Final Diagnosis -- High-grade Malignant Peripheral Nerve Sheath Tumor


FINAL DIAGNOSIS

High-grade malignant peripheral nerve sheath tumor arising in a background of diffuse neurofibroma.

DISCUSSION

Malignant peripheral nerve sheath tumors (MPNST) are neoplasms of nerve sheath derivation that account for approximately 10% or less of soft tissue sarcomas [1]. About half of the cases of MPNST arise in the setting of neurofibromatosis type 1 (NF1), with a lifetime risk of approximately 10%, with the remaining cases occurring sporadically or secondary to therapeutic irradiation [2]. Those cases of MPNST occurring in the setting of NF1 usually arise from a pre-existing plexiform neurofibroma. However, in extremely rare cases, NF1 associated MPNST has been demonstrated to arise from diffuse neurofibromas as was observed in our case [3].

MPNSTs tend to occur in adult patients with a mean age of 35 but have also been reported to infrequently occur in children typically with a history of NF1. Presenting symptoms are relatively non-specific, consisting of an enlarging mass that may or may not be painful, and other than evidence of arising from a large peripheral nerve or from a neurofibroma in a patient known to have NF1, there are no distinct radiographic characteristics that would help distinguish MPNST from other soft tissue sarcomas [2, 4].

Grossly, MPNSTs tend to be large deep-seated masses with a fleshy cut surface containing hemorrhage and necrosis that most commonly arise at sites with large nerve trunks, such as the proximal upper and lower extremities involving the brachial plexus and sciatic nerve, respectively[2-4].

Histopathologically, conventional MPNSTs are composed of densely cellular spindle to ovoid cells with wavy or buckled nuclei and indistinct cytoplasm that are arranged in sweeping fascicles that alternate with less cellular myxoid areas, which imparts a marbled appearance to the tumor at low power. Areas of geographic necrosis may be extensive, in which case the tumor cell may be seen to be accentuated around blood vessels, a pattern which is referred to as peritheliomatous. Heterologous differentiation may be seen in a subset of MPNST, approximately 15%, which may include any of the mesenchymal lines of differentiation, including skeletal muscle, which is termed a malignant triton tumor. In addition, a small subset of MPNST, less than 5%, may be composed of an epithelioid morphology rather than a conventional spindle cell pattern and is referred to as an epithelioid MPNST [2, 4].

The diagnosis of neurfibromatous lesions, especially MPNST in the setting of NF1, adds an additional level of complexity due to a progressive histologic spectrum from benign neurofibroma to high-grade MPNST that includes borderline lesions. However, a recent consensus overview describing the diagnostic criteria has been established to aid in classification of these challenging lesions [4, 5].

Whether MPNSTs arise in the setting of NF1, sporadically, or secondary to ratiation therapy, molecular studies have demonstrated a complex karotypes with frequent inactivating mutations in NF1, CDKN2A/CDKN2B, and components of the polycomb repressive complex 2 (PRC2) including EED and SUZ12 [4]. Interestingly, the PRC2 complex is involved in the trimethylation of histone H3K27, and inactivating mutations of its components with subsequent loss of trimethylation form the basis for the development of a new immunohistochemical marker, H3K27me3, to help aid in the diagnosis of MPNST [6-8].

Immunohistochemistry, unfortunately, plays a limited role in the diagnosis of MPNST as there are no markers that are diagnostic, and the main role is to rule out histologic mimickers [2]. However, around 50% of conventional MPNSTs will have focal to patchy expression of S100 and SOX-10 (with the epithelioid type having diffuse staining with loss of SMARB1 expression) eluding to its nerve sheath derivation [2, 4]. As mentioned previously, a newly discovered marker, H3K27me3, has shown potential promise in the diagnosis of conventional MPNST, being completely lost in cases of sporadic, NF1 associated, and post-radiation induced tumors (no loss in epithelioid MPNST) [2, 6-8]. However, as additional studies have been done in other tumor types, it is becoming clear that this maker is not as specific as was initially thought as loss has been observed in several other soft tissue sarcomas and melanomas [2, 6].

MPNSTs are highly aggressive neoplasm with poor prognosis even with advances in surgical technique and therapuetics (radiation/chemotherapy). In several large studies, both local recurences and distant metastasis developed in approximately 40% of cases within one year [9-11]. Overall survival for conventional MPNST has a reported 5-year survival of 51% that drops to 41% at 10-years, and malignat Triton tumors have an even more aggressive clinical course with a reported 5-year survival of 10% [2].

In conclusion, MPNSTs are diagnostically challenging neoplams with an aggressive clinical course and poor prognosis arising in the setting of either NF1, sporadically, or post radiation therapy.

REFERENCES

  1. Le Guellec S, Decouvelaere A-V, Filleron T, et al. Malignant Peripheral Nerve Sheath Tumor Is a Challenging Diagnosis: A Systematic Pathology Review, Immunohistochemistry, and Molecular Analysis in 160 Patients From the French Sarcoma Group Database. The American Journal of Surgical Pathology. 2016;40(7):896-908. doi:10.1097/PAS.0000000000000655
  2. Goldblum JR, Folpe AL, Weiss SW, Enzinger FM. Malignant Peripheral Nerve Sheath Tumors. In: Enzinger and Weiss's Soft Tissue Tumors. 7th ed. Philadelphia, PA: Elsevier Saunders; 2020:959-987.
  3. Schaefer I-M, Fletcher CDM. Malignant Peripheral Nerve Sheath Tumor (MPNST) Arising in Diffuse-type Neurofibroma: Clinicopathologic Characterization in a Series of 9 Cases. The American Journal of Surgical Pathology. 2015;39(9):1234-1241. doi:10.1097/PAS.0000000000000447
  4. Nielsen GP, Chi P. Malignant peripheral nerve sheath tumour. In: WHO Classification of Tumours. Editorial Board. Soft tissue and bone tumours. 5th ed. Lyon: IARC; 2020: 254-257.
  5. Miettinen MM, Antonescu CR, Fletcher CDM, et al. Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview. Human Pathology. 2017;67:1-10. doi:10.1016/j.humpath.2017.05.010
  6. Cleven AHG, Al Sannaa GA, Bruijn IB, et al. Loss of H3K27 tri-methylation is a diagnostic marker for Malignant Peripheral Nerve Sheath Tumors and an indicator for an inferior survival. Mod Pathol. 2016;29(6):582-590. doi:10.1038/modpathol.2016.45
  7. Schaefer I-M, Fletcher CD, Hornick JL. Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Modern Pathology. 2016;29(1):4-13. doi:10.1038/modpathol.2015.134
  8. Prieto-Granada CN, Wiesner T, Messina JL, Jungbluth AA, Chi P, Antonescu CR. Loss of H3K27me3 Expression Is a Highly Sensitive Marker for Sporadic and Radiation-induced MPNST. Am J Surg Pathol. 2016;40(4):479-489. doi:10.1097/PAS.0000000000000564
  9. 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(2):597-604. doi:10.1245/s10434-006-9053-5
  10. Zou C, Smith KD, Liu J, et al. Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome. Ann Surg. 2009;249(6):1014-1022. doi:10.1097/SLA.0b013e3181a77e9a
  11. 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(5):1065-1074. doi:10.1002/cncr.22098

Contributed by Bruce D. Leckey Jr. DO, Ivy John, MD




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