Primary intracranial sarcoma, DICER1 mutant (PIS-DICER1), has been added to the 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System. ^{Reference Louis, Perry and Wesseling1} Very few publications discuss the clinical management of PIS-DICER1, particularly in adults. This case report presents a successful therapeutic approach for a PIS-DICER1 adult patient with pertinent references to the currently available literature.

A 22-year-old female, previously healthy, was brought to our emergency department for altered level of consciousness and vomiting secondary to severe intracranial hypertension after sustaining a sudden episode of headache. A non-contrast-enhanced head CT scan showed a parenchymal hematoma centered in the right posterior parietal region (Figure 1A) measuring 4.9 × 5.4 × 5 cm inducing an important mass effect with a 10 mm midline shift. The patient underwent an urgent right parietal craniotomy and complete macroscopic excision of the hematoma without further imaging modalities given her unstable clinical condition. Intraoperative findings revealed a voluminous intracranial hematoma with an underlying grayish tissue suspicious for a lesion. Postoperative MRI confirmed no evidence of residual disease. Clinically, the patient made an uneventful recovery except for a residual left inferior quadranopsia.

Figure 1.

(A) Head CT at initial presentation and (B) preoperative MRI at recurrence 6 weeks after the first resection.

Pathology analysis was first performed, and a second opinion was requested following a preliminary report suggesting a PIS-DICER1.

The pathological sections showed a pleomorphic, highly cellular spindle cell tumor, with a fascicular pattern, with abundant mitoses and focal presence of cytoplasmic eosinophilic globules. A large panel of immunohistochemistry including glial markers, myogenic markers, cytokeratins, CD34 and SOX10 was non-contributory. P53 immunohistochemistry was negative. A loss of expression of ATRX was noted. There was no loss of nuclear expression of MMR proteins.

Molecular testing of the lesion revealed the following: a TP53 frame shift mutation [NM_000546.5:c.397del (p.Met133fs)] in exon 5 (Illumina AmpliSeq Brain Panel and Illumina TruSight RNA Pan-Cancer NGS analysis). It also showed two oncogenic alterations in DICER1 (Illumina TruSight RNA Pan-Cancer NGS analysis): a frame shift [NM_177438.2:r.1908del (p.Arg636Serfs*13)] and a missense mutation [NM_177438.2:r.5125g>a (p.Asp1709Asn)].

Germline testing was done via a 33 gene panel, including DICER1 (Invitae, San Francisco, CA). Sequencing, deletion and duplication analysis did not identify any pathogenic variants. These results are consistent with two somatically acquired DICER1 mutations within the limits of this methodology.

As pathology expertise was ongoing, the patient presented at our emergency department 6 weeks post-surgery with recurrent severe headaches over 3 days. Again, head CT scan showed a right parieto-occipital intra-axial hemorrhagic lesion of 5.0 × 4.3 × 5.5 cm with significant mass effect. MRI (Figure 1B) confirmed a recurrent of a 5.7 × 6.6 × 4.6 cm hemorrhagic tumor. Positron emission tomography (PET)/CTscan and Chest CT were performed before the second resection to rule out distant metastases and showed only the right parieto-occipital lesion with a 31.4 SUV max, and hypometabolic necrotic central area. A complete spine MRI 2 days postoperatively was normal.

The patient underwent a second right parietal craniotomy with successful complete gross total resection and no evidence of residual disease on postoperative MRI. Pathology confirmed a rapid and aggressive relapse of PIS-DICER1.

Adjuvant treatments strategy was discussed at neuro-oncology and sarcoma multidisciplinary tumor boards, in addition to reviewing the minimal literature available. ^{Reference Diaz Coronado, Mynarek and Koelsche2–Reference Robinson, Goold and Cannon5} In the end, the consensus was to urgently start local adjuvant radiotherapy (RT) followed by chemotherapy (CT).

Hence, nine days postoperatively, the patient received her first RT treatment and completed a course of 66 Gray (Gy) in 33 fractions intensity modulated radiation therapy (IMRT) (Figure 2) without significant side effects except fatigue and expected focal hair loss. 60 Gy in 30 fractions were delivered to a larger volume encompassing all areas of potential microscopic tumoral extension, including the extent of hemorrhage, using the second surgery preoperative and postoperative MRI T1W without contrast, T1W with contrast, T2W FLAIR images. An additional boost of 6 Gy in 3 fractions was delivered to the surgical bed.

Figure 2.

MRI following second surgical resection with radiotherapy planning volumes. (A) 60 Gy volume: red line = gross tumor volume (GTV) (surgical cavity + T2/FLAIR abnormalities); orange line = clinical target volume margin 10 mm (CTV); green line = planning target volume (PTV) margin 3 mm. (B) 6 Gy boost volume: pink line = GTV (surgical cavity); green line = PTV margin 3 mm (no CTV margin for boost volume).

Adjuvant ICE (Ifosfamide – Carboplatin – Etoposide) chemotherapy treatment was initiated 1 month following the last RT fraction. The patient completed the planned six cycles without significant toxicity except for fatigue and occasional nausea.

The patient was clinically monitored with brain MRI every 3 months during the first year, followed by assessments every 3–6 months. Three years after completion of adjuvant radiotherapy, she remains in complete remission, with no radiological evidence of recurrence or late radiation-induced toxicity. She fully recovered her left inferior visual field deficit.

In this case report, we describe the successful clinical and therapeutic approach to an adult patient with PIS-DICER1.

A few case reports and case series regarding the clinical management of this rare entity were retrospectively found in the literature, mostly in the pediatric population. ^{Reference Diaz Coronado, Mynarek and Koelsche2–Reference Yao, Duan, Feng, Changxiang and Qi4} Diaz Coronado et al. ^{Reference Diaz Coronado, Mynarek and Koelsche2} published the treatment results of 70 Peruvian patients with primary central nervous system (CNS) sarcomas, median age 6 years, and 26 cases presented with DICER1 mutation. Forty-six of the 70 patients, with nonmetastatic disease, were treated with a combination therapy, resulting in a 2-year progression-free survival (PFS) rate of 58% and 2-year overall survival (OS) of 71%. In their experience, the highest 2-year PFS rate (79%) was observed in patients who underwent upfront surgery, followed by adjuvant Ifosfamide-Carboplatin-Etoposide (ICE) chemotherapy and subsequent adjuvant radiotherapy. While this treatment sequence may remain the most appropriate in a pediatric population and/or in cases of other subtypes of PIS, all experts consulted on the clinical management of our reported patient recommended that adjuvant radiotherapy should be done first in view of the aggressive local recurrence 6 weeks following first resection.

Diaz Coronado et al. ^{Reference Diaz Coronado, Mynarek and Koelsche2} also reported a median dose of 60 Gy (n = 53) for adjuvant focal irradiation to the tumor bed. The clinical decision in this case report to proceed with a total irradiation dose of 66 Gy, 60 Gy prescribed to a larger volume including all areas of potential microscopic disease, followed by a 6 Gy boost focally targeting the tumor cavity, was mostly influenced by radiotherapy dose clinical guidelines for management of soft tissue sarcoma ^{Reference Salerno, Alektiar and Baldini6–7} with positive resections margins presenting in other different subtypes/anatomic locations. Also, current knowledge of normal brain structures tolerance to radiation doses ^{Reference Lawrence, Li and el Naqa8} and favorable tumor posterior parietal location allowed this adjuvant high-dose irradiation without a significant risk of sequelae.

This case report provides rare and valuable information for other clinicians on successful clinical management of a young adult with PIS-DICER1 mutant tumor.