Children suffering from NSCLC may be entirely asymptomatic, present respiratory or constitutive symptoms. Dyspnea, tachypnea, wheezing, persistent cough, hemoptysis, and refractory respiratory infections may be noted and may be accompanied by chest pain that worsens with deep breathing, laughing, or coughing [1] [2] [3] [4] [5]. Respiratory symptoms may aggravate when air escapes from cystic tumors into the pleural space, thereby causing a pneumothorax. On the other hand, children with NSCLC tend to lose their appetite and weight. They may suffer from fever, feel increasingly tired, show poor academic and physical performance.

One of the more common types of NSCLC is pulmonary carcinoid, a neuroendocrine tumor that may possibly provoke hormonal imbalances and/or carcinoid. These are paraneoplastic syndromes that result from the secretion of corticotropin, serotonin, and other mediators. They are rarely observed in patients with early-stage pulmonary carcinoid and are more likely to occur with large tumors, tumors that drain into circulation, and metastatic disease [4]. Non-carcinoid NSCLC may also form metastases and thus cause additional symptoms that depend on the localization of secondary tumors. Pleuropulmonary blastoma preferentially spreads to the central nervous system, bones, and liver.

The diagnosis of childhood NSCLC is based on the same techniques employed in adult patients [6]:

• Mass lesions observed in images are often the first sign that neoplastic processes may occur. Atelectasis and pulmonary infiltrates may also be observed. While chest X-rays are obtained first in the majority of cases, radiography is usually complemented by computed tomography, positron emission tomography, or scintigraphy to better assess the size and localization of the primary tumor, to evaluate the invasion of adjacent tissues and the presence of metastases [3].
• The cytological analysis of sputum may confirm the presence of cancer cells.
• Biopsy samples must be obtained to characterize the tumor, to differentiate between pleuropulmonary blastoma, pulmonary carcinoid, inflammatory myofibroblastic tumor, carcinoma, and other types of NSCLC. These same samples may be used for molecular testing, which is the basis for targeted therapies.
• Lung function tests give an idea about possible respiratory impairment and may be realized repeatedly over the course of the disease. They allow for a continuous evaluation of the patient but don't contribute to the diagnosis of NSCLC.

The spontaneous development of primary NSCLC in childhood is very rare. In most cases, the family or medical history of the young patient does provide indications as to possible causes. Triggers of childhood NSCLC may provoke other types of cancer, too, and should be determined to set up an adequate surveillance program. What's more, the identification of hereditary conditions predisposing to lung cancer and other malignancies should prompt a genetic workup, so affected relatives can also be monitored.

Sometimes, the histological features of childhood NSCLC strongly point to the underlying disease. This applies to one of the most common types of childhood NSCLC, to pleuropulmonary blastoma, which shall be discussed by means of an example. While type 1 pleuropulmonary blastoma takes the form of one or more pulmonary cysts, type 3 is entirely solid. Type 2 pleuropulmonary blastoma comprises cystic and solid parts and constitutes a transitional form between the other two. In type 1 pleuropulmonary blastoma, primitive mesenchymal cells form air-filled cysts that are lined by benign-appearing epithelium. The proliferation of these mesenchymal cells eventually results in the formation of nests and focal solidification. Solid areas of pleuropulmonary blastoma consist of a collage of primitive sarcomatous patterns resembling embryonal rhabdomyosarcoma, spindle cell sarcoma, or fibrosarcoma, plus blastemal islands surrounded by primitive mesenchyme, cartilaginous nodules, and anaplastic cells with large, bizarre nuclei and atypical mitotic figures [7]. These findings lead to the diagnosis of pleuropulmonary blastoma and warrant genetic studies to test for DICER1 mutations. If DICER1 syndrome is confirmed, the patient should be examined for characteristic comorbidities [3].

