Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome

Abstract

Background: Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions.

Methods: Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed. Freedom from progression (FFP) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using log-rank tests.

Results: Median follow-up was 4.1 years. All patients initially underwent surgery; 78% of patients with PPT of intermediate differentiation (PPTID) and all patients with pineoblastoma received adjuvant therapy. Pathologic re-review refined classification in 27% of cases, with the majority of these being adult patients with pineal tumors originally classified as pineoblastomas that more accurately resembled PPTID based on the 2007 WHO classification.

Classification: Our histologic review also identified that PPTIDs can be classified into small-cell and large-cell morphologic subtypes, which have distinct clinical outcomes. Tumor grade, extent of resection, and neuraxis spread were prognostic for FFP. PPTID subtype, extent of resection, and neuraxis spread were prognostic for OS. Genetic analysis of a pineoblastoma case identified somatic mutations of DICER1, ARID1A, and KDM5C genes.

Conclusions: PPTIDs can be classified into 1 of 2 novel morphologic subtypes that are associated with distinct clinical outcomes. Tumor grade, neuraxis spread, and extent of resection also influence outcome for patients with PPT.

Keywords: DICER1; pineal parenchymal tumor; pineal parenchymal tumor of intermediate differentiation; pineoblastoma; pineocytoma.

Fig. 1.

Study flowchart. Seventy-five patients who were originally diagnosed with and treated for pineal parenchymal tumor (PPT) were identified retrospectively, and 45 cases were available and pathologically re-reviewed using current grading criteria. Clinical follow-up was available for 38 of the 45 cases that were pathologically re-reviewed, and 17 of the 30 cases that were unavailable for re-review. Data from the 38 cases with available clinical follow-up and pathologic re-review were used for analyses of patient demographics, treatment characteristics, extent of resection, and pineal parenchymal tumor of indeterminate differentiation (PPTID) subtype (Table 1, Supplementary material, Table S1, Figs 1–3, and Supplementary material, Fig. S1). Data from all 55 cases with available clinical follow-up were used for analyses of tumor grade and neuraxial spread (Fig. 4 and Supplementary material, Fig. S2).

Fig. 2.

Pineal parenchymal tumor (PPT) outcomes according to revised histology. (A, B) For all patients regardless of tumor grade, gross total resection (GTR) is associated with improved disease control (P = .04) and improved overall survival (P = .04) by Fisher exact test when compared with subtotal resection and biopsy (sub-GTR). (C, D) For patients with PPTs of indeterminate differentiation (PPTIDs), small-cell morphology is associated with improved overall survival (P = .02) and a trend toward improved progression-free survival (P = .07) by log-rank test.

Fig. 3.

Pathologic review of pineal parenchymal tumors of intermediate differentiation (PPTIDs) identifies 2 distinct morphologic subtypes: large-cell and small-cell. (A–C) H&E stained sections of PPTID cases corresponding to the large-cell subtype, which have larger nuclei with greater nuclear pleomorphism, more abundant cytoplasm, and more abundant neurophil-like stroma in the background. (D–F) H&E stained sections of PPTID cases corresponding to the small-cell subtype, which have smaller, more uniform nuclei with inconspicuous nucleoli and scant cytoplasm with very little stroma in the background. Scale bar, 20 μm.

Fig. 4.

Pineal parenchymal tumor (PPT) outcomes from a pooled cohort of cases with and without pathologic re-review. (A, B) Tumor histology (P = .03) and neuraxis spread (P = .001) are significantly associated with freedom from progression by log-rank test. (B, C) Neuraxis spread at diagnosis is prognostic for overall survival (OS) by log-rank test (P = .0003), and tumor histology shows a trend for OS by log-rank test for trend (P = .11). Of note, one patient treated with GTR and adjuvant chemoradiation for pineoblastoma without evidence of neuraxis spread at diagnosis died after 23 years of follow-up from a secondary high-grade sarcoma of the lumbar spine. The surgical specimen for this patient could not be located for pathologic re-review.

Fig. 5.

Genomic analysis of a pineoblastoma arising in a young pediatric patient identifies novel somatic mutations involving DICER1, ARID1A, and KDM5C. (A) Coronal T1 post-gadolinium and (B) sagittal fluid-attenuated inversion recovery MR imaging of an 18 month-old boy demonstrating a large, avidly enhancing mass centered in the midline within the region of the pineal gland and causing compression of the subjacent cerebellar vermis. (C) H&E stained section of the tumor showing a primitive small round blue cell neoplasm arranged in sheets with nuclear molding, numerous mitotic figures, and apoptotic debris. Scale bar, 20 μm. (D) List of somatic mutations that were identified upon targeted next-generation sequencing of 510 cancer-associated genes on genomic DNA isolated from peripheral blood and tumor tissue. MAF, mutant allele frequency.