Abstract
Tumors of the chest in the pediatric population represent a large collection of pathologies. They can differ in location from the chest wall, to the mediastinum, to the lung itself. They can be benign or malignant, primary or metastatic. Therefore, depending on the etiology, the incidence and epidemiology differ widely. Despite the wide differential, using a systemized approach can lead to the correct diagnosis and treatments that lead to favorable outcomes for the patient. This chapter covers the wide range of processes that can lead to solid tumors in the pediatric population in the chest, how to organize them within systems, and their most common manifestations and treatments.
Keywords
tumors, chest wall, pediatric, mediastinal tumors, pleuropulmonary blastoma, germ cell tumors
Epidemiology
Tumors of the chest in the pediatric population represent many pathologies. They can differ in location from the chest wall, to the mediastinum, to the lung itself. They can be benign or malignant, primary or metastatic. Therefore, depending on the etiology, the incidence and epidemiology differ widely. All forms of primary neoplasms of the lung in the pediatric population are rare. A lung mass in the pediatric population is 10 times more likely to be a benign process than a malignant one. Chest wall tumors account for only 1.8% of all pediatric solid tumors, but tend to be malignant. The most common location of chest tumors is the mediastinum, and mediastinal masses can be further divided by their location into three compartments: anterior, middle, and posterior mediastinum. Mediastinal masses tend to occur early in the pediatric population, with around 40% of mediastinal masses occurring before the age of 2. A case series of 120 patients showed that roughly 30% of these masses occur in the anterior mediastinum, around 25% in the middle mediastinum, and 40% in the posterior mediastinum.
Etiology
The etiology of tumors of the chest ranges widely, depending on the location of the tumor. In terms of primary pulmonary lesions, tumors can arise from both the tracheobronchial tree and the pulmonary parenchyma itself, and they can accompany a wide variety of subtypes, from benign (inflammatory pseudotumor and hamartomas) to malignant (bronchial adenoma, bronchogenic carcinoma, pleuropulmonary blastoma).
Benign Primary Pulmonary Lesions
Plasma Cell Granuloma
Plasma cell granulomas have also been known as inflammatory pseudotumor, histiocytoma, inflammatory myofibroblastic tumor, and fibrohistiocytoma. These lesions are typically seen in patients less than 40 years old, with the majority in the pediatric population occurring in the age group between 8 and 12 years old. They are the most common benign lung tumors in the pediatric population, making up more than 50% of benign lesions and 20% of all primary lung lesions. They usually present as a solitary peripherally based pulmonary nodule, but can also become locally invasive, causing symptoms such as fever, cough, pain, and hemoptysis, which require resection. In a cases series of 28 patients, there was predominance toward male patients, and up to 85% of the diagnosed cases required surgical intervention.
It is unclear whether the underlying etiology is that of a primary inflammatory process or a low-grade malignant process with an inflammatory component. There have been reports that plasma cell granulomas are usually preceded by respiratory infections. Most of these lesions are slow growing, although in some rare cases they can spread quickly, leading to airway compromise.
Hamartomas
Hamartomas were first described by Eugen Albrecht in 1904. They are benign malformations composed of disorganized components of normal lung tissue, including cartilage, epithelium, fat, and muscle. The lesions are usually located peripherally in the parenchyma of the lung but have also been noted, rarely, to be located centrally, as well as within the chest wall. Hamartomas are the most common benign lesion in the adult population and the second most common benign pulmonary lesion in the pediatric population (18%–23%). Unlike in adults, where they tend to be asymptomatic, hamartomas can grow to be large and symptomatic in children, causing respiratory distress and requiring surgical excision. Popcorn-like calcifications are considered pathognomonic and they can be part of a triad (Carney) consisting of pulmonary hamartomas, extraadrenal paraganglioma, and gastric smooth muscle tumors.
