Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, established new approaches to both CNS tumor nomenclature and grading, emphasizing the importance of integrated diagnoses and layered reports. This edition increased the role of molecular diagnostics in CNS tumor classification while still relying on other established approaches such as histology and immunohistochemistry. Moreover, it introduced new tumor types and subtypes based on novel diagnostic technologies such as DNA methylome profiling. Over the past decade, molecular techniques identified numerous key genetic alterations in CSN tumors, with important implications regarding the understanding of pathogenesis but also for prognosis and the development and application of effective molecularly targeted therapies. This review summarizes the major changes in the 2021 fifth edition classification of pediatric CNS tumors, highlighting for each entity the molecular alterations and other information that are relevant for diagnostic, prognostic, or therapeutic purposes and that patients' and oncologists' need from a pathology report.

Analysis of microsatellite instability (MSI) in pediatric gonadal and extra-gonadal germ cell tumors.

Gonadal and extragonadal pediatric germ cell tumors (GCTs) are rare neoplasms with different clinical behavior. Although surgery and cisplatin-based chemotherapy are resolutive in most cases, some patients do not respond to chemotherapy and have a worse outcome. Microsatellite instability (MSI) was correlated to resistance to chemotherapy and sensitivity to immunotherapy in different neoplasms. A series of 21 pediatric GCTs were tested by immuno-histochemistry and PCR to evaluate MSI status. Next generation sequencing was applied to further evaluate cases with discordant results between immunohistochemistry and PCR. Twenty-one cases of pediatric GCT were included in the series. The mean age ranged between 1 and 10 years. Nine cases were gonadal GCTs and the remaining 12 were extra-gonadal GCTs. By immunohistochemistry, one case showed a deficit of Mismatch repair (MMR) proteins. This case was a 1-year-old children affected by gonadal yolk sac tumor. However, all cases resulted microsatellite stable (MSS) by PCR and NGS. MSI was not detected in our series of pediatric GCTs, as well as the data present in literature about adult patients with GCTs. Molecular techniques could have a role to confirm the MSI status in case of dMMR by immunohistochemistry.

Extra-neural metastases in pediatric diffuse midline gliomas, H3 K27-altered: presentation of two cases and literature review.

Introduction: Pediatric diffuse midline gliomas (DMG), H3 K27- altered, are the most aggressive pediatric central nervous system (CNS) malignancies. Disease outcome is dismal with a median survival of less than one year. Extra-neural metastases are an unusual occurrence in DMG and have been rarely described. Methods and results: Here, we report on two pediatric patients affected by DMG with extra-neural dissemination. Their clinical, imaging, and molecular characteristics are reported here. An 11-year-old male 5 months after the diagnosis of diffuse intrinsic pontine glioma (DIPG) developed metastatic osseous lesions confirmed with computed tomography (CT) guided biopsy of the left iliac bone. The patient died one month after the evidence of metastatic progression. Another 11-year-old female was diagnosed with a cerebellar H3K27- altered DMG. After six months, she developed diffuse sclerotic osseous lesions. A CT-guided biopsy of the right iliac bone was non-diagnostic. She further developed multifocal chest and abdominal lymphadenopathy and pleural effusions. Droplet digital polymerase chain reaction (ddPCR) on pleural effusion revealed the presence of H3.3A mutation (c.83A>T, p.K28M). The patient died 24 months after the diagnosis of DMG and 3 months after the evidence of metastatic pleural effusion. Discussion: Extra-neural metastasis of DMG is a rare event and no standard therapy exists. An accurate and early diagnosis is necessary in order to develop a personalized plan of treatment. Further research is needed to gain further insights into the molecular pathology of DMG, H3K27- altered and improve the quality of life and the final outcome of patients with this deadly disease.

Tumors of Choroid Plexus and Other Ventricular Tumors.

