A rare case of an adult primary intracranial sarcoma associated with a DICER1 mutation

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To the Editor: Primary intracranial malignant mesenchymal tumors remain a universal diagnostic challenge for neuropathologists. This challenge is not only because of their rarity but also because of their perplexing histologic heterogeneity. Herein, we report a case involving a 22-year-old man with a primary brain tumor that was histologically characterized as a spindle cell neoplasm. The patient underwent an initial left frontal craniotomy for resection of a large mass that required a second resection a few months later due to significant, rapid recurrence. Ultimately, genetic testing and deoxyribonucleic acid (DNA) methylation profiling provided the crucial information necessary to make the diagnosis of a primary intracranial sarcoma, DICER1-mutant. This report highlights the integrated histologic, immunohistochemical (IHC), molecular, and epigenetic characterization of an adult primary intracranial sarcoma, DICER1-mutant. Additionally, this case further emphasizes the critical importance of methylome profiling and genetic analysis to avoid misdiagnosis and achieve appropriate tumor subclassification. The potential oncogenicity of the DICER1 gene was first described in 2007 by a research group studying precursor lesions involving adenocarcinomas of the lung (1). It was only recently discovered that pathogenic germline mutations of the DICER1 gene were recognized as a unique pleiotropic tumor syndrome primarily associated with an increased risk of benign and malignant tumors (2). It should also be noted that DICER1 mutations can be somatically acquired after postzygotic development. The majority of these somatic DICER1 mutations tend to occur in the RNase IIb domain; however, they have been known to occur elsewhere (3). The DICER1 gene is located on chromosome 14q32.13 and encodes endoribonuclease, a dicer protein, which functions as a ribonucleic acid (RNA) and nucleotide cleaver (4). Endoribonucleases are responsible for processing the hairpin precursor microRNAs (miRNAs) into functionally mature miRNAs through several biochemical cleavage pathways (4). These mature, single-stranded miRNAs then go on to regulate gene expression by binding to target messenger RNA (mRNA) molecules leading to their translational repression and/or degradation (5). The dysregulation and disruption involving the biogenesis and cleavage pathophysiology of miRNAs results in numerous downstream effects directly affecting the translation of mRNA molecules. Ultimately, this posttranscriptional mRNA interference by miRNAs leads to the development of tumorigenesis. We report the case of a 22-year-old right-handed man with no previous extracranial history of malignancy who initially presented to the emergency department with altered mental status, speech difficulties, nausea, vomiting, and severe headache. Brain magnetic resonance imaging (MRI) demonstrated an intraparenchymal enhancing mass in the left frontal lobe and an enhancing mass along the paramedian left frontal convexity with associated intraparenchymal, intraventricular, and subdural hemorrhage (Fig. 1A, B). The patient was immediately admitted to the intensive care unit and was consulted by the neurosurgery team. The decision was made to pursue a left frontal craniotomy for resection of the mass. T1-weighted postcontrast and T2/FLAIR brain MRIs documenting initial tumor occurrence, rapid recurrence, and postoperative imaging with patient timeline. (A, B) Initial preoperative intraparenchymal enhancing mass in the left frontal lobe. (C, D) Postoperative findings of the initial surgical resection highlighting intraparenchymal iatrogenic associated hemorrhage with no evidence of residual tumor. (E, F) Large enhancing, recurrent mass at the vertex along the superior aspect of the left superior frontal gyrus. (G, H) Postoperative findings from the second resection highlighting expected interval surgical changes with no evidence of residual nodular tumor enhancement. (I) Patient timeline. Intraoperatively, much of the tumor was gray and soft in consistency. This portion of the tumor was easily removed via gentle suction and bipolar cautery. Deep and posterior to the soft, gray area of the tumor, a firm, rubbery portion of the tumor was encountered. This portion of the tumor was removed en bloc and it was felt that a gross total resection had been achieved. Several pieces of tumor were sent for frozen section; these were called at the time of initial resection, “high-grade neoplasm.” This was also the preliminary pathologic diagnosis given on permanent sections pending further molecular characterization. It was reported that the patient did quite well during postoperative recovery without complications. Postoperative brain MRI from his first resection demonstrated a left frontal intraparenchymal hemorrhage with associated gas changes within the hematoma without convincing evidence of residual enhancing tumor (Fig. 1C, D). He was discharged home with a 5-day dexamethasone taper and Keppra 500 mg twice daily. During his follow-up with neuro-oncology, the patient reported worsening headaches. A repeat brain MRI demonstrated a large enhancing mass (6.7 cm×3.9 cm) at the vertex along the superior aspect of the left superior frontal gyrus with probable dural and intravascular extension indicating significant reoccurrence (Fig. 1E, F). Additionally, there was nodular mass-like enhancement along the dural surface adjacent to the mass with extension to the ependymal surface of the left frontal horn, likely reflecting glial-lymphatic or subependymal spread. The patient was then referred for urgent surgical re-resection for a left frontal craniotomy. Intraoperatively, the tumor was immediately identified and described as soft, gray, and hemorrhagic. The tumor was entirely resected using gentle suction and bipolar electrocautery. Sections of tumor were sent for frozen pathology and were called, “spindle cell neoplasm.” Shortly thereafter, the molecular results from the initial tumor resection had been received and provided invaluable guidance for appropriate diagnostic subclassification for the second tumor resection. The pathologic diagnosis for the rapidly recurrent/residual tumor was a “malignant sarcomatous neoplasm,” which is discussed in greater detail below. A postoperative brain MRI from the second resection demonstrated the expected interval surgical changes of the left frontal/superior sagittal sinus mass resection with no residual nodular enhancement within the postoperative blood products (Fig. 1G, H). After the patient’s second craniotomy, he received radiation therapy followed by 6 cycles of adjuvant chemotherapy consisting of doxorubicin and ifosfamide. Because of the rapid recurrence, he has continued maintenance chemotherapy with most recent imaging revealing no evidence of recurrence since initiation of treatment. Postprocedural complications include a tumor thrombus along the superior sagittal sinus that was managed with 325 mg aspirin and tumor related epilepsy currently on lacosamide. Histological analysis of the initial left frontal mass showed a hypercellular tumor infiltrating the brain parenchyma with possible neuronal differentiation. The tumor cells appeared hyperchromatic with elongated nuclei with some areas displaying predominate spindle cell morphology and multinucleated giant cells (Fig. 2B). There was extensive small vessel/capillary proliferation with hyalinization comprising the background stroma. The mitotic index was significantly increased with up to 20 mitoses per 10 high-power fields (HPFs) (Fig. 2C). Apoptotic bodies were noted to be scattered throughout all tissue sections. Necrosis was not identified. A few areas of the tumor were composed of a mixture of small round blue cells (Fig. 2A) to spindle-appearing cells with a focal cartilaginous nodule, indicating a dedifferentiation of the tumor (Fig. 2D). No cytoplasmic eosinophilic globules or rhabdomyoblasts were identified. Neuropathology.

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