Malignant Primary Pulmonary Lesions
Bronchial Adenomas
Bronchial adenomas are tumors that derive from the mucous gland of the bronchi or the cells that line the excretory ducts of these glands. While the name adenoma suggests a benign process, bronchial adenomas can become malignant. There are three histologic types of bronchial adenomas: carcinoid, cylindroma, and mucoepidermoid. Around 80%–85% of bronchial adenomas in children are the carcinoid type, and they are similar in resemblance to carcinoid tumors of the small bowel. Bronchial carcinoids are thought to derive from neuroendocrine Kulitchsky cells. They are low-grade tumors, which can metastasize, but most are slow-growing tumors that can grow into the bronchial wall. Carcinoid syndrome itself is rare, although it has been reported in the pediatric population. Cylindromas make up around 10%–15% of bronchial adenomas, and they consist of cuboidal or flattened epithelial cells that derive from the mucous secreting cells of the larynx and tracheobronchial tree. They are also low-grade, slow-growing malignancies, but they are considered the most aggressive of all three histologic types and can metastasize. Mucoepidermoid tumors originate in the larger airways and are the rarest subtype, comprising only 1%–5% of bronchial adenomas.
Bronchial adenomas usually present with vague pulmonary symptoms such as fever, cough, chest pain, recurrent pneumonitis, and hemoptysis as the tumor slowly grows into the airway and causes incomplete obstruction. These symptoms can cause children to be treated for asthma. The rarity of these disorders commonly causes a delay in diagnosis, often for years. The tumors usually involve the right main bronchus and are 5 times more likely to be seen in boys.
Treatment consists primarily of resection of a segment, lobe, or complete lung, according to the degree of involvement, which may be done thoracoscopically or via thoracotomy, depending on the location and extent of the lesion. Luminal excision by bronchoscopy should not be done because it does not permit complete removal of the tumor. Rarely a bronchial adenoma can be removed by bronchial or sleeve resection, followed by airway reconstruction.
Bronchogenic Carcinoma
Bronchogenic carcinomas are exceedingly rare in the pediatric population, with only 60 reported cases in children, and they represent approximately 20% of primary malignant lung tumors. Most present during adolescence. Most pediatric bronchogenic carcinomas are undifferentiated adenocarcinomas, with squamous cell carcinomas being much less common in the pediatric population, in contrast to the adult population. Usually asymptomatic, the majority of cases present late in the course of the disease leading to a poor prognosis; the mortality is more than 90%, with a mean duration of survival of only 7 months. Localized lesions can be resected with postoperative chemotherapy, but this applies to only a small subset of patients. The presenting symptoms are vague, including cough, hemoptysis, and weight loss. The tumor presents as a central pulmonary mass with endobronchial growth.
Pleuropulmonary Blastoma
Pleuropulmonary blastomas (PPB) are rare malignant tumors that arise from the primitive interstitial mesenchyme of the lung. These typically occur in younger children prior to the age of 6 years and can behave aggressively with high rates of metastasis. There are three pathologic types of PPBs. Type I is purely cystic and is diagnosed around the age of 10 months, with a survival rate of 80%–85%. Type II is a combination of cystic and solid, and type III is a purely solid lesion. There is evidence that all three types may develop on a continuum, where type II and III types present later, with type II presenting around 34 months and type III around 44 months. There have been reports linking congenital pulmonary airway malformations (CPAM) to PPB. Specifically, type IV CPAMs are highly suspicious for malignancy and may be cystic PPB. With CPAMs, the presence of symptoms, lack of a systemic feeding vessel, and hyperinflated lung lead toward a higher suspicion of possible malignancy. There appears to be a familial component to PPB in up to 25% of cases. The DICER 1 gene has been implicated as an important genetic factor in the development of familial pleuropulmonary blastoma. Often, PPBs occur in the right chest with metastasis to the liver, brain, and spinal cord. Surgical excision of cystic PPBs, with or without adjuvant chemotherapy, offers cure rates exceeding 85%. However, cure rates drop significantly if PPBs present later to care, when they have evolved into mixed cystic/solid or solid phases.