Tumors arising inside the ventricular system are rare but represent a difficult diagnostic and therapeutic challenge. They usually are diagnosed when reaching a big volume and tend to affect young children. There is a wide broad of differential diagnoses with significant variability in anatomical aspects and tumor type. Differential diagnosis in tumor type includes choroid plexus tumors (papillomas and carcinomas), ependymomas, subependymomas, subependymal giant cell astrocytomas (SEGAs), central neurocytomas, meningiomas, and metastases. Choroid plexus tumors, ependymomas of the posterior fossa, and SEGAs are more likely to appear in childhood, whereas subependymomas, central neurocytomas, intraventricular meningiomas, and metastases are more frequent in adults. This chapter is predominantly focused on choroid plexus tumors and radiological and histological differential diagnosis. Treatment is discussed in the light of the modern acquisition in genetics and epigenetics of brain tumors.

Giant malignant sacrococcygeal germ cell tumor in a newborn: A rare case report.

Malignant germ cell tumors constitute about 3%-4% of all neoplasms occurring before the age of 15. They arise in the ovaries, the testes, and in several other locations, including the lower back, the chest, the brain, and the abdomen. In infants and young children, the sacrococcygeal region is the most common site for extragonadal germ cell tumors, and teratomas account for the vast majority of sacrococcygeal germ cell tumors. Neonatal sacrococcygeal teratomas are usually benign and rarely they may contain a malignant component that is predominantly a yolk sac tumor. In this article, we describe a rare case of a male newborn with a giant sacrococcygeal mixed germ cell tumor composed of grade 3 immature teratoma and malignant yolk sac elements.

Angioma serpiginosum: Two cases in children and review of literature.

Angioma serpiginosum (AS) is a rare benign vascular lesion that typically arises in early childhood, with a prevalence in female, and then grow up over a period of months/years. It is characterized by small asymptomatic purple-red dots that cluster together and they do not disappear on diascopy. It is mainly localized on the arms but some cases on face and neck have been reported. The etiology of AS is unknown, dermoscopy may aid in the diagnosis but usually the biopsy is necessary. We report 2 cases: one male and one female with angioma serpiginosum, aged 13 and 8 years old.

Posterior Fossa Tumours in the First Year of Life: A Two-Centre Retrospective Study.

Posterior fossa tumours (PFTs) in infants are very rare, and information on these tumours is scarce in the literature. This retrospective study reports their pathological characteristics and describes surgical aspects and treatment outcomes. A two-centre cohort of infants with PFTs treated from 2007 to 2018 was retrospectively reviewed. Patient characteristics, clinical, and treatment data were reviewed. Survival curves for progression-free survival (PFS) and overall survival (OS) were generated. Thirty-three infants were retrieved. There were 11 low grade and 22 high-grade tumours. The most common presenting symptom was intracranial hypertension. Fifteen children out of thirty-three progressed. Five-year PFS was significantly lower in children with high-grade tumours (38.3%) than those with low-grade tumours (69.3%), p = 0.030. High-grade pathology was the only predictor of progression (HR 3.7, 95% CI 1.1-13.31), p = 0.045. Fourteen children with high-grade tumours died, with a 5-year OS of 55.25%. PFTs in children below one year of age still represent a unique challenge. Infants with high-grade tumours display the worst outcomes and the lowest survival, indicating that more effective strategies are needed.

Pathologist's approach to paediatric and neonatal eosinophilic gastrointestinal disorders.