The therapeutic approach largely depends on the type, grade, and stage of NSCLC [5]:

• Pleuropulmonary blastoma requires surgery. If the tumor cannot be removed in its entirety, neoadjuvant chemotherapy may be applied to reduce the bulk. With regards to adjuvant treatment, chemotherapy is also preferred. Radiotherapy may be considered if the neoplasm fails to respond to chemotherapy and cannot be resected.
• Similarly, surgery is the first-line treatment of pulmonary carcinoid [4] [8].
• Treatment of inflammatory myofibroblastic tumor is primarily a complete but conservative surgical excision. Surgery may be complemented with chemotherapy if the tumor cannot be resected in its entirety [1]. Notwithstanding, there are case reports about the favorable response of affected children to immunotherapy. Crizotinib has been shown to induce the remission of inflammatory myofibroblastic tumor [9] [10]. It acts as a tyrosine kinase inhibitor and may be administered according to the molecular features of childhood NSCLC. Promising results have also been achieved with racotumomab, an antibody targeting membrane glycoconjugates expressed in aggressive solid tumors [11].

Pulmonary carcinoid has a low malignant potential and is related to a favorable prognosis, even in the presence of metastasis to the regional lymph nodes [8] [12]. Five-year survival rates differ between typical and atypical carcinoids and amount to 90 and 60%, respectively [4] [12].

Type 1 pleuropulmonary blastoma is associated with a good prognosis and five-year survival rates of 89%. Progression to type 2 or type 3 pleuropulmonary blastoma reduces the likelihood of a favorable outcome, with only 71 and 53% of affected children remaining alive five years after the initial diagnosis [13].

Inflammatory myofibroblastic tumors are characterized by their tendency to local recurrence and a small, but non-negligible risk of distant metastasis [14]. Nevertheless, five and ten-year survival rates have been estimated at 89% [1].

Genetic alterations and cancer predisposition syndromes may contribute to the individual risk of pediatric NSCLC [15]. One of these conditions is the DICER1 syndrome, which predisposes to pleuropulmonary blastoma, cystic nephroma, sex cord tumors of the ovary, thyroid neoplasms, and embryonal rhabdomyosarcoma. The penetrance of germline mutations of the DICER1 gene is <15%, and it a second, somatic hit has been speculated to be required for tumorigenesis in these patients [16]. Pleuropulmonary blastoma as a type of childhood NSCLC typically manifests in children aged <5 years [13]. Furthermore, lung cancer has been described in patients with Li-Fraumeni syndrome. The latter is caused by mutations of the TP53 tumor suppressor gene and predisposes to soft-tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, adrenocortical carcinoma, and lung cancer, among others. The diagnosis of tumors related to Li-Fraumeni syndrome follows a bimodal distribution, with many patients being diagnosed before the age of 10 and a second peak between the ages of 30 and 50 years [15]. Children and young adults may thus present with multiple primary neoplasms including NSCLC.

Besides genetic factors, environmental influences may promote cancerogenesis. Smoking is the single most important risk factor for NSCLC in adults, and variations in the regional incidence directly reflect smoking prevalence [17]. Children don't typically smoke, but they may be exposed to environmental tobacco smoke, and in this context, it has been confirmed that passive smoking during childhood increases the lung cancer risk in adulthood by more than threefold [18]. Yet, such detrimental consequences of passive smoking or exposure to other air pollutants will only be visible in the longer term and don't usually result in pediatric lung cancer.

Pediatric exposure to ionizing radiation is another risk factor for the premature development of NSCLC and primarily occurs in the scope of radiotherapy. Children are considered to be more sensitive to radiation than adults because of their developing organs and tissues, but also due to their longer post-exposure life expectancy. Similar to what has been stated with regard to smoke exposure, decades may pass until radiation-induced secondary malignancies are diagnosed. In rare cases, though, they may be identified before adulthood [19].

Finally, primary malignancies metastasizing to the lungs may result in secondary childhood NSCLC [5].

