2021 NPB-12

This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A previously healthy eight-year-old girl presented with irritability followed by sudden loss of consciousness associated with violent muscle contractions and loss of bladder continence. After a few minutes, the patient regained consciousness but was drowsy. MRI of the head showed a well-circumscribed, contrast-enhancing mass in the left parietal lobe (Image A). Gross total resection of the lesion was accomplished. In addition to the stains illustrated below, IHC stains for INI1 and BRG1 showed retained immunoreactivity, while staining for H3K27me3 showed loss of immunoreactivity. Negative IHC stains included GFAP, OLIG2, S100, SOX10, CD34, STAT6, SSTR2A, EMA, synaptophysin, CAM5.2, and beta-catenin. Targeted sequencing was performed and showed a truncating nonsense mutation as well as a hotspot missense mutation of the Ribonuclease IIIb domain of DICER1, likely occurring on opposite alleles. Computed tomography of the chest, abdomen, and pelvis was performed and showed no additional tumors.

Tissue Site
Brain, left parietal lobe

The whole slide image provided is an H&E-stained slide from the right parietal brain tumor resection.

DICER1 syndrome is a pleiotropic tumor predisposition syndrome with an increased risk of rare malignant and benign tumors that typically manifest in childhood. DICER1 is a microRNA processing gene located on chromosome 14q32.13. It encodes the endoribonuclease Dicer protein of the ribonuclease III family. The predisposing germline alteration in DICER1 is most often loss of function (LOF, nonsense, frameshift mutation causing LOF, or deletion). A second somatic event usually involves missense alterations involving one of five amino acid residues in the RNase IIIb domain of the DICER1 gene.

Tumor type and frequency is highly variable in DICER1 syndrome. Up to 40% of patients have pleuropulmonary blastoma (PPB) and lung cysts, although less than 10% have PPB types I-III which are capable of distant metastasis. Conversely, 65% of children with PPB have a DICER1 pathologic germline variant. Multinodular goiter is common, particularly in women with the syndrome, and is present in ~75% of women by the age of 40 years. Ovarian sex cord-stromal tumors occur in <10% of females with the disorder, while cystic nephroma is found in ≤ 10% of both sexes. Ciliary body medulloepithelioma is present in ~3% of DICER1 syndrome patients.

Multiple other tumors are associated with DICER1 syndrome, but these occur even less often. Those that involve the CNS include metastatic PPB (the most frequent CNS tumor), pituitary blastoma, pineoblastoma, embryonal tumor with multilayered rosettes (ETMR)-like infantile cerebellar tumor, and primary DICER1-associated CNS sarcoma (DCS).

Early work suggests that DCS shows higher tumor mutational burden and a tendency for additional alterations in oncogenic pathways including TP53 inactivation and activating alterations of RAS pathway genes including KRAS and NF1.

The microscopic features illustrated are representative of DCS. Review of DICER1-associated sarcomas (CNS and otherwise) by Warren et al. observes a histologic pattern mimicking pleuropulmonary blastoma in DCS and extra-CNS sarcomas: undifferentiated small round blue cells, poorly differentiated spindle cells, and large bizarre pleomorphic cells (anaplasia, Image B and Image C), often with rhabdomyoblastic and/or chondroid differentiation, and rare bone/osteoid formation. Eosinophilic cytoplasmic globules are variably present (Image D) and can be a clue to the diagnosis. As with other sarcomas, reticulin deposition around individual cells is characteristic (Image E). DCS is often compared with rhabdomyosarcoma, since it usually shows focal desmin immunoreactivity (Image F). DCS may show strong p53 immunoreactivity (Image G) suggestive of a TP53 mutation, but this is nonspecific. Other IHC markers are usually uninformative, although recent work by Alexandrescu et al. shows loss of immunoreactivity for H3K27me3 and strong immunoreactivity for TLE1 (a marker of synovial sarcoma) in most DCSs.

DICER1 mutations are required for the diagnosis of DCS. Most often, as in this case, a LOF mutation is observed within one allele and a hotspot missense mutation of the RNase IIIb domain of DICER1 is found in the second DICER1 allele. While postzygotic mutations may occur, and can manifest as mosaicism or sporadic tumors, germline alteration is frequent. The temporal order of RNase IIIb and LOF mutations is important: uncommon patients with mosaicism for an RNase IIIb hotspot mutation tend to present earlier in life and with multiple DICER1-associated tumors. Biallelic LOF in tumors is rare and appears to be largely limited to DICER1-associated pineoblastoma, where complete absence of microRNA processing by Dicer is felt to play an important role in pathogenesis.

Since DCS can be histologically indistinguishable from metastatic PPB, which occurs relatively commonly, CT of the chest is recommended when encountering DCS. Bulky thoracic PPB increases the likelihood that CNS tumors are metastatic PPB; conversely, the absence of thoracic disease argues for DCS when one encounters an isolated CNS tumor. Differences in the mutational profile between DCS and metastatic PPB may exist, with early evidence showing generally higher tumor mutational burden and enrichment of alterations in oncogenic pathways in DCS (TP53 mutation, for instance, as in this case), but molecular profiles are overlapping. Ambiguous cases with both CNS tumor and PPB may require targeted sequencing of both, with comparison of hotspot mutations and other events.

• CNS sarcomas with rhabdomyoblastic differentiation (usually patchy desmin immunoreactivity) should prompt consideration of DCS, with molecular analysis of the tumor and referral for DICER1 genetic testing and counselling.
• Tumor sequencing for alterations in DICER1 is required for the diagnosis of DCS.
• DCS is associated with germline DICER1 mutation. A subset of tumors harbor biallelic somatic DICER1 alterations; such non-syndromic tumors may be difficult to distinguish from tumors resulting from mosaicism of DICER1 mutations. Genetic counseling and systemic review is indicated in all cases.
• Metastasis of thoracic pleuropulmonary blastoma (PPB) is the most frequent CNS tumor in DICER1 syndrome patients. In addition, DCS and metastatic PPB may be histologically indistinguishable. Chest CT is recommended at the time of diagnosis to confirm that the tumor is the primary disease site.

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