Brain Pathology Case of the Month - August 2019

FINAL DIAGNOSIS

High grade intracerebral myxofibrosarcoma

DISCUSSION

Myxofibrosarcoma is a common malignant fibroblastic neoplasm with variably myxoid stroma and represents one of the most common soft tissue sarcoma types in elderly patients [1, 6]. It tends to arise in the extremities, whereas an origin in visceral organs, abdominal cavity, and retroperitoneum or intracranially is extremely rare [6]. Half of the cases develop in subcutaneous tissue and the rest of them deep in the fascia or the skeletal muscle [1]. The term myxofibrosarcoma was originally proposed by Angervall et al. back in 1977 and it was considered to be synonymous with the myxoid variant of malignant fibrous histiocytoma [1].

To the best of our knowledge eight cases of intracranial myxofibrosarcoma have been published until now in the English literature [2-5, 7, 9-13]. It should be noted that some of these cases regard extra-axial lesions infiltrating the brain parenchyma [6], whereas others represent radiation-induced neoplasms [9]. The exact prevalence of intracranial myxofibrosarcoma is hard to be determined with accuracy due to the continued evolution of classification and terminology. Some of the published cases mentioned in this review were designated as malignant fibrous histiocytoma-myxoid variant [11, 12]. Herein, we report the ninth case of a primary intracranial myxofibrosarcoma.

Although, myxofibrosarcoma shows a varying degree of pleomorphism, cellularity and proliferative activity depending on the histological grade, all cases share some common morphological features, including myxoid stroma and multinodular growth pattern with incomplete fibrous septa [6]. The presence of prominent, elongated, thin-walled blood vessels with perivascular aggregates of neoplastic cells is considered a characteristic histological finding, especially in low-grade myxofibrosarcomas [6]. World Health Organization (WHO) recommends a three-tier grading system (low-, intermediate- and high-grade tumors) [6].

Low-grade myxofibrosarcomas are hypocellular neoplasms composed of non-cohesive, stellated or spindled cells with ill-defined cytoplasm and hyperchromatic, atypical nuclei embedded in a myxoid matrix. Mitotic activity in these neoplasms is low. Intermediate-grade myxofibrosarcomas are more cellular and pleomorphic compered to low-grade neoplasms, but lack pronounced cellular pleomorphism and necrosis, which characterized the high-grade lesions. High-grade myxofibrosarcomas are hypercellular lesions composed of atypical cells with hyperchromatic nuclei and pronounced cellular pleomorphism, which are arranged in solid sheets. The myxoid stroma is variable whereas the mitotic activity is high in this tumor grade. Areas of hemorrhage and necrosis are common. Furthermore, pleomorphic, multinucleated, bizarre neoplastic cells are not an uncommon finding. The presence of low-grade areas in high-grade tumors and the histological progression of low- to high-grade lesion in recurrences indicate a continuum from low-, to intermediate- and high-grade neoplasms. Local recurrence is common and occurs in up to 50-60% of cases, regardless of the histological grade [6].

The neoplastic cells of myxofibrosarcomas exhibit ultrastructural features of a fibroblastic differentiation. Immunohistochemically, they show strong and diffuse positivity for vimentin. A focal immunoreactivity for SMA can be observed and is suggestive of focal myofibroblastic differentiation. Cytogenetic studies revealed that karyotypes of myxofibrosarcomas tend to be highly complex, with extensive intratumoral heterogeneity. Specific aberrations have not been observed [6].

The differential diagnosis of myxofibrosarcoma varies depending upon the location of the tumor. Specifically, the differential diagnosis of intracranial myxofibrosarcomas includes lesions with myxoid stroma, such as myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, and low-grade fibromyxoid sarcoma, all of which have been reported as intracranial lesions [3, 5, 7, 8], and other more common entities presented intracranially, such as glioblastomas and gliosarcomas. The final diagnosis is based mainly on morphological, immunohistochemical and even molecular findings.

Myxoid liposarcomas exhibit a plexiform vascular pattern ("chicken wire"), which can be highlighted with immunostains for endothelial markers, such as CD31, CD34 [6]. Lipoblasts may be observed, although their presence is not necessary for the diagnosis [6]. More than 95% of myxoid liposarcomas are characterized by the recurrent translocation t(12;16)(q13;p11), that results in FUS-DDIT3 gene fusion [6]. The remaining cases are characterized by the recurrent translocation t(12;22)(q13;q12), that results in EWSR1-DDIT3 gene fusion [6]. Immunohistochemically, the neoplastic cells of myxoid liposarcomas are positive for S-100 protein [6].