Children are not simply miniature adults. The evaluation of their gastrointestinal disorders is therefore different from that in full-grown adults and requires a particular clinical/pathologic approach.Different studies have tried to assess the normal eosinophil distribution in the gastrointestinal tract in adults while very few studies have investigated the paediatric population, consequently complicating the pathologist's ability in identifying an abnormal number of eosinophils in this setting of patients.When evaluating gastrointestinal tract biopsies with eosinophilia, eosinophilic count must be considered along with other histological features like eosinophil distribution in the gastrointestinal wall, their degranulation, cryptitis and crypt abscesses, other accompanying inflammatory cells, apoptotic bodies, foreign material or microorganisms; these findings, although rarely specific, may be a useful aid for diagnosis.Reports should not include a diagnosis of primary eosinophilic gastrointestinal disorders (EoGID) if clinical data and test results do not rule out other forms of gastrointestinal eosinophilia. A more descriptive definition like "with eosinophilic pattern" should be favoured over a specific diagnosis of "eosinophilic disorder" in order to avoid potential confusion between different entities.

Primary leptomeningeal medulloblastoma: a case-based review.

BACKGROUND: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for 40% of childhood tumors in posterior fossa. Metastatic disease, occurring in 20-30% of all medulloblastoma cases at diagnosis, is largely exclusive to the leptomeninges. On the contrary, primary leptomeningeal medulloblastoma or so-called chameleon medulloblastoma, defined by the absence of a detectable intraparenchymal lesion with a widespread diffusion along leptomeninges, is a rare entity of difficult diagnosis with only a few cases reported in literature. METHODS AND RESULTS: A comprehensive literature search of three databases (PubMed, Ovid Medline, and Ovid Embase) have been conducted to identify pertinent papers focusing on the diagnostic process, management, and treatment of primary leptomeningeal medulloblastoma and its peculiar features. To our knowledge, only eight cases are described in literature, including five pediatric patients and three adults, two of which with the initial involvement of the spinal cord. In addition, we report another two pediatric cases, showing widespread primary diffusion along leptomeninges of brain and spinal cord. Finally, we analyze in-depth the peculiar morphological MRI features of this tumor. CONCLUSION: The classification and treatment of medulloblastomas are likely to change in the coming years due to new insights into the molecular biology of medulloblastoma. Primary leptomeningeal medulloblastoma could represent another potential challenge for biologists to start exploring the underlying mechanisms of this different clinical and pathological entity, with different implications for diagnosis and its management.

Osteofibrous dysplasia: A rare case in 3-day-old female.

Osteofibrous dysplasia (OFD) is a nonneoplastic tumor-like lesion, made up of fibrous matrix with immature bone tissue surrounded by osteoblasts, occurring usually in the cortex of tibial diaphysis. OFD is usually seen in the first decade of life and, according to literature, it is rarely seen in the newborn period. Diagnosis of congenital OFD in the newborn is challenging because it is uncommon in this age group and can be confused with other bone benign or malignant lesions. Imaging plays an important role in diagnosis, although histological confirmation is often required. Our report presents a rare case of pathologically confirmed congenital OFD in 3-day-old female which presented with a swelling of her right leg. We will focus on imaging findings of OFD and main differential diagnosis of this lesion in neonatal age.

Early diagnosis of Meigs syndrome in children A case report and a review of the literature.

Meigs syndrome is a rare disease defined by the coexistence of benign ovarian neoplasm, ascites and hydrothorax, which mainly affects women over the age of 30. This clinical condition refers only to cases in which the ovarian neoformation is a fibroid, a thecoma, a granulosa cell tumor or a Brenner tumor with disappearance of symptoms and effusions after removal of the neoplasm. Meigs syndrome is most frequently characterized by the presence of an ovarian fibroid, which in childhood is very rare and not commonly associated with the disease. In this article we report the case of an 11- year-old girl who came to our observation for a high fever for five days accompanied by cough and abdominal pain; imaging methods revealed bilateral hydrothorax, ascites, and a voluminous expansive right ovarian formation. On histological examination, the mass showed a cellular fibroid and the diagnosis of Meigs syndrome was made. Furthermore, we present a review of the literature aimed at detecting the state of knowledge on this disease in pediatric age, giving particular emphasis to the condition for which, in the presence of pleural effusion and ascites, an ovarian neoformation is not necessarily malignant. KEY WORDS: CT, Meigs syndrome, Pediatric, Pelvic mass, Ultrasounds.

