Jochen Hubertus and Dietrich von Schweinitz

5Tumors in childhood and adolescence

5.1Introduction

5.2Primary lung tumors in childhood and adolescence

5.2.1General considerations

Primary lung tumors are extremely rare entities in children and adolescents. In most cases, diagnosis is difficult owing to the non-specificity of the symptoms and rarity of the disease. The overall incidence of primary, malignant, pediatric lung tumors is estimated to be 0.5 per 1,000,000 children and adolescents younger than 19 years of age, comprising only 0.2% of all pediatric malignancies [1]. In contrast, the incidence of benign lung tumors is 5 times higher, and that of metastatic lung lesions originating from Wilms tumors, osteosarcomas, Ewing sarcomas or rhabdomyosarcomas is 60 times higher [2]. Neville et al. reported an equal sex ratio, as observed in other studies [1]. The median age at diagnosis is 16 years, and the incidence increases with age; 65% of patients are between 15 and 19 years of age [1].

Unspecific symptoms are specific for primary lung tumors in this cohort. They include cough, wheezing, hemoptysis, and recurrent pneumonia [3]. Owing to this unspecific appearance and the rarity of the disease, patients are treated for respiratory infections first, and diagnosis is often delayed for up to 1 year [4, 5]. Despite this delay, the prognosis of these lesions is good to excellent for most entities [1]. The exceptions are malignancies commonly appearing later in life, including squamous cell carcinoma (SCC), adenocarcinoma and small cell lung carcinoma (SCLC). One third of these tumors would have already metastasized at time of diagnosis, and the prognosis of these patients decreases to 28% [1].

As previously described, both benign and malignant tumors are observed, while metastatic diseases are the most clinically relevant. The most common malignant histology of primary pulmonary tumors is carcinoid tumors (51.3%–63%), followed by mucoepidermoid carcinoma (9%–18%), SCC (4.5%–9%), adenocarcinoma (6.5%–8%), broncheoalveolar carcinoma (2%), SCLC (1%), pulmonary blastoma (4.5%) and others (3.9%) [1, 3].

Benign tumors include inflammatory myofibroblastic tumors (42%), arteriovenous malformations (29%), hemangiomas (11%), lymphatic/venous malformations (11%), papillomas (5%), leiomyomas (1%), mucus gland tumors (1%) and others (1%) [2, 6].

Treatment is sometimes complicated by the rarity of the tumors and their delayed diagnosis. As such, no standardized treatment protocols exist, and therapy is guided by personalized strategies. In this context, surgery plays a crucial role because complete resection of the tumor is usually feasible and essential to cure the patient. Negative predictive factors related to surgery are tumor size (>5 cm) and positive lymph nodes [3]. Another negative predictor is histology. In particular, SCC, adenocarcinoma and SCLC have poor outcomes. The different entities and their specific characteristics will be described in detail hereafter.

5.2.2Bronchial carcinoid tumor

Bronchial carcinoid tumors account for 51.3%–63% of primary lung tumors in children and adolescents [1, 3], with an incidence of 0.25 per 1,000,000 children and adolescents younger than 19 years of age [1]. They belong to the so-called neuroendocrine tumors that can arise in almost every part of the body. Most of the well-differentiated neuroendocrine tumors are located in the intestine, while 25% originate from neuroendocrine cells in the bronchi, known as enterochromaffin cells or Kulchitsky cells [7]. More than 90% of carcinoid tumors are considered low-grade malignant tumors (<2 mitoses/10 high-power fields [HPF], nuclear pleomorphism and absence of necrosis) [7, 8]. In general, neuroendocrine bronchial tumors range from low-grade (typical bronchial carcinomas, Grade 1) to intermediate-grade (atypical bronchial carcinoids, Grade 2) to high-grade (large cell neuroendocrine carcinoma and SCLC, Grade 3) malignancies [7]. The molecular biology and cytogenetics of carcinoid tumors are still under investigation. In contrast to other carcinoid tumors, the bronchial ones do not seem to be associated with multiple endocrine neoplasia type 1 (MEN-1), an autosomal dominant genetic disorder otherwise associated with tumors of multiple endocrine organs. Sporadic neuroendocrine/carcinoid tumors have been linked to loss of heterozygosity at the MEN1 locus (chromosome 11q13) [9]. Deletions of chromosome 11q were identified in 66% of atypical and 47% of typical carcinoid tumors. The 11q deletion was rarely identified in poorly differentiated neuroendocrine lung cancers [10].

