96: Pediatric Primary and Secondary Lung Tumors

Pediatric pulmonary tumors are extremely uncommon entities without a unifying presenting symptomatology, clear diagnostic strategy, or definitive therapeutic regimens. Patients may present with all manner of symptoms or complaints, and these concerns are almost always nonspecific. Secondary to their rarity and the heterogeneous nature of the presenting findings, tumors are seldom thought of as the causative factor for a child presenting to a primary care provider with respiratory complaints, especially in light of the prevalence of other, far more common diseases in young patients such as reactive airway disease, upper and lower respiratory infections, or even inhaled/ingested aerodigestive foreign bodies. The published data document that the proportion of benign lesions to metastatic lesions to primary malignancies is on the order of 60:5:1.^1,2 As such, the most critical factor in diagnosing these lesions is a high index of suspicion, especially if symptoms do not abate with the intended treatment strategies directed at the suspected underlying causative agent (i.e., asthma that is refractory to standard therapies or the respiratory infection that fails to resolve in a timely fashion with appropriate antimicrobial drugs). There is often a significant delay then, from the initial presentation to a healthcare provider and definitive histopathologic diagnosis. Staging, treatment strategies, and outcomes will be tumor-specific, but surgery generally plays a critical role if cure is to be achieved in all lesions.

Presentation/Evaluation

Presenting symptoms in pediatric patients can range from the incidentally found tumor or lesion in the asymptomatic child to the child who presents in extremis with severe hemorrhage or cardiorespiratory collapse from parenchymal or mediastinal compression or invasion. The size, location, number, degree of vascularity, specific tracheobronchial anatomic location, associated organ (heart, great vessels) or structure (trachea) involvement (directly or indirectly), and malignant potential all are factors known to influence the precise constellation of presenting symptoms. Patients presenting with benign tumors are most commonly asymptomatic (24%).^3,4 However, when patients with benign tumors do present with symptoms, fever, cough, and pneumonitis have been documented to have the highest reported frequency (~10%) in this cohort. Those pediatric patients who are found to have metastatic lung cancers are also most commonly asymptomatic, as these lesions are generally small, numerous, and peripherally located on staging studies. Seldom does the child with pulmonary metastases present with pulmonary symptoms as the initial physical complaint. Primary malignant tumors in children generally do present with symptoms, however, and two large series found only 6% of children were asymptomatic upon presentation.^3,4 In fact, these reports document that one-third of patients present with a refractory cough, and a not so insignificant number (10%–25% per symptom) also present with evidence of fever, pneumonitis, respiratory distress, or hemoptysis.

As previously stated, however, these symptoms are nonspecific, and definitive diagnosis is almost always delayed. A high index of suspicion with close, diligent follow-up is mandated in all patients who do not respond to appropriate interventions directed at the suspected disease process that could be masking the presence of a mass. An algorithm has been published⁵ documenting at least one approach that may be used in the treatment of pediatric patients suspected of harboring a pulmonary tumor (Fig. 96-1). Ideally, the patient is evaluated at presentation and a baseline history and physical examination is conducted with acquisition of chest radiographs (two views) and disease-appropriate laboratory evaluations. A close interval follow-up examination (2–4 weeks) is generally recommended to ensure the symptoms have resolved or responded to treatment. For persistent, recurrent, or ongoing symptoms refractory to treatment interventions, a return visit with further studies, including a chest computed tomogram (CT) should be entertained if there is any question on the interpretation of the data collected during the prior visit. Although the risks of secondary malignancies from radiation exposure in children are not trivial,⁶ missing a tumor is of even more concern since extirpation is always a component of cure and if the lesion is discovered when small, parenchymal preservation approaches with negative margins and reduced rates of lymph node metastases would be expected. Although other imaging modalities, including magnetic resonance imaging and positron emission tomography, have been described in pediatric pulmonary tumors, their widespread application and utility remain unproved. An early referral to a pediatric pulmonologist also may be warranted to provide for another opinion on the child with refractory pulmonary symptoms and to investigate the utility of bronchoscopic evaluation. Again, close-interval follow-up is warranted to ensure symptom resolution. If a lesion is found on chest CT or bronchoscopy and is amenable to resection without undue perioperative morbidity or mortality, then resection is warranted after appropriate staging studies are performed. Preoperative pulmonary function testing also may be desired in cases where pneumonectomy and/or combined chest wall resection may be indicated so as to have a baseline to predict postoperative recovery and function. A biopsy procedure (bronchoscopically, image-guided, or surgical) can be entertained and discussed, especially in the case of large, central, or invasive tumors that are not amenable to upfront resection without significant perioperative risk. One must be careful in this setting, however, since soiling the pleural space with tumor may be detrimental in specific subtypes, and there is a significant risk of peribronchoscopic hemorrhage with mortal outcomes in the setting of endobronchial lesions.^7–9 While commonplace in the adult literature, definitive therapeutic bronchoscopically directed strategies are not recommended treatment modalities in children with endobronchial pulmonary tumors because there can be significant technical limitations in small patients and the ability to achieve a wide local resection with negative margins using these techniques is often not possible.