Chest Wall Tumors
Chest wall tumors are rare, and they encompass a wide variety of disease processes based on tumor types, tissue of origin, and behavior, so it is difficult to characterize them. They can be primary or secondary to invasion from adjacent structures. They are primarily mesenchymal tumors and are divided into benign and malignant disease, with up to 60% being malignant. The majority of chest wall tumors come from skeletal structures (55%), with the remainder originating in the soft tissues of the chest wall (45%).
Chest wall masses often present as seemingly innocuous lumps that are noticed on the chest, which may demonstrate growth. They are typically slow-growing and asymptomatic, but pain can be a presenting symptom that raises the concern for a malignant process. A small percentage of these tumors can have effects on respiratory mechanics, depending on their location and size.
Benign tumors of the chest wall are less common than malignant ones and have a wide variety of etiologies. Lipomas of the chest wall are rare in the pediatric population. The most common soft tissue benign lesion of the chest wall derives from the myofibroblast, including infantile myofibromatosis and desmoid fibromatosis tumor. Infantile myofibromatosis typically presents at birth or early in life and usually undergoes spontaneous regression. In contrast, desmoid fibromatosis can be more challenging to deal with, as they originate as overgrowths of fibrous tissue that can extend through muscle and fascial planes. Full excision can be challenging, and these patients often undergo multiple surgeries.
Benign Tumors
Mesenchymal hamartomas are benign lesions typically found at birth that may present as a deforming chest mass, or they may be found incidentally on chest radiograph. These lesions tend to grow intrathoracically, causing respiratory symptoms. They have a characteristic appearance on radiograph with large calcifications arising from one or more ribs causing distortion of the osseous thorax. Although this description suggests an aggressive, possibly malignant process, mesenchymal hamartomas are benign, with no reports of malignant degeneration, recurrence, or metastasis after resection. Resection should only be undertaken to relieve respiratory symptoms related to mass effect from the lesion.
The most common benign skeletal neoplasms are osteochondromas, and they account for almost half of all tumors arising from the ribs. These tumors consist of bony and cartilaginous components occurring near the end of long bones. They present during puberty, with an almost 3 : 1 predominance in males. They are frequently asymptomatic, but they can present with pain, can grow into adjacent nerves, may cause pathologic fractures, and can cause physical asymmetry of the chest, which is often cosmetically distressing. There is a characteristic “cartilage cap” seen on plain radiograph, and if the cap is greater than 1 cm, there is concern for the risk of chondrosarcoma.
Chondromas are benign tumors that arise in the costal cartilage and are composed of mature hyaline cartilage, usually at the sternocostal junction. They are typically slow-growing, painless masses that are not aggressive in nature. While benign, they are very similar in clinical course and in terms of imaging features to chondrosarcomas. Therefore they often have to be treated with wide local excision.
Malignant Tumors
In contrast, chondrosarcomas are rare malignant tumors in the pediatric population, typically peaking in adult males in their thirties. However, given their similar appearance to chondromas, they are important to distinguish. They are slow-growing lesions that can start to cause pain, and they have a risk of late metastasis. The direction of growth appears to be entirely internal, thus stimulating the radiologic appearance of a primary pleural or mediastinal tumor. However, there is usually an externally visible and palpable mass. Chemotherapy and radiotherapy are not effective against chondrosarcomas. Thus they require a wide resection, as there is a high risk for local recurrence.