5.2.2.1Typical and atypical bronchial carcinoids (Grade 1/2)

Clinical presentation

Since both types of bronchial carcinoids are always located centrally in the bronchial tree, they become conspicuous, with symptoms of central obstruction, cough, hemoptysis, asthma-like symptoms or recurrent pneumonia. These symptoms are unspecific, but their recurrence in a child with obstructive pneumonia localized in the same lobe, persistent cough or wheezing that is not responsive to the usual therapy should alert the physician and suggest diagnostic procedures such as chest X-ray and bronchoscopy [8]. Carcinoid syndrome, which presents with flushing, diarrhea, palpitations and asthma-like symptoms, is caused by serotonin release from the tumor. Unlike in the gut, classic carcinoid syndrome is rare in bronchial carcinoids and is generally associated with metastatic disease [8, 11].

Diagnosis and imaging

Upon encountering the persistent symptoms described above, physicians should be aware of bronchial carcinoids as a rare, but important differential diagnosis. As a first diagnostic step, a chest radiograph is required. Additionally, endoscopy plays a central role in the diagnosis and initial management of carcinoids. A bronchial biopsy should be taken whenever possible. The macroscopic appearance of a bronchial carcinoid is a smooth, pink–reddish or yellow endobronchial mass often covered by intact mucosa [8]. Despite harvesting a biopsy for histological confirmation of the diagnosis, debulking of the obstructing mass with or without a laser is also feasible. The physician should be aware of the risk of a major hemorrhage, and careful endoscopic assessment should only be performed in specialized centers with great experience.

Laboratory parameters include chromogranin A, neuron-specific enolase (NSE), and serotonin. Urinary tests with 24-hour urinary excretion of 5-hydroxyindolacetic acid are also indicated [12]. Computed tomography (CT) of the chest with intravenous contrast enables the visualization of extra-bronchial components to distinguish tumors from atelectasis and staging of the disease. An ultrasound study of the upper abdomen is also recommended. An octreotide scintigraphy scan is useful in the case of disseminated disease or Cushing’s syndrome for staging; it can also be useful during follow-up to detect local recurrence or distant metastasis. Due to the high grade of differentiation of typical bronchial carcinoids and its low metabolic activity, the role of fluorodeoxyglucose–positron emission tomography (F18-FDG-PET) scanning is more uncertain [8]. In fact, gallium-68 (Ga-68-) DOTA-PET seem to be the PET tracers of choice in the initial evaluation of patients with suspected bronchial carcinoids (Fig. 5.2.1). In this setting, Ga-68-somatostatin analogue PET/ CT could be performed primarily and, if negative, F-18-FDG PET/ CT could be performed subsequently [13].

Treatment

Surgery represents the treatment of choice for pulmonary carcinoids, achieving longterm survival in cases of radical resection in both adults and children [14]. Since most tumors are low-grade, lung-sparing surgery is feasible in almost all cases and should be performed whenever possible. In addition, resection can be performed with free margins of only 1–2 mm without an increase in the local recurrence rate. Oncological results are similar to those of pneumonectomy, but the quality of life and orthopedic outcomes are better after lung-sparing surgery [14], compromising bronchoplasty, wedge resection or sleeve resection (Fig. 5.2.2).

Fig. 5.2.1: PET/CT scan of an typical carcinoid of the right lower bronchus.

Lymph-node dissection should always be performed during tumor resection. However, whether a radical lymph-node dissection is necessary for bronchial carcinoid treatment or whether lymph-node sampling might be enough remains controversial. The prognostic relevance of lymph-node involvement in adult bronchial carcinoid has been described [15], but this is not yet established for children.

Fig. 5.2.2: Bronchoscopic view after resection of the carcinoid.

Currently, there is no consensus on adjuvant therapy in pulmonary carcinoids after complete resection. Indeed, both prognostic studies and trials in the adjuvant setting are lacking. Only patients with atypical carcinoids with positive lymph nodes, especially if there is a high proliferative index, should be considered for adjuvant therapy and on an individual patient basis in the context of a multidisciplinary tumor board meeting. Clinical trials are needed in this setting [16].

Prognosis

Even if the prognosis is excellent after complete tumor resection (20-year disease-free survival of 94% [8]), long-term follow-up is strongly recommended because late, local recurrences have been described.