Biology/Epidemiology

Benign and malignant pediatric pulmonary tumors are rare entities overall, but benign lesions are tenfold more common than malignant ones.¹⁰ Metastatic lesions encompass over 80% of all pediatric lung tumors sampled and 95% of all cancerous lesions.¹⁰ From two large series on the topic, at least 60% of all primary pediatric lung tumors are malignant with a mortality rate of roughly 30%.^3,4 Benign lesions, however, do not necessarily confer significant survival advantage. Depending on the exact anatomical site of origin, these lesions have a collective mortality risk of 8% since they can be locally invasive to the heart, great vessels, and/or other mediastinal structures.^3,4 Below we present specific data for each tumor class (malignant [primary, secondary] and benign) and type.

Technical Considerations

Primary or secondary pulmonary tumor resections can be performed by a variety of different techniques or approaches. The surgeon should be familiar with all thoracic incisions and operative approaches, since the best oncologic operation, and hence patient outcome, will be facilitated by using the proper incision. Minimally invasive surgical (MIS) approaches (as described in Chapter 52) are acceptable as long as oncologic principles can be maintained and executed without compromising patient safety. The surgeon must also have thorough knowledge of the technical limitations of patient size and equipment availability needed in these techniques. Preoperative patient assessment and determination of suitability for surgery, in addition to perioperative anesthetic and pain and sedation management techniques described elsewhere (see Chapter 5), also apply to pediatric patients.

For children requiring hemithoracic exploration and extirpation of metastases from osteosarcoma or for the performance of a pneumonectomy (extra- or intrapleural), a sleeve resection, or difficult lobectomy, the authors prefer to use a complete muscle-sparing vertical thoracotomy technique as modified from the initial description by Sir Denis Browne.¹¹ This technique since first described over seven decades ago has been utilized and modified by both adult and pediatric surgeons for the treatment of many intrathoracic conditions and diseases.^12–16 The advantages of this approach are numerous, but it is particularly noted for decreasing the risk of musculoskeletal deformities and resultant pulmonary complications commonly found in children who undergo standard antero- or posterolateral thoracotomy.^17–20 With younger patients, the chest is far more compliant than in adults, and this incision has proved to be both versatile and simple. The conduct of the operation involves standard lateral positioning (Fig. 96-2) after appropriate lung isolation (double-lumen endotracheal tube vs. use of a bronchial blocker depending on patient age) and placement of central (epidural) or regional (paravertebral) perioperative pain adjuncts have been achieved. The skin incision (Fig. 96-3) is marked with the arm in full abduction to ensure a straight incision. Otherwise, if the incision is made while the arm is flexed, it will curve anteromedially towards the chest. The dermis is incised longitudinally at the medial border of the latissimus dorsi from the inferior axillary line to the ninth interspace. If the border of the latissimus cannot be identified secondary to body habitus, the incision should be placed in the posterior axillary line. Monopolar electrocautery is used to separate the subcutaneous tissues. The medial border of the latissimus (Fig. 96-4) is identified and dissected in the axis of the wound. Care is taken not to damage the underlying neurovascular structures in the axilla, especially the thoracodorsal neurovascular complex and the long thoracic nerve during this dissection. Once identified, the latissimus dorsi muscle is dissected off the underlying serratus anterior muscle back toward the tip of the scapula (Fig. 96-5) without damaging or violating either muscle. The edge of the serratus anterior muscle is then located at its insertion on the tip of the scapula and the fascial plane connecting it to the chest wall is incised sharply (Fig. 96-6). Once this plane is entered, the serratus is dissected off the chest wall medially, rostrally, and caudally until it is completely separated. Caution must be exercised to avoid damage to the muscle or the neurovascular structures in the area, and once free, a blunt dissection can take place to identify the appropriate intercostal space to enter for the proposed operation as is standard for all thoracotomies. Once the chest is entered, the required pulmonary or thoracic operation can be performed as described elsewhere in this text. The wound is closed by reapproximating the intercostal space and all muscle, subcutaneous and dermal layers, with absorbable sutures.