Of malignant chest wall lesions, primitive neuroectodermal tumors (PNET), often referred to as Ewing’s sarcoma or Askin’s tumors, are the most common in the pediatric population. They were first described by Askin and colleagues in a series of 20 children. These tumors originate from embryonal neural crest cells and behave aggressively. It should be assumed that there is micrometastasis present at the time of diagnosis. PNETs of the chest typically present in the early teenage years, with a 2 : 1 male to female ratio. Symptoms include the development of a painful mass, dyspnea, weight loss, and, in some cases, Horner syndrome. Radiographs show lytic destruction, with an accompanying pleural effusion. Often computed tomography (CT) scan and magnetic resonance imaging (MRI) are needed to define the extent of the lesion and to determine presence of pulmonary metastasis, which can occur in up to 25% of cases at the time of presentation. Cytogenetic studies have shown that PNETs have a characteristic balanced translocation between chromosome 11 and 22 (t11:22 [q24:q21]). Treatment of PNETs is multimodal including chemotherapy, wide excision, and radiotherapy due to their high local recurrence rate. Prognosis for these tumors can be quite dismal, with 2- and 6-year survival rates being reported at 38% and 14%, respectively.
Mediastinal Tumors
The mediastinum is the portion of the body that lies between the lungs and contains all the structures within the thoracic cavity except the lung. It is bounded anteriorly by the sternum and posteriorly by the vertebrae and extends superiorly from the suprasternal notch to terminate inferiorly at the diaphragm. Cysts or tumors that arise within the mediastinum may originate from any of the structures contained therein or may be the result of developmental abnormalities.
For ease of definition of sites of disease, the mediastinum may be thought of as divided into three compartments: (1) the anterior mediastinum—the portion of the mediastinum that lies anterior to the anterior plane of the trachea; (2) the middle mediastinum—the portion containing the heart and pericardium, the ascending aorta, the lower segment of the superior vena cava, bifurcation of the pulmonary artery, the trachea, the two main bronchi, and the bronchial lymph nodes; and (3) the posterior mediastinum—the portion that lies posterior to the anterior plane of the trachea.
Lymphomas
The most common mediastinal masses in children are lymphomas. Any lymph node enlargement in a child should be viewed with suspicion, since lymphatic tumors are one of the more frequently observed malignant growths in childhood. Lymphoma is the third most common malignancy in children overall and represents almost half of all mediastinal malignancies. Hodgkin disease, lymphosarcoma, and reticulum cell sarcoma are found primarily in children older than 3 years of age, with a peak incidence between 8 and 14 years of age. Lymphomas can occur in any of the compartments of the mediastinum, but in children, they most frequently are in the anterior and middle mediastinum. One-third of the lymphomas are Hodgkin lymphoma and two-thirds are non-Hodgkin lymphoma. Non-Hodgkin lymphoma is more likely to occur in younger children, while Hodgkin lymphoma tends to present in adolescent populations.
More than 95% of children with primary lymphatic malignancy have lymph node enlargement as the presenting sign. Tonsillar hypertrophy and adenoidal hyperplasia, pulmonary hilar enlargement, splenomegaly, bone pain, unexplained fever, anemia, infiltrative skin lesions, and rarely central nervous system symptoms may also be present.
The diagnosis should be sought through the study of peripheral blood smears, lymph node biopsy, pleural fluid examination, and bone marrow examination.
If all other diagnostic studies are negative, the mediastinal node can be biopsied. Fine-needle aspiration is usually not satisfactory; thus core needle biopsy (directly or via mediastinoscopy, thoracoscopy, or anterior thoracotomy) is frequently required. Importantly, anesthetic management is complicated if there is greater than 50% tracheal luminal compression or significant preoperative dyspnea. Surgery is rarely required in the treatment of lymphomas, although the diagnosis is often made via surgical biopsy. Biopsy of mediastinal lymph nodes requires careful, multidisciplinary preoperative planning. Often there are palpable cervical or axillary nodes, which may be amenable to biopsy and may pose less risk in establishing the diagnosis.
Hyperplasia of the Thymus
Hyperplasia of the thymus is the most frequent of the thymic lesions. Because the normal thymus varies greatly in size and with age, thymic hyperplasia is a relative term. Steroids, infection, androgens, and irradiation may cause involution; the stimuli that cause hyperplasia are not well understood. As in other ductless glands, variations in size are probably related to patient individuality.