Lung cancer is the leading cause of cancer-related mortality, and about 85% of all cases correspond to NSCLC [17]. The median age of patients with newly diagnosed NSCLC is 71 years, with patients aged <40 years being considered "young patients". They account for about 1% of all cases, and even within this group of patients, pediatric NSCLC is an increasingly rare entity [20]. There's some literature about pleuropulmonary blastoma, inflammatory myofibroblastic tumor, and pulmonary carcinoid, the most common types of childhood NSCLC, while few cases are documented with regards to other conditions [5].

According to a long-term study conducted in the United States, pulmonary carcinoid, inflammatory myofibroblastic tumor, and pleuropulmonary blastoma are the most common types of childhood lung cancer. Small-cell carcinoma and adenocarcinoma have also been identified [5]. Primary pulmonary rhabdomyosarcoma and fibrosarcoma have been described elsewhere [21] [22]. Little is known about the events triggering cancerogenesis in any of these cases, which is best illustrated by the "evolution" of the aforementioned inflammatory myofibroblastic tumor: Initially, it had been classified as an inflammatory pseudotumor [14]. It was then considered a benign neoplasm of the lung and has finally been named a clonal neoplasm with myofibroblastic and fibroblastic differentiation and malignant potential. Still, inflammatory cells are characteristic of this type of tumor, and affected children typically present with laboratory findings of chronic inflammation such as leukocytosis, elevated platelet count, hypergammaglobulinemia, and increase of erythrocyte sedimentation rate and C-reactive protein [1]. Further research is required to identify the pathophysiological events that link inflammatory processes in the airways with the uncontrolled proliferation of fibroblasts and myofibroblasts.

Families known to harbor mutations predisposing for childhood NSCLC and other types of cancer may benefit from genetic counseling. Family members at risk should be identified and included in surveillance programs, which may not prevent the development of neoplasms but allow for their early recognition. Such measures should not be limited to pulmonary lesions but be extended to comorbidities characteristic of the respective syndrome. For instance, those diagnosed with pleuropulmonary blastoma due to DICER1 mutations should be examined for cystic nephroma and vice versa. Because some types of childhood NSCLC are known to affect very young children, as is the case with pleuropulmonary blastoma, surveillance should be started early in life. Lung cysts may even be detected during prenatal diagnosis [7]. Still, no consensus has yet been reached as to the optimum frequency and extent of preventive cancer screenings [23] [24].

With regards to those tumors that develop in the absence of known genetic disorders, no recommendations can be given to prevent the onset of childhood NSCLC.

Primary lung cancer is rarely seen in pediatric patients. Notwithstanding, a wide range of histopathological tumor types may be identified. The incidence of these lesions, risk factors contributing to tumor development, and the prognoses associated with specific diagnoses are still largely unknown. Therapies are usually limited to standard cancer treatment, i.e., surgery, chemotherapy, and radiation.

This article shall provide an overview of pulmonary malignancies that may be seen in pediatrics, where delays in the workup are frequently attributable to the apparent improbability of the diagnosis. Awareness shall be raised to prevent such delays, to accelerate the diagnosis of childhood NSCLC, and to improve the prognosis of the young patients.

Childhood non-small cell lung cancer (NSCLC) is a rare type of lung cancer. In adults, smoking is the single most important risk factor for lung cancer, but the development of pulmonary malignancies in children is triggered by other factors. In detail, children may be genetically predisposed to NSCLC or may develop such lesions after suffering from other types of cancer. The symptoms of childhood NSCLC are non-specific and comprise breathing difficulties, persistent cough, bloody sputum, and recurrent respiratory infections. They may complain about chest pain, feel increasingly tired, show poor academic and physical performance. Fever is another common symptom, and the patients may also lose their appetite and weight. Others remain entirely asymptomatic. A thorough workup is the basis for an early diagnosis, which improves the patient's prognosis. Five-year survival rates of children with NSCLC amount to approximately 90%.

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