5.2.3Mucoepidermoid carcinoma of the bronchus

Mucoepidermoid carcinoma, as defined by the World Health Organization, is a combination of mucus-secreting, squamous and intermediate cell types. These three cell types can be organized into different patterns including glands, tubules, cysts, nests and solid areas. The relative frequency of these three cell types in a given case varies considerably and serves as one of the histologic criteria for grading this tumor. It is not uncommon in adults, but it is rare in children, even if the true incidence is unclear. The majority of the literature consists of case reports or small series. Mucoepidermoid carcinoma of the lung, however, is rare, with a reported frequency of 0.1% to 0.2% of all primary lung tumors. Usually, mucoepidermoid carcinomas arise in the parotid and submandibular salivary glands and in the minor salivary glands of the oral cavity and perimaxillary region. Mucoepidermoid carcinoma of the bronchus occurs in patients with a wide range of ages (from 3 to 78 years), and both sexes are affected equally [17].

Clinical presentation

Since mucoepidermoid carcinomas arise from salivary glands of the main bronchial tree, the clinical symptoms are unspecific and manifest as central airway obstruction with cough, hemoptysis, bronchitis, wheezing, fever and chest pain [18]. Owing to these unspecific symptoms, diagnosis is delayed in most cases.

Diagnosis and imaging

Mucoepidermoid carcinomas typically arise from bronchial mucous glands in the main stem bronchus or in the proximal portion of lobar bronchi as an endobronchial polypoid growth. Similar to the recommendations for bronchial carcinoids, every therapy refractory finding of obstructive pneumonia should lead to further investigations, starting with a chest radiograph and a bronchoscopy. However, since the tumor is covered by normal respiratory epithelium, bronchial lavage and brushing are seldom diagnostic, and forceps biopsy must be performed. Mucoepidermoid carcinomas usually present as exophytic luminal masses, which can be sessile or polypoid with a broad base connected to the bronchial wall, or pedunculated with a well-formed stalk. The cut surface is gray-white-tan with a glistening mucoid texture. Cystic degeneration can be observed in some mucoepidermoid carcinomas. The size of the tumor varies considerably within a range from several mm to 6 cm in diameter in some studies [17].

An additional chest CT scan with contrast media is necessary to visualize the size, location and involvement of the surrounding structure of the tumor. In general, lymph nodes are not involved, but they should be considered. Radiological findings include hilar or perihilar masses and associated obstructive changes (atelectasis, consolidation, bronchocele or hyperinflation) [19].

Finally, diagnosis is made histologically. As mentioned previously, mucoepidermoid carcinomas consist of three cell types that serve as one of the histologic criteria for tumor grading. The coexistence of three cell types is very characteristic for a lowgrade mucoepidermoid carcinoma, but some debate remains regarding the definition of high-grade mucoepidermoid carcinoma. High-grade lesions usually demonstrate necrosis, nuclear pleomorphism, active mitosis and a solid or nested pattern of growth for the intermediate or squamous cells. In the literature, most mucoepidermoid carcinomas of the bronchus are categorized as low grade, but high-grade mucoepidermoid carcinomas arising from the bronchus have been reported in adults with a frequency as high as 50% in a few small series. Low-grade mucoepidermoid carcinoma is usually confined to the bronchus and does not involve adjacent lung parenchyma. However, in high-grade neoplasms, the tumor can infiltrate into the surrounding lung parenchyma [17, 18, 20].

Recent cytogenetic studies independently demonstrated several reciprocal chromosomal translocations frequently involving chromosome 11. Translocations of t(1;11)(p22;q13) result in overexpression of cyclin D1, and the translocations t(11;19) (q14-21;p12) and t(11; 19)(q21;p13) are capable of disrupting the Notch signaling pathway since they encode a novel fusion product, MECT1-MAML2 [17, 21].

Treatment

The regimen depends on the histological sub-type. Since low-grade tumors have a low risk of local and distal recurrences, treatment is surgical, and lung-sparing surgery is the technique of choice that can be performed as a sleeve resection, local resection, segmental resection or even lobectomy. In general, neither pneumonectomy nor endoscopic resection is recommended.

One study reported 54 patients with disease-free follow-up from 8 months up to 21 years. One patient with lymph node metastasis died, one patient developed lymph node metastasis 5 years after the initial treatment and one patient had questionable lymph node metastasis [18]. Owing to the possibility of late-onset metastatic disease, patients with mucoepidermoid carcinoma of the lung should be provided with longterm clinical follow-up. Even if the likelihood of high-grade mucoepidermoid carcinomas is extremely rare in childhood, treatment is directed by local infiltration, tumor size and lymph node metastasis. In this case, therapy is more aggressive and has to be adapted to the individual case.