Inflammatory Myofibroblastic Tumor

The most common benign pediatric pulmonary tumor is an inflammatory myofibroblastic tumor (IMT). Some caution must be utilized in describing this lesion against the known literature; however, as the terminology describing this tumor has only recently been codified and previous reports over several decades may have misinterpreted or even misrepresented this tumor. Nevertheless, we do know that it was found in over 50% of all benign tumors resected in the two largest series to date,^3,4 and it was recently classified by the World Health Organization (WHO) as an intermediary lesion.²¹ Microscopically, it is characterized as a spindle cell soft tissue tumor with infiltrative plasma cells, lymphocytes, and eosinophils. Molecularly, it is defined by a specific genetic signature with a known rearrangement at locus 2p23 involving the tyrosine kinase receptor anaplastic lymphoma kinase (ALK) which has been implicated in other malignancies,²² but this chromosomal aberration has not been found in all IMTs to date. This lesion usually presents in the periphery of the lung and is known to grow slowly, invade local structures, and even metastasize (though rarely). Local recurrence has been reported to be as high as 14%²³ and is a significant issue in the cohort of patients who present with disease outside of the lung proper where the recurrence rate can rise as high as 46%.²³ If one considers that 27% of patients present with locally invasive disease, this fact becomes even more telling. Complete extirpation is warranted, even if a pneumonectomy is needed with concomitant chest wall resection to achieve negative margins. Careful reconstructive techniques must be employed and long-term surveillance will be needed, as the pediatric patient will grow and can have significant thoracic dystrophy and other concerns as they age. While radiotherapy²⁴ and chemotherapeutic regimens (including anti-inflammatory drugs)^25–27 have been used, there is no agreed upon regimen that has been critically evaluated.

Hamartoma

Hamartomas are found in the liver and lung in children, and they are the second most common benign pediatric pulmonary tumor. These tumors are formed by normal parenchymal components arranged in a haphazard and disorganized fashion. Both cartilaginous and gland-like clusters of cells are irregularly arranged and grow unchecked without the benefit of capsule or pseudocapsule. Macroscopically, they are found to be well demarcated from the normal, surrounding lung with glandular tissue separated by septae of fibrous tissue. These lesions represent roughly 20% of all benign pediatric pulmonary tumors,^3,4 and in the minority of cases (no more than 25%) they present with the pathognomonic stippled popcorn calcification on chest radiograph.²⁸ They tend to start in the periphery, but they can grow to become quite large and pose operative challenges during resection with deaths reported at surgery secondary to their size and location.⁴ Complete resection is warranted in all cases, and parenchymal preserving approaches should be considered if possible. Finally, this disease may also serve as a harbinger of the presence of Carney triad²⁹ (gastrointestinal stromal tumor, paraganglioma and/or pheochromocytoma, pulmonary hamartoma) in the afflicted patient. Hence, when found, referral to a geneticist and pediatric oncologist may be warranted to investigate the presence of this disease and treatment of other tumors if discovered.

Bronchial Adenomas

Bronchial adenomas encompass three distinct tumor types: carcinoid tumors, mucoepidermoid carcinomas, and adenoid cystic carcinomas. Combined, they comprise approximately 40% of malignant pediatric pulmonary lesions^3,4 and are the largest group of cancerous tumors encountered in children.