Midsternal bump: an infrequent localization of dermoid cysts.

A 5-month-old boy was evaluated for an unusually large presternal bump present since birth. The ultrasound examination revealed a well-defined soft tissue mass with an oval shape. The lesion demonstrated a regular and well-demarcated outline, with an upper margin that was thinned and inserted into the upper skin plane; the content was anechoic with a small echogenic formation, mobile with changes in the patient's decubitus. The histologic diagnosis was dermoid cyst. Although dermoid cysts are commonly seen in the midline, the midsternal location, found in our patient, is rare. Dermoid cysts can have ultrasonographic features similar to those of other subcutaneous cystic masses. However, if an anechoic cyst with an internal well-circumscribed echogenic ball-like formation is seen within the presternal subcutaneous fat layer, as in our patient, dermoid cyst should be considered in the differential diagnosis of subcutaneous cystic masses.

The Challenge of Melanocytic Lesions in Pediatric Patients: Clinical-Pathological Findings and the Diagnostic Value of PRAME.

Pediatric melanoma is a rare disease especially in children aged younger than 10 years old. Recent estimates report a rise of disease incidence in both adults and children. Diagnostic work-up is challenging in pediatric melanoma, as it displays a wide range of clinical presentations. Immunohistochemical biomarkers have been reported as predictors of malignancy in melanoma, however data specific to pediatric melanoma are poor. Our study aims to contribute to provide evidence of pediatric melanoma clinical features and differential diagnosis in this patient population. We describe our experience with a retrospective case series of pigmented skin lesions including malignant melanoma, atypical spitzoid tumor, and benign nevi in children and adolescents aged less than 16 years. We described the clinical and demographic characteristics of the cohort and evaluated the immunohistochemical expression of the PReferentially expressed Antigen in MElanoma (PRAME) for differential diagnosis of melanoma in children. The series displayed a similar distribution of melanoma between males and females, and the most common site of melanoma onset were the upper and lower limbs. In our cohort, PRAME was negative in most cases. Focal and slight positivity (from 1 to 5% of the neoplastic cells) was observed in four cases (two Spitz nevi and two atypical Spitz tumors). A moderate positivity in 25% of the neoplastic cells was observed in one case of atypical Spitz tumor. Immunohistochemical expression of PRAME might be useful in the differential diagnosis of malignant melanoma.

Ileal inflammatory pseudotumor in adolescent male patient with prior Burkitt lymphoma: A challenging diagnosis.

Inflammatory pseudotumor is a rare benign mesenchymal pediatric neoplasm, that can mimic tumoral residue or relapse at metabolic imaging with nonspecific clinical presentation and difficult diagnosis. We present the case of a 14year old male patient with fever of unknown origin and large ileal mass, diagnosed with and treated for Burkitt lymphoma, who performed several 18-fluoro-deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) scans, during and after first line chemotherapy, showing persistent and focal uptake, while ileal mass volume decreased dramatically and the patient was clinically asymptomatic. Histopathological analysis of residual ileal mass was suggestive for xanthomatous pseudotumor, a type of inflammatory pseudotumor. No more treatment was performed and a short-term follow up with 18F-FDG PET/CT showed tracer uptake intensity decreasing progressively over the next few months. This case reports an uncommon presentation of a rare disease, inflammatory pseudotumor of the small bowel developed at the site of treated Burkitt lymphoma, underscoring the potential role of 18F-FDG PET/CT imaging in the diagnosis and management of these rare neoplasms, particularly in asymptomatic patients.

WITHDRAWN: Congenital sialoblastoma in a newborn: diagnostic challenge of a rare entity.

Ahead of Print article withdrawn by publisher.

Desmoplastic infantile astrocytoma and ganglioglioma: a series of 12 patients treated at a single institution.

