International perspective on pediatric cytology

Cytopathology is an efficient and cost-effective tool for diagnosing pediatric lesions worldwide, and there is increasing use and global literature describing cytopathology in the pediatric age group. Although there is some overlap with adults, many diagnostic entities are unique to the pediatric population. In the current era of personalized treatment and targeted therapies, it is more important than ever to have proper identification, classification, and management recommendations specific to the pediatric population.

There are many advantages to fine-needle aspiration biopsies (FNABs): they are quick to perform and for reaching a diagnosis, and they are highly cost-effective. A multi-institutional study in South Africa has shown high diagnostic accuracy in a resource-limited setting.¹ A major advantage is that FNABs can be performed in the clinic or at the bedside, and do not need to be performed in the operating room. Some children may even tolerate FNA biopsy without a general anesthetic. This makes FNABs especially useful in low-resource settings, as well as in areas where operating room availability may be limited or delayed. Additionally, diagnostic accuracy is also very high, even more so with the availability of ancillary testing. The sensitivity, specificity, and accuracy of FNABs in diagnosing malignant pediatric tumors is excellent throughout the global literature, with rates of 94%–100%, 92.7%–94.0%, and 97.7%–100%, respectively, in two reports,^{2, 3} and with many other reports in the literature of high diagnostic accuracy.^4-7 FNABs are also low risk and minimally invasive, with very low complication rates, which are reported at 1%.^{4, 8} As such, reports from throughout the world have shared success of pediatric FNABs, including head and neck masses in Nigeria,⁹ lymphadenopathy in Sudan,¹⁰ various tumors in India,¹¹ deep organ tumors in South Africa,¹² and many more.

Various types of cytologic specimens are reported in the pediatric age group in daily cytopathology practice. As in adult practice, nongynecologic exfoliative specimens are very common, which comprised 97.0% of cases (including bronchoalveolar lavage and cerebrospinal fluid) in one report.¹³ FNABs are less common but often more diagnostically challenging, and thus will be the focus of this report. Although FNABs are relatively rare in the pediatric population, it is the diagnostic specimen of choice for thyroid and salivary gland lesions. Rarely, FNABs are performed for pancreatic/gastrointestinal and mediastinal/lung lesions via endoscopic ultrasound guidance and endobronchial ultrasound guidance, respectively. These biopsies are limited in practice and in the literature because of the rare nature of these lesions, limited availability of trained pediatric proceduralists, and anatomic limitations in very small children. FNABs are also very useful for soft tissue lesions, lymph nodes, and solid organ lesions, often in conjunction with rapid onsite evaluation (ROSE) and immediate tissue triage by a cytopathologist, and sometimes in conjunction with core needle biopsy.

Although the widely and globally adopted standardized reporting systems for cytopathology specimens do not exclude the pediatric population, it is important to focus on and evaluate these reporting systems in the pediatric population specifically. Special consideration is due because the entities and management in the pediatric population are often different from those in the adult population. The recent pediatric cytology symposium in Australia, where global pediatric cytopathologists were gathered, highlighted this fact, and called for international pathologists to share their experience.^{14, 15}

Thyroid nodules are uncommon in the pediatric population (0.5%–5% of children and 13% of adolescents); however, when present, they are more likely to be malignant (22%–26%) than in the adult population.¹⁶ Some specific pediatric populations with predisposing environmental factors or genetic risk factors are more prone to develop malignant thyroid carcinoma. When developed, these malignant thyroid carcinomas are more likely to present with extrathyroidal extension, regional lymph nodes, and distant (usually lung) metastasis and recurrence, although the reported mortality in these age groups is less than in the adult population.¹⁷ Nevertheless, The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is used in the pediatric setting, and there is a growing body of literature describing the use of TBSRTC in pediatric patients. A recent meta-analysis included 17 articles investigating the use of TBSRTC in pediatric thyroid nodules, and found a higher resection rate and similar risk of malignancy as in adults.¹⁸ An additional recent publication described the performance of TBSRTC in a large cohort of pediatric thyroid nodules from four institutions in two countries. This study reports a higher risk of malignancy than in the adult population but also high surgery rates, such that only 50% of patients operated on had a malignant diagnosis.¹⁹ The updated 2023 edition of TBSRTC has newly included percentages for the risk of malignancy for the six diagnostic categories for pediatric patients, as follows: nondiagnostic: 14% (0%–33%); benign: 6% (0%–27%); atypia of undetermined significance (AUS): 28% (11%–54%); follicular neoplasm: 50% (28%–100%); suspicious for malignancy: 81% (40%–100%); and malignant: 98% (86%–100%).²⁰ Possible management recommendations for pediatric thyroid FNAB diagnoses are also included; AUS diagnoses may undergo repeat FNABs or surgical resection, whereas follicular neoplasm, suspicious for malignancy, and malignant diagnoses should be followed by surgical resection.