Carcinoid tumors are the most prevalent cancerous pulmonary tumor in children, and pulmonary tumors account for almost 28% of all carcinoid tumors.³⁰ These tumors are derived from Kulchitsky cells from the amine precursor uptake and decarboxylation (APUD) system involved in tryptophan metabolism. As such, they are involved in the synthesis of vasoactive amines which when produced to excess can lead to the development of carcinoid syndrome – palpitations, flushing, diarrhea, abdominal pain, bronchospasm – which is a hallmark of this disease, although found rarely (less than 10%)³¹ and generally signifies significant extrapulmonary disease. Furthermore, this pathway also serves a means to test for the disease, since the patient's urine can be tested for 5-hydroxyindoleacetic acid (5-HIAA) levels and if elevated, confirm the diagnosis. These tumors are generally found in isolation, although they can be a component of patients with multiple endocrine neoplasia type I (MEN I) syndrome in a minority of cases (4%). Histologically, they can be separated into typical (90%) and atypical (10%) variants with the atypical subtype demonstrating a more aggressive phenotype with necrosis and increased mitoses on histopathologic review. However, both variants are known to both metastasize and recur. It is also apparent that atypical variants have a higher proportion of lymph node metastases (30%–75%³² vs. 5%–10%⁸) and a worse prognosis by stage than their typical counterparts. Regardless of subtype, however, complete resection with lymph node dissection and removal of all disease (gross and microscopic) is the mainstay of treatment as there is no effective cytotoxic chemotherapy. Distant metastases can be treated with metastasectomy or other local control measures (radiofrequency ablation, chemoembolization) in combination with adjuvant therapies (chemotherapy, radiotherapy, somatostatin analogues) to treat symptoms of excess vasoactive amine production. The widespread use of these techniques in children, however, is not necessarily recommended as their utility is unknown.

Mucoepidermoid tumors are the second most frequent malignant pulmonary tumor in children.^3,4 They arise in the mucous glands of the mucosa and submucosa of the respiratory tract with a penchant for presenting in the more proximal airways (central lesions). They do not readily metastasize to regional lymph nodes or distant sites, and complete extirpation is the recommended treatment. Histopathologically, they are divided into high- and low-grade lesions with the latter being most commonly found in children.^7,33–35 High-grade lesions are known to carry a dismal prognosis almost regardless of presentation or treatment strategies employed.³⁶

The final tumor in this class is adenoid cystic carcinoma (cyclindroma). These cancers are deemed salivary gland-type lesions, and they have a propensity to recur locally and metastasize.³² Their growth pattern is slow, radial expansion in the submucosa with direct extension into the pulmonary parenchyma.³² They are known to spread to local and regional lymph node basins with direct perineural extension as well. Curative treatment involves complete resection with lymphadenectomy.

Bronchogenic Carcinoma

These tumors are the second most common pediatric pulmonary malignancy accounting for roughly 17% of cancerous lesions.³ Of the various subtypes, adenocarcinomas and undifferentiated carcinomas are the most frequently reported,^3,4 and the basaloid variant of the bronchioloalveolar subtype has been reported to have a better prognosis.³⁷ In comparison to adults, these cancers are extremely rare in children with an incidence of 0.16% in the first decade of life, 0.9% in the second decade of life, and only 1.2% under the age of 40 years.^38,39 Treatment mirrors the adult regimens described elsewhere, and outcome data in children demonstrate that these lesions typically present late in the course of their disease and generally have an ominous prognosis.⁴ Of note, however, these cancers have been reported to arise from and/or coexist in embryological cystic pediatric lung lesions (bronchogenic cysts, cystic pulmonary adenomatoid malformations [CPAMs]).^40,41 Hence, any child presenting antenatally or postnatally with a cystic lung lesion should be evaluated for complete operative extirpation within the first year of life.