5.2.4Adenoid cystic carcinoma

The third entity of salivary gland tumors is adenoid cystic carcinoma. Typically, they arise in the lower part of the trachea or main stem bronchi, and they show extra-luminal growth [22]. These tumors are extremely rare in childhood, and only two cases have been reported [23, 24]. As for all of the other tumors described thus far, the symptoms are unspecific and include bronchial irritation or obstruction, such as cough, hemoptysis, atelectasis or pneumonitis.

The main diagnostics include a CT-scan of the chest and bronchoscopy. In contrast to bronchial carcinoids and mucoepidermoid carcinoma, adenoid cystic carcinomas are seldom observed with bronchoscopy due to the extraluminal growth.

Treatment consists of complete resection whenever feasible, adjuvant chemotherapy and radiation [5]. Neoadjuvant chemotherapy was not administered in the published reports. The surgical procedure depends on the localization and extension of the primary tumor. Resection of the trachea and reconstruction of the continuity, lobectomy, sleeve resection or even pneumonectomy are potential options.

Prognosis is poor and 8-year survival is 19.5% in adults [5]. Prognosis depends on surgery, early resection, (lung) metastasis and extra luminal extension of the tumor. Therefore, early diagnosis is mandatory for survival [5].

5.2.5Pulmonary blastoma

Pulmonary blastomas are rare, primary lung neoplasias. The first peak incidence occurs in childhood, and 20%–25% of cases occur before 15 years of age [25]. Girls are slightly more affected (2.6:1 f:m) [26]. The etiology is still unknown, but there were some cases described in siblings with a germ-line mutation and another with proven Epstein-Barr virus infection. Finally, some pulmonary blastomas seem to arise within cystic pulmonary diseases (CPAM) [27].

These tumors are structured as fetal lung with mesenchymal and epithelial differentiation, and the primitive epithelial tissue is embedded in immature embryonic mesenchyme with areas of cartilaginous and/ or striated muscle differentiation [27].

Clinical presentation

This tumor appears as a solid mass, sometimes with cystic areas, on chest radiographs (Fig. 5.2.3). The space-occupying mass displaces the remaining lung and a mediastinal shift occurs [27]. Further diagnostics include a CT-scan (Fig. 5.2.4) and magnetic resonance imaging (MRI) to reveal infiltration of surrounding structures, the dimensions of the tumor, lymph node involvement and compression of the trachea and major vessels. Bronchoscopy and a biopsy complete the diagnostics [25]. Histologically, pulmonary blastoma is a biphasic tumor consisting of immature or primitive epithelial and mesenchymal components and resembles an embryonic lung. The epithelial component is composed of glands lined by columnar cells with glycogen-filled vacuoles, often resembling fetal adenocarcinomas. Squamoid morules may also be observed, and the mesenchymal component is primitive, consisting of spindle to oval cells in a myxoid stroma, sometimes including osteosarcoma, chondrosarcoma or rhabdomyosarcoma [28].

Management

Complete resection of the tumor should be targeted. However, infiltration of surrounding structures and friability of the tumor may complicate excision. In these cases, surgery is limited to obtain tissue for histology and to reduce the tumor burden. Even in cases of macroscopically complete resections, local recurrence within a few months is quite common. Irrespective of the success of the surgery, recurrence seems to occur during the first year after diagnosis or not at all. Larsen et al. reported successful surgical excision of local recurrences in a few cases [29].

Fig. 5.2.3: Plain chest radiograph of a patient with pulmoblastoma.

Fig. 5.2.4: Corresponding chest CT scan with large mass of pulmoblastoma.

In contrast, the role of chemotherapy and radiation for the treatment of pulmonary blastoma is still unclear owing to the lack of data [29]. Sarnacki et al. reported of their experience with nine cases of pulmonary blastoma; they stated that owing to the high chemosensitivity of these tumors, pneumonectomy should be avoided for otherwise unresectable tumors and the decision to administer radiotherapy should be restricted to cases of persistent viable tumor. In order to define adjuvant chemotherapy strategies in the future, multi-institutional trials are needed.

