Pediatric cancer predisposition syndromes involving non-central nervous system solid pediatric tumors: a review on their manifestations with a focus on histopathology

Abstract

Germline genetic alterations and their associated cancer predisposition syndromes (CPS) are an important cause of pediatric cancer. Early recognition is of great importance for targeted surveillance, early detection, and prompt (personalized) therapeutic interventions. This review provides an overview of non-central nervous system solid pediatric tumor types, in relation to their associated CPS, with an emphasis on their histology. It serves as a guide for (pediatric) pathologists to increase their awareness of histological clues that suggest a CPS and warrant referral to the clinical geneticist.

Keywords: Cancer predisposition syndrome; Histology; Pathology; Pediatrics.

Fig. 1

Schematic representation of solid tumor types in selected cancer predisposition syndromes (CPS) with multiple solid tumor types occurring in the pediatric age range. Abbreviations. ADH, atypical ductal hyperplasia; FND, follicular nodular disease; HCC, hepatocellular carcinoma; GI, gastrointestinal; GIST, gastrointestinal stromal tumor; MPNST, malignant peripheral nerve sheath tumor; NET, neuroendocrine tumor; NF, neurofibromatosis

Fig. 2

Nine-year-old boy with osteosarcoma in the context of Li-Fraumeni syndrome with germline TP53 pathogenic variant. A Tumor histology showing extensive anaplasia of tumor cell nuclei in myxoid background. B Copy number variation profile typical of TP53-related osteosarcoma with numerous chromosomal gains and losses

Fig. 3

Hematoxylin and eosin-stained section of diffuse hyperplastic perilobar nephrogenic rests in the context of nephroblastomatosis in a patient with Beckwith-Wiedemann syndrome

Fig. 4

Four-year-old boy with Beckwith-Wiedemann syndrome, presenting with liver tumor at age 2 months, diagnosed as fetal epithelial hepatoblastoma. A detail of combined fetal and embryonal differentiation can be seen (A), with the corresponding area positive for cytoplasmic and nuclear staining with beta-catenin (B), positive for nuclear staining mostly in embryonal cells (C), and cytoplasmic staining in all tumor cells for glypican 3 (D). At 2 years and 9 months follow-up, he presented with a right renal mass, suspected of hepatoblastoma relapse. However, the tumor was found to be a non-anaplastic Wilms tumor, as can be seen on the HE staining (E), supported by nuclear positivity for WT1 (F)

Fig. 5

A Hematoxylin and eosin-stained section of prophylactic thyroidectomy showing proliferation of epithelial cells, suggestive of C-cell hyperplasia; B corresponding calcitonin immunostaining showing positive staining of the proliferating epithelial cells, confirming the diagnosis of C-cell hyperplasia in a patient with MEN2A syndrome. This proliferation falls short of incipient medullary thyroid carcinoma, for lack of infiltrative growth, lack of desmoplastic stroma, and lack of amyloid deposition

Fig. 6

Typical histology of pleuropulmonary blastoma in a DICER1 patient, showing profound nuclear pleomorphism in tumor cells with ample eosinophilic cytoplasm suggesting rhabdomyoblastic differentiation