Pleuropulmonary Blastoma

Pleuropulmonary blastoma (PPB) accounts for approximately 16% of childhood pediatric lung cancers and was ultimately histopathologically characterized in 1988.⁴² Prior to this report, it was a confusing lesion that was called many different names secondary to the fact that it is composed of mesenchymal elements and embryonic stroma, but lacking a neoplastic epithelial component. It is thought to be derived from somatopleural mesoderm or thoracic splanchnopleura, and the tumors have been subclassified based on the degree of cystic elements present (Type I: all cyst, Type III: no cyst, and Type II: mixed).⁴³ As with bronchogenic carcinomas, these lesions have been reported to coexist or arise from congenital cystic lung lesions,⁴⁴ and one series reported almost one-third of PPBs were found with congenital pulmonary lesions.⁴⁵ These lesions are typically quite aggressive and prognosis is poor, regardless of subtype with a 10-year 8% survival rate reported in one large series.⁴⁶ Treatment involves complete extirpation of all disease if possible at diagnosis, but if not, neoadjuvant chemoradiation is recommended with surgery thereafter. Unfortunately, there is no agreed upon regimen to treat these tumors, and they tend to be quite large involving the lung, mediastinal structures, and chest wall when diagnosed.

The surgical treatment of pediatric pulmonary metastases is a field whereby sound data are lacking. There exist no large randomized prospective studies documenting its utility in any one disease. Data do exist in regard to specific tumor types, but these studies are usually case series from a single institution with a broad range of patients treated over a long period of time and often with varying regimens. Kayton⁴⁷ published the best work to date summarizing the most relevant and applicable data, but this work can only be considered a guide and not an absolute recommendation. Despite this dearth of knowledge, however, there are four principles that must be accounted for prior to undertaking pulmonary metastasectomy in the pediatric patient. First, the pathology of the primary tumor and accurate staging must be established and the data in regard to the timing and utility of pulmonary metastasectomy measured against this knowledge. Some tumors are readily responsive to adjuvant therapies and resection is not warranted except to confirm the presence (or absence) of pulmonary disease so as to guide therapy. Furthermore, the existence of other metastatic sites may temper the need to attempt pulmonary metastasectomy. Therefore, knowledge and confirmation of the primary tumor type and stage is critical to understanding the benefits and limitations of surgical therapies for the pulmonary disease. Second, the primary tumor site should be treated first and adequate disease control – surgical, medical – established prior to entertaining pulmonary metastasectomy as a component of cure. Third, the primary tumor site should have effective adjuvant therapies available so that micrometastatic disease can be treated in and around the timing of the pulmonary metastasectomy. Last, the type of surgery (thoracoscopic vs. thoracotomy), degree of resection (wedges vs. anatomic resection), and approach (sternotomy, uni- vs. bilateral and/or anterior vs. posterior thoracotomy) must also be considered on a case-by-case basis, tempered by the underlying disease and surgeon preference. The goal would be to preserve as much lung function as possible with the least morbidity in the fewest operations. Some tumors (osteosarcoma, adrenocortical carcinoma) mandate very aggressive approaches, while others do not. Ultimately, extensive discussions with the oncology, pulmonary, anesthesia, and critical care teams must commence early in the course of the patient's disease process so all are prepared and ready for any possible clinical course and to ensure the best possible outcome.

Technical Considerations

Pulmonary metastasectomy can be performed safely with minimal morbidity and a mortality rate of less than 1% as documented in the International Registry of Lung Metastases.⁴⁸ The type of pulmonary resection can be either anatomic or nonanatomic (“wedge”), but the majority of pulmonary metastasectomies performed in children are “wedge resections” where the lesion is completely excised with a small rim of normal lung parenchyma (<5 mm). Collective studies document the success of this procedure without the need for formal lung resection along anatomic boundaries.^48–53

The use of MIS approaches for the resection of pulmonary lesions has been described in several studies.^54–59 It has become an established technique, except in the case of osteosarcoma where multidetector CT scanning has been shown to underestimate the number of lesions and formal thoracotomy has been recommended.⁶⁰ Therefore, staged or sequential bilateral thoracotomies or bilateral thoracic exploration through a sternotomy are recommended in patients with osteosarcoma, although this approach has not been shown in a prospective study to prolong either event-free survival or overall survival. Ultimately, the decision about the precise approach utilized in the treatment of a child with a pulmonary metastasis will be surgeon dependent.