5.2.6Bronchioloalveolar carcinoma/adenocarcinoma in situ

Bronchioloalveolar carcinoma is a subclass of non-small-cell lung cancer and of adenocarcinomas in particular. In 2011, a revised classification renamed these tumors as adenocarcinomas in situ [30]. These tumors account for approximately 2% of malignant lung cancer in children [3]. They arise from distal bronchioles and alveoli and show a low tendency for invasive growth and metastatic spread. Rojas et al. described four cases of adenocarcinomas in situ in children [3]. None of them had metastatic disease, and the therapy of choice was complete resection with lobectomy. Radiation was not applied, and chemotherapy was administered to only one patient. Regional lymphadenectomy was performed in one patient, and none of these patients had metastases [3]. However, prognosis is excellent with a 5-year overall survival of 100% [31]. Interestingly, there are signs that adenocarcinomas in situ are associated with benign pulmonary lesions such as congenital cystic adenomatoid malformations (CPAM) or other malignant tumors [32]. Kayton et al. described in these patients with coincidental malignancies an accumulation of KRAS mutation or EGRF mutations. They proposed a lung-sparing surgery to resect the adenocarcinoma in situ.

5.2.7Hemangiopericytoma

Hemangiopericytoma is a highly vascularized soft-tissue sarcoma (Fig. 5.2.5). These tumors are derived from fibroblastic cells and are classified as fibroblastic/ myofibroblastic tumors [33]. Most hemangiopericytomas are located at the lower extremity and the pelvis, but other regions can also be affected. Approximately 10%–20% are metastasized at the time of diagnosis, and 5%–10% of all hemangiopericytomas occur in children and adolescents. Primary lung hemangiopericytomas are extremely rare, but the lung is the primary site of metastatic disease, especially of intracranial hemangiopericytomas [34]. Interestingly, hemangiopericytomas in patients younger than 1 year show a good response to chemotherapy. Fernandez-Pineda et al. reported of good results with actinomycin D, vincristine and cyclophosphamide. The biological behavior in older children is similar to that in adults, and the response to chemotherapy is poor [33]. However, surgical resection is the most effective treatment, and complete removal of the tumor has to be sought. Results after incomplete resection are poor, and both chemotherapy and radiation are of limited value [34]. Finally, there are no histological markers defining the aggressiveness of these tumors, and late recurrences are known. Therefore, a diagnostic follow-up for at least 10 years is recommended [33].

Fig. 5.2.5: Bronchoscopic view at a hemangioperizytoma.

5.2.8Inflammatory myofibroblastic tumors

Inflammatory myofibroblastic tumors are rare neoplasias that occur in children and young adults. One-third of these tumors are located in the lung, but all other sites of the body can be affected as well [35]. Inflammatory myofibroblastic tumors can arise from the lung parenchyma, bronchus and the pleura and are associated with a clinical syndrome in 15% to 30% of patients [35].

Histology

Originally, inflammatory myofibroblastic tumors were considered to be benign tumors, but there are some inflammatory myofibroblastic tumors with malignant characteristics and, occasionally, an unfavorable prognosis [36]. Additionally, identification of recurrent clonal rearrangements involving chromosome 2p in approximately 50% of cases is sufficient to characterize these tumors as true neoplasms [35].

Both the ‘‘benign’’ and ‘‘malignant’’ forms share similar morphologic features, which are not predictive of prognosis or etiology. They are characterized by fascicles of bland myofibroblasts admixed with a prominent inflammatory component [36]. Histological features include variably cellular spindle cell proliferation in a myxoid to collagenous stroma with a prominent inflammatory infiltrate composed primarily of plasma cells and lymphocytes, with occasional admixed eosinophils and neutrophils. Coffin et al. described three basic histological patterns that are often seen in combination within the same tumor: a myxoid/vascular pattern, a compact spindle cell pattern and a hypocellular fibrous (fibromatosis-like) pattern [35, 37].

Even if the etiology is still unclear, some viruses such as the Epstein-Barr virus and human herpes virus 8, have been implicated in the etiology of these tumors [36]. To date, there are no molecular markers with prognostic value.

Clinical presentation

Inflammatory myofibroblastic tumors of the lung become symptomatic with nonspecific respiratory symptoms in most cases [36]. A constitutional syndrome consisting of fever, weight loss and malaise is seen in 15%–30% of the patients [35].

Diagnosis and imaging

Laboratory tests may reveal microcytic anemia, an elevated erythrocyte sedimentation rate, thrombocytosis, and/or polyclonal hypergammaglobulinemia. In some cases, the mass may be found only after an extensive workup for a fever of unknown origin or growth failure [35]. A plain chest radiograph is useful as first-line imaging since these tumors are large enough in most cases. A chest CT scan is the next diagnostic step (Fig. 5.2.6), and the application of contrast media is advisable [38]. An additional PET-scan may be useful to screen for metastasis. However, histological examination is key to diagnosis. Biopsy can be achieved by video – assisted thoracoscopy or true-cut needle biopsy.

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