The neoplastic cells of extraskeletal myxoid chondrosarcomas are also positive for S-100 protein in up to 20% of cases and CD117 positive in up to 30% of cases [6]. More than 90% of extraskeletal myxoid chondrosarcomas are associated with NR4A3-fusions [t(9;22)(q22;q12), t(9;17)(q22;q11) and t(9;15)(q22;q21)], which have not been found in other sarcoma types and therefore considered as characteristic for this type of sarcoma [6].

Low-grade fibromyxoid sarcomas exhibit the same immunophenotype as myxofibrosarcomas, but unlike myxofibrosarcomas, they are associated with FUS translocation [6]. A FUS-CREB3L2 fusion [t(7;16)(q33;p11)] is detected in 76-96% of the cases of low-grade fibromyxoid sarcomas and a FUS-CREB3L1 fusion [t(11;16)(p11;p11)] in 4-6% of the cases [6].

Unlike myxoid liposarcomas, extraskeletal myxoid chondrosarcomas, low-grade fibromyxoid sarcomas and myxofibrosarcomas, the neoplastic cells of glioblastomas and partly (at least the astroglial component) of gliosarcomas are positive for GFAP.

In summary, we present a case of a myxofibrosarcoma arising in an unusual location. Pathologists, radiologists and clinicians should be aware of the possibility to encounter in their daily praxis intracranial sarcomas, which may resemble clinically and radiologically more common intracranial tumors, such as glioblastomas. It is therefore of outmost importance the combination of morphological, immunohistochemical and in some cases even molecular studies in the establishment of the final diagnosis.

REFERENCES

  1. Angervall L, Kindblom LG, Merck C (1977) Myxofibrosarcoma. A study of 30 cases. Acta Pathol Microbiol Scand A. 85A(2):127-140
  2. Buccoliero AM, Castiglione F, Garbini F, et al. (2011) Primary cerebral myxofibrosarcoma: clinical, morphologic, immunohistochemical, molecular, and ultrastructural study of an infrequent tumor in an extraordinary localization. J Pediatr Hematol Oncol. 33(7):e279-83.
  3. Chen N, Gong J, Nie L, et al. (2015) Primary intracranial low-grade fibromyxoid sarcoma with FUS gene rearrangement. Neuropathology. 35(4):348-353.
  4. Costa DA, Barata P, Gouveia E, Mafra M (2016) Right cardiac intracavitary metastases from a primary intracranial myxo fi brosarcoma. BMJ Case Rep. :1-5.
  5. Dulou R, Chargari C, Dagain A, et al. (2012) Primary intracranial extraskeletal myxoid chondrosarcoma. Neurol Neurochir Pol. 46(1):76-81.
  6. Fletcher CDM, Bridge JA, Hogendoorn PCW MF (2013) WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon.
  7. Guo L, Cao DB, Yan X, Zou YB, Ma HX (2013) Primary intracranial myxoid liposarcoma: report of a case. Zhonghua Bing Li Xue Za Zhi. 42(12):843-844.
  8. Iliadis A, Pazarli E, Chytoudis-Peroudis CC, Chondromatidou S, Tsitouridis I, Efstratiou I, et al. 74-year old female with a well circumscribed parietal lobe mass. Brain Pathol. (In Press). Jan 2018 case 2
  9. Kuo JR, Chio CC, Wang CC, Chu YH, Lin KC, Chuang SS (2008) Radiation-induced intra- and extra-cranial high-grade myxofibrosarcoma with tumor bleeding. J Clin Neurosci. 15(10):1151-1154.
  10. Majumdar K, Mandal S, Saran RK, Gupta R (2013) Recurrent intracranial myxofibrosarcoma presenting as an extensive fronto-parieto-occipital SOL: An unusual sarcoma of meningeal origin. Clin Neurol Neurosurg. 115(3):354-358.
  11. Oliveira AM, Scheithauer BW, Salomao DR, Parisi JE, Burger PC, Nascimento AG (2002) Primary sarcomas of the brain and spinal cord: a study of 18 cases. Am J Surg Pathol. 26(8):1056-1063.
  12. Paulus W, Slowik F, Jellinger K (1991) Primary intracranial sarcomas: histopathological features of 19 cases. Histopathology 18(5):395-402.
  13. Shukla P, Gupta D, Gupta P, et al. (2009) Myxofibrosarcoma of right fronto-temporal region with intracranial extension: A case report. Internet J Oncol. 6(1):1-5.

Contributed by Sotiris Sotiriou, Stavroula Pervana, Stella Chondromatidou, Ioannis Efstratiou, Dimitrios Kanakis

International Society of Neuropathology