Adrenocortical Carcinoma

Pulmonary metastases from adrenocortical carcinoma should be resected and every effort should be made to control the disease for both symptom control and for attempted cure. Effective adjuvant therapies are not available as the 5-year event-free survival was only 54% as reported in the International Pediatric Adrenocortical Tumor Registry.⁶¹ While the authors of this work could not postulate on the effectiveness of metastasectomy because of data analysis issues, several series^62–65 have documented the utility of initial and subsequent pulmonary metastasectomy in these patients. Of note, however, these studies dealt primarily with adult patients and the assumption that the biology of these tumors is the same as that in children may not be true.

Differentiated Thyroid Cancer

Pulmonary metastases from differentiated thyroid cancer should be sampled to confirm the underlying nature of the lesion, but they should not be aggressively resected since adjuvant medical therapies exist that are both effective and well tolerated. The largest series exploring this question was reported by Demidchik et al.⁶⁶ who reviewed the records of 740 children presenting with differentiated thyroid cancer. Roughly 18% of patients had evidence of pulmonary metastases at presentation and all were treated with radioactive iodine therapy. The 10-year survival rate in this cohort was 98.8% with only five children succumbing to their disease at 115 months from last report. As this is an indolent disease, however, continued diligent follow-up is warranted in these children even into adulthood.

Germ Cell Tumors

Pulmonary metastases from gonadal germ cell tumors (GCTs) should be considered for resection not so much for local disease control and treatment, but for the histopathologic evaluation of residual disease in order to help guide future therapies. Although GCTs are chemoresponsive and have known tumor markers that can be monitored, radiographically identifiable disease at the conclusion of therapy may harbor live, active tumor even in the setting of negative tumor markers in up to 40% of patients.^67–71 The existence of active disease at the conclusion of standard adjuvant treatments would then warrant the initiation of second-line adjuvant therapies to eradicate the disease and give the best chance at cure.

Hepatoblastoma

Pulmonary metastases from hepatoblastoma should be considered for resection at the conclusion of adjuvant therapies if radiographically identifiable lesions persist. The data^72–74 supporting this statement are drawn from the observation of several reports documenting that patients who did not undergo resection of identifiable disease at the conclusion of treatment had worse outcomes than those who did undergo metastasectomy as sustained disease response to chemotherapy alone was no greater than 26%. In fact, in the same cohort of patients reviewed, the majority of long-term survivors had surgery and adjuvant chemotherapy for their disease.

Neuroblastoma

Pulmonary metastases in neuroblastoma are an ominous finding that generally signifies very aggressive disease with near certain lethality in a short time.^75,76 The role of surgery in these cases is simply to confirm that the lesions identified on imaging studies are not due to an infection or some other nononcologic cause that may influence the overall treatment strategy.

Nephroblastoma

Pulmonary metastasectomy in the setting of nephroblastoma should only be performed to confirm that the lesions present on imaging studies are in fact cancers. Several reports^77–79 have documented the effectiveness of adjuvant chemotherapy and locally directed radiotherapy in the treatment of pulmonary metastases in this disease. However, the importance of confirming that metastases truly exist prior to the initiation of adjuvant radiotherapy was recently highlighted by Ehrlich et al.⁸⁰ who reported that almost one-third of patients with small (<1 cm) nodules found on CT did not have histopathologic evidence of cancer when biopsied. Hence, the practitioner must be cautious in this setting so as not to overtreat patients.

Osteosarcomas

Pulmonary metastasectomy in the setting of osteosarcoma is a well-established practice that dates back to the first report by Martini et al.⁸¹ over four decades ago. Numerous other reports^82,83 have documented the utility of repeated, open thoracic explorations for the removal of all evidence of disease as this confers a survival advantage. Unfortunately, these metastases are often quite small (<2 mm) and can be significantly underrepresented by conventional radiologic studies,⁶⁰ hence the need and importance of direct inspection and palpation of the entire lung to locate and remove all evidence of disease. Parenchymal preserving approaches should be utilized in all cases, as patients may develop repeated metastatic foci that mandate subsequent resections. Finally, these operations should not take place, however, until there is definitive disease control at the primary site and in the absence of other metastatic sites.