BACKGROUND: Desmoplastic infantile astrocytomas and gangliogliomas (DIA/DIG) usually present with a large size, large cystic component, large dural implant, encasement of big vessels, clinical presentation within 18 months of life, high incidence of seizures and overall good prognosis, even if tumour surgery can be very challenging at first procedure. METHODS: We retrospectively reviewed clinical and radiological data of patients diagnosed with desmoplastic infantile tumours who were surgically treated between 2008 and 2019. RESULTS: The series included 12 patients. The median age at surgery was 91 days. The average tumour volume was 212 cm3. Cystic components were predominant ranging from 0 to 295 cm3. Active hydrocephalus was pre-operatively evident in 5 cases. Eight patients (66.6%) received total or subtotal removal, three of them (25%) underwent partial removal, and one patient (8.3%) received a biopsy. One patient died within 24 h after surgery due to severe hypotension, as a consequence of significant intraoperative blood loss. Overall, seven (58.3%) patients were reoperated on the tumour after the first procedure: 4 patients were operated twice; 3 patients were operated 3 times. Two patients presented remote localizations and underwent chemotherapy. At last follow-up, 7 patients were tumour-free, 2 are alive with stable disease, and 2 are alive with progressive disease (leptomeningeal seeding). CONCLUSION: Desmoplastic infantile tumours are rare giant neonatal tumours. Total removal is the goal of treatment, but prognosis remains good even if total removal is not achieved. In case of tumour progression or epilepsy from residual tumour, reoperation is the first option, with chemotherapy reserved to unresectable or disseminated cases with mixed results, while, to date, radiotherapy still plays no role.

NTRK Fusions, from the Diagnostic Algorithm to Innovative Treatment in the Era of Precision Medicine.

In the era of precision medicine, the identification of several predictive biomarkers and the development of innovative therapies have dramatically increased the request of tests to identify specific targets on cytological or histological samples, revolutionizing the management of the tumoral biomaterials. The Food and Drug Administration (FDA) has recently approved a selective neurotrophic tyrosine receptor kinase (NTRK) inhibitor, larotrectinib. Contemporarily, the development of multi-kinase inhibitors with activity in tumors carrying TRK fusions is ongoing. Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes result in constitutive activation and aberrant expression of TRK kinases in numerous cancer types. In this context, the identification of tumors harboring TRK fusions is crucial. Several methods of detection are currently available. We revise the advantages and disadvantages of different techniques used for identifying TRK alterations, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and next generation sequencing-based approaches. Finally, we propose a diagnostic algorithm based on histology and the relative frequency of TRK fusions in each specific tumor, considering also the economic feasibility in the clinical practice.

PATZ1 Is Overexpressed in Pediatric Glial Tumors and Correlates with Worse Event-Free Survival in High-grade Gliomas.

Glial tumors are the leading cause of cancer-related death and morbidity in children. Their diagnosis, mainly based on clinical and histopathological factors, is particularly challenging because of their high molecular heterogeneity. Thus, tumors with identical histotypes could result in variable biological behaviors and prognoses. The PATZ1 gene has been recently shown to be expressed in adult gliomas, including glioblastomas, where it correlates with the proneural subtype and with a better prognosis. Here, we analyzed the expression of PATZ1 in pediatric gliomas, first at mRNA level in a public database, and then at protein level, by immunohistochemistry, in a cohort of 52 glial brain tumors from young patients aged from 6 months to 16 years. As for adult tumors, we show that PATZ1 is enriched in glial tumors compared to the normal brain, where it correlates positively and negatively with a proneural and mesenchymal signature, respectively. Moreover, we show that PATZ1 is expressed at variable levels in our cohort of tumors. Higher expression was detected in high-grade than low-grade gliomas, suggesting a correlation with the malignancy. Among high-grade gliomas, higher levels of PATZ1 have consistently been found to correlate with worse event-free survival. Therefore, our study may imply new diagnostic opportunities for pediatric gliomas.