Comparative analysis of clinical features, methylation and immune microenvironment in pediatric and adult papillary craniopharyngiomas: results from a multicenter study

Abstract

Papillary craniopharyngioma (PCP) was previously believed to occur only in adults. Sporadic pediatric PCP (PPCP), confirmed by detection of the BRAF V600E mutation, has been reported since 2018. The differences between PPCP and adult PCP (APCP) remain unclear. This comprehensive study aimed to enhance understanding of PPCP and elucidate the distinctions between PPCP and APCP. We conducted a systematic analysis of cases of PPCP and APCP, focusing on BRAF V600E mutation, methylation profiles, histology, cell proliferation, imaging features, immune microenvironment, and prognosis. This study compiled 17 cases of PPCP from 6 medical centers, constituting 3.11% of the total 546 PCP cases. Both PPCP and APCP cases exhibited the BRAF V600E mutation with no differences in methylation patterns. However, imaging showed PPCP was predominantly cystic and located beneath the diaphragma sellae with some progression to the sella. APCP typically manifested as solid lesions, primarily located in the suprasellar region, inferior to the third ventricle. PPCP histologically displayed extensive inflammatory cellular infiltration, suppurative change, and occasional small granular calcifications, whereas APCP was largely devoid of calcifications. Compared to APCP, PPCP exhibited significantly lower PD-L1 (an immune checkpoint protein expressed on tumor cells) expression and higher expression levels of CD38 (an immunosuppressive marker), S100A8/A9 (a neutrophil marker), and MPO (myeloperoxidase, a neutrophil marker). Additionally, stromal expression of CD163 (an M2 macrophage marker) was lower in PPCP compared to APCP, while CD68 (an M1 macrophage marker), CD3 (T cell marker), and CD20 (B cell marker) expression showed no significant difference. Ki-67 expression exhibited a banded pattern on PPCP epithelium, contrasting with a punctate pattern in APCP, with significantly higher levels observed in PPCP. Postoperative prognosis did not differ between PPCP and APCP. While driver genes and methylation profiles may not differentiate PPCP from APCP, substantial discrepancies exist in tumor location, histology, imaging features, cell proliferation, and immune microenvironment.

Keywords: Adult; Diagnosis; Papillary craniopharyngioma; Pathophysiology; Pediatric.

Fig. 1

Patient characteristics and differences in imaging features. (A) Age distribution: 7.5y (pediatric) vs. 46.1y (adult). (B) Case composition: 17 pediatric vs. 529 adult PPCP. (C and D) Imaging contrast: PPCP predominantly infradiaphragmatic cystic lesions (star: sand-like calcification) vs. APCP suprasellar solid masses (red arrow: homogeneous enhancement). (E) Significant cyst-solid pattern divergence between groups ( χ2 test, P < 0.01).

Fig. 2

Difference in histology and proliferation between PPCP and APCP. (A–D) PPCP-specific histology: Pan-layer inflammatory infiltration (A), mucin-ciliated epithelial complexes (B arrows), calcification (C), Rathke’s cyst epithelial migration (D arrows). (E and F) APCP representative H&E. (G and H) Ki-67 spatial dichotomy: Band-like distribution (PPCP) vs. scattered dot-like pattern (APCP). (I) Quantified proliferative disparity (t = 6.146, P < 0.01). Staining markers: Blue arrow-mucin vacuoles, Red arrow-ciliated epithelium, Yellow arrow-pheochromocyte-like cells.

Fig. 3

BRAF V600E, β-catenin, and methylation profiles in PPCP and APCP. (A, C) Parenchymal BRAF V600E positivity (stroma-negative) in both groups. (B, D) Pan-cytoplasmic β-catenin expression (nuclear-negative). (E, F) Hierarchical clustering analysis and t-stochastic neighbor embedding analysis revealed no significant difference in the methylation profiles between PPCP and APCP.

Fig. 4

PD-L1, PD-1 and CD38 expression profiles in PPCP and APCP. (A-B) PD-L1 cytoplasmic localization in tumor parenchyma. (C-D) Absence of PD-1 in parenchyma/stroma. (E) Lower PD-L1 expression in PPCP vs. APCP (t = 4.351, p < 0.01,). (F-H) CD38 stromal expression with higher intensity in PPCP vs. APCP (t = 9.452, p < 0.01). (I) PD-1 stromal detection by immunofluorescence. (J-K) Correlation analysis: PPCP (r = 0.4433, p = 0.1294); APCP (r= − 0.2549, p = 0.020).

Fig. 5

Expression of S100A8/A9 and MPO in PPCP and APCP. (A, B) Ubiquitous S100A8/A9 expression in tumor parenchyma and stroma. (C, D) MPO detection in both subtypes. (E) Comparable parenchymal S100A8/A9 between groups. (F) PPCP exhibited significantly higher S100A8/A9 expression in stromal cells compared to APCP (t = 11.92, p < 0.01) (G, H) PPCP shows elevated MPO in both parenchyma (t = 7.718, P < 0.01) and stroma (t = 2.879, P < 0.01). (I, J) No significant correlations between MPO parenchyma and S100A8/A9 stroma in either subtype. (K) Immunofluorescence validation of S100A8 spatial distribution. (L, O) Lack of stromal MPO-S100A8/A9 correlations across compartments (all P > 0.05).

Fig. 6

Expression of CD68, CD163, CD3, and CD20 in PPCP and APCP. (A, B) Stromal-enriched CD68 pattern conserved across subtypes. (C, D) No intergroup differences in CD68 distribution (parenchyma P > 0.05, stroma P > 0.05). (E, F) Bicompartmental CD163 expression. (G) Comparable stromal CD163 between groups. (H) Significantly higher parenchymal CD163 in APCP vs. PPCP (t = 5.393, P < 0.01). (I–N) Conserved stromal CD3/CD20 expression without intergroup differences (all P > 0.05).

Fig. 7

Comparative analysis of immune marker expression between non-recurrent and recurrent PPCP using immunohistochemistry (IHC). (A, B) Comparable CD163 stromal/parenchymal IHC scores. (C) PDL1 parenchymal expression parity. (D–G) Stable S100A8/A9 and MPO profiles across compartments. (H–J) Conserved CD68/CD38 stromal distribution. (K, L) Unaltered stromal CD3/CD20 infiltration.

Fig. 8

Difference in prognosis between PPCP and APCP. (A) Comparable overall prognosis between PPCP and APCP (χ2 test, P > 0.05). (B) Significant prognostic association with initial resection extent (Fisher’s exact test, P < 0.01, total vs. partial). (C) Progression-free survival parity post-last surgery (Kaplan–Meier curves, P > 0.05).