containing a glandular component, commonly referred to as glandular PNSTs, are rare tumors found largely in patients with NF1.2 Up to 92% of glandular PNSTs are malignant, consisting of a malignant spindle-cell stroma and benignappearing glands.2 The malignant potential of a glandular PNST is usually determined by the character of the spindlecell component.2 It is especially rare for MPNSTs to contain glandular elements with malignant features, and to our knowledge, only 5 cases with malignant glandular components have been previously described in the literature (Table 1). The clinical behavior of glandular MPNST is aggressive, with 2013 Lippincott Williams & Wilkins
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Malignant Peripheral Nerve Sheath Tumor
FIGURE 1. The tumor specimen shows a biphasic population of spindled cellular areas and glandular spaces on low power view.
all previously reported cases progressing to metastatic disease and death from 6 months to 3 years after diagnosis. The principal differential diagnosis includes benign and malignant soft tissue tumors. The benign tumor most likely to be confused with glandular PNST is the schwannoma with entrapped epithelium.18–20 To make the diagnosis of glandular PNST, evidence supporting a true glandular component may be necessary. The glands should have characteristic components of epithelium21 that are not entrapped or pseudoglandular in appearance.22 The glands of entrapped sweat glands, however, are surrounded by a myoepithelial lining, unlike glandular elements within glandular PNST.2 Biphasic synovial sarcoma with glands is a malignant tumor most readily confused with glandular MPNST; it is stated that the glandular structures of synovial sarcoma should be devoid of neuroendocrine cells with stromal cells rarely expressing S-100 and more frequently keratins.21 A sharp distinction between the spindle and glandular components is lacking, and goblet cells are absent. Our case demonstrates a distinctly biphasic appearance with the spindle areas showing a fascicular and trabecular architecture composed of cytologically malignant spindle cells, admixed with cytologically malignant glandular structures containing goblet cells, thus resembling bowel epithelium. The tumor showed a weak S-100 positivity within the spindle-cell component, whereas the glandular epithelium expressed AE1/AE3, CDX2, synaptophysin, and chromogranin, supporting the diagnosis of glandular MPNST. In addition, the tumor shows a hitherto unreported positivity of spindle cells with Melan-A, Inhibin, WT-1, and CD56, raising the differential diagnosis of metastatic ovarian Sertoli-Leydig cell tumor with heterologous elements. However, the clinical history of NF1, the presence of areas classic for MPNST, and clinical follow-up without presentation of a primary ovarian tumor by clinical imaging criteria are all consistent with the diagnosis of glandular MPNST. The combined expression of Melan A, WT-1, and Inhibin is 2013 Lippincott Williams & Wilkins
FIGURE 2. A, Monotonous population of spindle cells with a fascicular and trabecular architecture. Cells display cytological atypia and numerous mitoses. B, The spindle-cell component transitions to glandular structures, some having a distinctly neuroendocrine appearance. C, Other glandular structures within the tumor display large intracytoplasmic mucin-containing vacuoles with a goblet cell appearance. www.amjdermatopathology.com |
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unusual and is described in the context of sex cord stromal tumors.23 Expression of WT-1 is noted in most MPNST,24 and rare cases of Melan A expression are reported. The latter is considered an indicator of melanocytic differentiation, leading to the proposed appellation of “malignant neuroectodermal tumor with melanocytic differentiation.”25 Inhibin expression is hitherto undescribed in MPNST; we might hypothesize the possibility of adrenal cortical differentiation in this instance. In summary, we report an extraordinarily rare case of glandular MPNST with unusual morphological and IHC findings, raising the differential diagnosis of metastatic ovarian Sertoli-Leydig cell tumor. The morphological and immunohistochemical heterogeneity of the present case supports the general concept of divergent differentiation of MPNSTs and expands the differential diagnosis of these neoplasms. The unremarkable follow-up of the patient, which may be related to the relatively small size of the tumor at presentation, indicates the possibility of long-term disease-free survival despite aggressive behavior of all previously reported glandular MPNSTs. REFERENCES
FIGURE 3. A, The spindle-cell proliferation shows diffuse but weak positivity for S-100. B, The spindle-cell proliferation shows diffuse positivity for inhibin. C, The glandular epithelial component lining shows positivity for chromogranin.
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