Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): a report from the International Pleuropulmonary Blastoma/DICER1 Registry

Abstract

Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic), type II (cystic and solid), and type III (solid). Prognosis varies by PPB type. Most cases are associated with a germline pathogenic mutation in DICER1; however, there is limited data on the factor(s) at a cellular level that drive progression from type I to type III. In this study, we evaluated the expression of p53 and its prognostic implications. A total of 143 PPB cases were included in the study with the following distribution in PPB types: Ir (14%), I (23%), II (32%), and III (31%). P53 expression by immunohistochemistry (IHC) was recorded as four groups: 0%, 1-25%, 26-75%, and 76-100%. All type I PPBs showed 0-25% p53 expression compared to the higher p53 expression (>25%) in type III PPB (p < 0.0001), to support the argument that p53 has a role in tumor progression. In addition, type Ir with the architectural hallmarks of type I PPB, but lacking the primitive cell population, has negligible p53 expression. High p53 expression (staining observed in >25% of the tumor cells) was significantly associated with age over 1 year (p = 0.0033), neoadjuvant therapy (p = 0.0009), positive resection margin (p = 0.0008) and anaplasia (p < 0.0001). P53 expression was significantly associated with recurrence-free survival (p < 0.0001) and overall survival (p = 0.0350), with higher p53 expression associated with worse prognosis. Comparisons of concordance statistics showed no significant difference in prognostication when using morphologic types compared to p53 expression groups (p = 0.647). TP53 sequence was performed in 16 cases; the most common variant identified was a missense variant (12 cases), and in one case a frameshift truncating variant was noted. Based on these findings, we recommend performing p53 IHC in all newly diagnosed cases of types II and III PPB to further aid in risk stratification.

Figure-1.

Type Ir PPB is characterized by multicystic structures where the septa lack the characteristic small primitive cells underneath the epithelium (a, b). In contrast, type I PPB is characterized by the presence of these small primitive cells which can either present as a continuous or discontinuous growth pattern (c, d, e, f). In more than half of the cases the primitive cells underneath the epithelium are rhabdomyoblasts, and a classic association with immature island of cartilage is seen in PPB regardless of type (c, d). Occasionally the cystic septa are expanded by the immature cells, a possible sign of early progression to type II (e, f).

Figure-2.

Type II PPB are characterized by the presence of both cystic and solid areas. Underneath the epithelium of the cystic structures a condensation of the immature cells can be noted in some cases forming a cambium-like layer (a). The solid components can have a wide range of morphology from a fibrosarcoma-like appearance (a) to a predominance of a rhabdomyoblasts proliferation (b). In some cases, the solid areas are composed of primitive small immature cells (c). The solid areas might also show frank anaplasia (d). All photomicrographs represent different cases.

Figure-3.

PPB composed exclusively of solid areas are consistent with a type III PPB. The solid component can have a broad morphology spectrum with the most classically seen being a rhabdomyosarcoma which is often associated with immature cartilaginous islands (a, b). In some cases, an undifferentiated sarcoma is seen with prominent anaplasia (c).

Figure-4.

Separate cases of PPB paired with p53 immunostains showing various degrees of expression: 0%, group 0 (a, b); 10%, group 1 (1 – 25%) (c, d); 50% group 3 (26 – 75%) (e, f); 80% (g, h); and 100%, group 4 (76 – 100%) (i, j).

Figure-5.

Kaplan-Meier plots of recurrence-free and overall survival for PPB types.

Figure-6.

Kaplan-Meier plots of recurrence-free and overall survival for p53 expression groups.