On the chest radiograph of normal infants, a thymic shadow of variable size and shape is typically present during the first month of life. The mediastinal shadow in young infants is proportionally wider than in older children and adults, because of the proportionally larger heart and thymic shadow. The thymic shadow typically disappears by 1 year of age. Among children older than 4 years of age, 2% still have a recognizable thymus on radiographic examination. Cervical extension of the thymus gland is common. If the thymus is in the superior thoracic inlet, its enlargement may cause tracheal compression ( Fig. 74.1 ).
In the unusual situation in which an enlarged thymus causes respiratory obstruction, treatment may be carried out in one of three ways. While the thymus does respond rapidly to small doses of irradiation (70–150 cGy), the concern of a carcinogenic effect has caused this method of treatment to be abandoned. Corticosteroids cause a rapid decrease in the size of the thymus, usually within 5–7 days. However, after cessation of corticosteroid therapy, the gland may reach a size greater than that before treatment was instituted. Such a response may also be used in distinguishing between a physiologic enlargement of the thymus and a neoplasm ( Fig. 74.2 ). Excision may be indicated both for the treatment of respiratory obstruction and for diagnosis.
Neoplasms of the Thymus
Malignant thymic tumors in children are quite rare. Lymphosarcoma is more frequent, and primary Hodgkin’s disease of the thymus and carcinoma have both been described. In only one 19-year-old patient has there been an associated myasthenia gravis syndrome. An ectopic parathyroid carcinoma located in the thymus has also been documented.
Benign Thymoma
Rarely benign thymic tumors have been reported in children, accounting for only 1%–2% of mediastinal masses ( Fig. 74.3 ). Roughly one-third of patients with thymomas will have symptoms of local invasion. They are classified as invasive or noninvasive, depending on whether they extend past their fibrous capsule.
Thymic Cysts
Thymic cysts are rare, cystic remnants of the thymopharyngeal duct. Multiple small cysts of the thymus are frequently observed in necropsy material, but large thymic cysts are rare ( Fig. 74.4 ). While they are typically asymptomatic, manifesting after 2 years of age, there have been reports of cysts causing respiratory failure in infants, as they can be located anywhere between the pyriform sinus and the anterior mediastinum. Techniques and operative approaches are site-specific. Thymic cysts have been resected from a cervical approach ( Fig. 74.5 ).
Teratoma of the Thymus
Several cases of thymic teratoma have been reported. Patients typically have a good prognosis after resection.
Teratoid Mediastinal Tumors
Teratoid tumors of the mediastinum may be classified as: (1) benign cystic teratomas, (2) benign teratoids (solid), or (3) teratoids (carcinoma). They make up 10%–12% of all teratomas and 20% of all mediastinal pediatric neoplasms.
Benign Cystic Teratoma
Teratoma of the anterior mediastinum probably results from faulty embryogenesis of the thymus or from local dislocation during embryogenesis. Benign cystic teratomas (mediastinal dermoid cyst) contain such elements of ectodermal tissue as hair, sweat glands, sebaceous cysts, and teeth. Other elements, including mesodermal and endodermal tissue, may also be found when benign cystic teratoid lesions are subjected to comprehensive examination; thus such tumors are more properly classified as teratoid than dermoid cysts.
Cystic teratomas are more common than solid ones. These lesions are predominantly located in the anterior mediastinum and may project into either hemithorax, more commonly the right. In children, females are affected more often than males. Malignant degeneration is less common than in the solid form of teratoid tumor.
These cystic masses usually cause symptoms because of pressure on, or erosion into, the adjacent respiratory structures. Symptoms usually include vague chest discomfort associated with cough, dyspnea, and pneumonitis. Infection may cause a sudden exacerbation of symptoms, and rupture of the mass into the lung may occur with expectoration of hair and other materials; rupture into the pleura or pericardium may also occur.
On radiography, the lesion is well outlined, with sharp borders; definite diagnosis on plain radiograph is not possible unless teeth can be demonstrated in the mass. Calcification, which is not unusual, appears as scattered masses rather than as diffuse stippling. Cystic swelling in the suprasternal notch may be visible.