Similar to the cytology reporting for thyroid nodules, the management guidelines for thyroid nodules are also not strictly defined for the pediatric population. The American Thyroid Association (ATA) put forth a recommendation for the management of pediatric thyroid nodules and differentiated carcinomas in 2015,²¹ which was not adopted globally. In 2022, with the recommendation made by the ATA, the European Thyroid Association also put forth their recommendation for the management of pediatric thyroid nodules and differentiated carcinomas.²²

The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was first introduced in 2018, with the second edition published in 2023. Although the MSRSGC primarily focuses on adult patients, some institutional experiences in the pediatric population have been published. A recent multicenter international retrospective study with 477 pediatric aspirates found that the MSRSGC can be reliably applied to salivary gland FNABs in the pediatric population.²³ Additional smaller studies have also shown that the MSRSGC performs well in the pediatric population.^{24, 25} A recent study suggests that the nondiagnostic MSRSGC category in the pediatric population has a minimal risk of malignancy, and thus may be followed clinically/radiologically only.²⁶

Soft tissue lesions are relatively rare, and can be difficult to diagnose because of many overlapping patterns and a wide spectrum of diagnoses. Although FNAB cytopathology can be a reliable method of distinguishing benign soft tissue lesions from malignant soft tissue lesions, additional ancillary testing and/or core needle biopsy is often needed for a definitive diagnosis of soft tissue lesions. Immunocytochemistry and other ancillary studies including fluorescence in situ hybridization have been reported to be useful in subtyping malignant soft tissue lesions.²⁷ Additional studies found that FNAB could accurately classify pediatric soft tissue and bone sarcomas when used in conjunction with ancillary studies and core needle biopsy.^{28, 29}

Although undervalued, lymph node FNAB for lymphadenopathies in the pediatric population has been reported to have a high sensitivity, specificity, positive predictive value, and negative predictive value of 93%, 100%, 100%, and 98%, respectively, according to one report.³⁰ The application of ROSE during FNAB helps to triage inflammatory/reactive lymphadenopathies from neoplastic processes and to facilitate the collection of additional samples for additional studies, which are often necessary to make a definitive diagnosis. Although many times a core or excisional biopsy specimen is needed to adequately diagnose and categorize lymphoproliferative disorders, lymph node FNABs are often helpful in diagnosing inflammatory/reactive conditions, and thus in preventing unnecessary surgical intervention. At some institutions, FNAB has been shown to be an effective diagnostic tool for the accurate and rapid diagnosis of nodal tuberculosis in children.³¹ The use of FNAB to diagnose nonneoplastic entities and exclude malignancy may be underused in parts of the world with robust health care infrastructure. A recent systematic review of pediatric cervical lymphadenopathy found that FNAB can be used to avoid a surgical biopsy in up to 61% of cases.³² Given that pediatric lymphadenopathy is common and rarely malignant, the primary use of FNAB should be considered across the globe.

In conclusion, the published literature in pediatric cytopathology supports that FNAB is an efficient, less invasive, and reliable method for diagnosing a wide variety of pediatric entities throughout the world. However, the lack of standardized reporting systems for various organs in cytopathology specifically published for the pediatric population and their wide adoption are still challenges for global pediatric cytopathologists to overcome. To further the wide adoption of pediatric cytopathology, global cytopathologists should come together in a pediatric cytopathology–specific consortium where the challenges and advantages of these special age groups can be discussed and streamlined.

The authors declare no conflicts of interest.