Benign cystic teratomas should be removed. In cases in which infection, perforation, intracystic hemorrhage, or malignant degeneration has occurred, complete removal may be difficult or impossible, owing to adherence to surrounding vital structures.
Benign Solid Teratoid Tumors and Malignant Teratoid Tumors
Teratomas are the most common tumor occurring in the anterior mediastinum of infants and children ( Fig. 74.6 ), and the mediastinum is the second most common location for these masses. The solid tumors in the teratoid group are much more complex and have a greater propensity for malignant change ( Fig. 74.7 ). The incidence of malignancy has been reported as 10%–25%. In addition to standard imaging studies, preoperative serum studies should include serum α-fetoprotein, carcinoembryonic antigen, and β-human chorionic gonadotropin, both as diagnostic markers and as baseline values to monitor disease burden.
Patients present with chest pain, cough, dyspnea, and rarely hemoptysis. Most mediastinal teratomas are present at birth, and many are now detected prenatally. However, there are multiple reports of large masses discovered only in adulthood.
Benign solid teratoid tumors have well-differentiated structures that are rarely observed in malignant tumors. They contain tissue from one or more of the three germ cell layers. The connective tissue stroma of malignant teratomas is usually poorly arranged, but that of benign teratomas is dense and of the adult type. In the benign type, nerve tissue, skin, and teeth may be found. Skin and its appendages are usually present and remarkably well formed. Hair follicles preserve their normal slightly oblique position relative to the free surface and are always accompanied by well-developed sebaceous glands. Sweat glands, often of the apocrine type, are frequently located near the sebaceous glands. Smooth muscle closely resembling arrectores pilorum is occasionally encountered.
Mesodermal derivatives, such as connective tissue, bone, cartilage, and muscle arranged in organoid patterns, are frequently found. When present, hematopoietic tissue is found only in association with cancellous bone. Smooth muscle is most often observed as longitudinal or circular bundles in organoid alimentary structures. Occasionally it is also seen in bronchial walls. Endodermal derivatives representing such structures as intestine and respiratory and pancreatic tissue are also present.
The final diagnosis of malignancy can be determined only after removal and histologic study of the tumor. Malignant degeneration is typically rare and generally only involves one of the cellular components. In general, the outcome is poor with malignant teratomas, chemotherapy and radiotherapy notwithstanding, which usually consists of etoposide, bleomycin, and cisplatin.
Nonseminomatous Germ Cell Tumors
The nonseminomatous germ cell tumors or embryonal tumors consist of a wide variety of diseases such as seminomas, yolk-sac carcinomas, choriocarcinomas, and embryonal carcinomas. These tumors are all malignant and require multimodal therapy, including resection and chemotherapy. Standard workup should always include cross-sectional imaging, and preoperative serum studies should include serum α-fetoprotein, carcinoembryonic antigen, and β-human chorionic gonadotropin.
Vascular-Lymphatic Abnormalities of the Mediastinum
Vascular-lymphatic abnormalities of the mediastinum may be classified as (1) cavernous hemangioma, (2) hemangiopericytoma, (3) angiosarcoma, or (4) lymphangioma (cystic hygroma).
Vascular tumors isolated to the mediastinum in children are rare, and they may occur at any level in the mediastinum but are more frequent in the upper portion of the thorax and in the anterior mediastinum. They are uniformly rounded in appearance and are moderately dense. There are two major subtypes of hemangiomas: rapidly involuting and nonrapidly involuting. If hemangiomas do not cause respiratory symptoms, they are left untreated as they tend to disappear over time.
Though rare, isolated mediastinal lymphangiomas occur more often in infants and children than in adults. These tumors consist of masses of dilated lymphatic channels that contain lymph; they are lined with flat endothelium and are usually multilocular. They may appear to be isolated in the mediastinum ( Fig. 74.8 ) but usually have an associated cervical component. They may be rather large and unilateral, with lateral masses in the superior mediastinum.
