Pediatric Pulmonary Tumors: Primary and Metastatic

Seminars in Pediatric Surgery (2008) 17, 17-29

Pediatric pulmonary tumors: primary and metastatic

Christopher B. Weldon, MD, PhD, Robert C. Shamberger, MD

From the Department of Pediatric Surgery, Harvard Medical School, Children’s Hospital Boston, Boston, Massachusetts.

KEYWORDS Pediatric pulmonary tumors are rare. There is often a significant delay in diagnosis of pulmonary tumors Pediatric; secondary to their rarity and nonspecific presenting physiologic and radiographic findings. A high index Lung; of suspicion in pediatric patients with recurrent or persistent pulmonary symptoms is of paramount Tumor; importance in diagnosing pulmonary tumors at an early stage. Malignant pulmonary tumors are more Benign; frequently diagnosed than benign lesions, with metastatic cancers being the most common. Complete Malignant; surgical resection remains the basis of therapy for primary lesions, and its role in secondary cancers is Review becoming more established. Adjuvant therapies are frequently employed depending on the precise tumor involved. Mortality rates vary greatly depending on tumor location, stage, and type. © 2008 Elsevier Inc. All rights reserved.

Primary pediatric lung neoplasms are rare entities. Sec- icant mortality (8%) owing to the anatomic location of ondary cancers far outnumber primary tumors, and one many of these lesions and their propensity to invade into report documents that 80% of all lung tumors, and over 95% surrounding structures in the mediastinum. Anatomically, of all malignant lung tumors, are metastatic disease from primary lesions arise from both the tracheobronchial tree nonpulmonary cancers.1 However, the number of neoplastic and pulmonary parenchyma proper, and they include a wide lesions pale in comparison to benign pulmonary disease variety of histological subtypes: benign (inflammatory myo- processes. Reports have documented a ratio of 1:5:60 for fibroblastic tumors, 52%; hamartomas, 23%) and malignant primary cancers to metastatic lesions to benign disease (bronchial adenoma, 40.5%; bronchogenic carcinoma, 16%; entities in the pediatric lung.2,3 Secondary lesions encom- pleuropulmonary blastoma, 15%). pass diseases from most known pediatric cancers, including Presenting symptoms can vary widely depending on the the adrenal gland, thyroid gland, gonads, liver, kidney, soft tumor type, size, rate of proliferation, malignant potential, tissue, and bones. vascularity, and the location of the tumor within the respi- Two comprehensive series to date (published a decade ratory system. Symptoms for benign and malignant disease apart with the second building on the first)4,5 have attempted processes differed.4,5 Benign lesions were asymptomatic in to document the quantitative and qualitative aspects of these the majority of cases (24%) owing to the fact that they are lesions by combing through institutional series and combin- more often peripheral lesions. The most common symptoms ing these cases with others reported in the medical literature for benign lesions, when present at diagnosis, were fever resulting in data comprising over 383 patients. These series (14%), cough (12%), and pneumonitis (10.5%). For primary document that the majority of primary lung tumors are malignant lesions, however, cough (35%), pneumonitis malignant (65-76%) with an overall mortality rate of 30%. (23%), fever (18%), respiratory distress (12%), and hemop- However, benign pulmonary masses are not without signif- tysis (11%) were the most common findings, and this cor- relates with the fact that the most common tumors, bronchial adenomas, are predominantly endobronchial lesions. Address reprint requests and correspondence: Christopher B. Wel- don, MD, PhD, Department of Pediatric Surgery, 300 Longwood Avenue, Only 6% of patients with malignant lesions were asymp- Fegan 3, Boston, MA 02115. tomatic. There is often a delay in diagnosis of these lesions E-mail: [email protected]. in children due to the nonspecific nature of many of the

1055-8586/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2007.10.004 18 Seminars in Pediatric Surgery, Vol 17, No 1, February 2008 symptoms and their extreme rarity.1,6-9 Often, infectious for endobronchial lesions. Furthermore, the extent of these causes or reactive airway disease are the presumed diag- tumors is notoriously underestimated on bronchoscopy, and noses, and the patients are treated medically for several hence, they are often referred to as the “tip of the iceberg” months or even years before diagnosis.1,5,7 lesions. Finally, this mode of treatment has not been uni- Diagnostic studies initially consist of chest radiographs. versally accepted by the pediatric medical community and is Findings on these studies are helpful but are not specific for only recommended for small, benign lesions where com- any single entity, and include atelectasis, hyperinflation, plete excision is likely.2,5 infiltrative processes, mass lesions, pleural or pericardial Operative exploration with total gross and microscopic effusions, and hyperlucency. Many of these findings, as resection of all involved tissues is recommended for all 2,4,5 previously mentioned, will be attributed to more common types of lesions, regardless of histologic subtype. Both diagnoses, such as reactive airway disease, foreign body open and minimally invasive techniques have been em- aspiration, or infectious processes. Obviously, a mass found ployed in the resection of these lesions; however, the larger on a chest radiograph will prompt further imaging studies, and more centrally located lesions that may require compli- but this is not often appreciated, especially for small, cen- cated sleeve resections or tracheobronchial reconstruction trally located lesions. Furthermore, combining the symp- are more suitable for a formal thoracotomy. The goal of any toms of coughing and wheezing with hyperlucency on chest procedure, however, should be the preservation of as much radiographic examination would likely be more suspicious normal parenchyma as possible. Caution must also be men- for a foreign body inhalation than a pulmonary tumor based tioned in regard to pneumonectomy in an infant or young 28 on the frequency of the two lesions. If suspicions and child, for severe kyphoscoliosis may develop. Therefore, symptoms persist, computed tomography with three-dimen- parenchymal-sparing resections are recommended, if possi- sional reconstruction is the next modality employed. It is ble. A proposed treatment algorithm for the management of more sensitive (97%) than a chest radiograph in detecting pediatric lung lesions is shown in Figure 1. masses, especially for central lesions.10,11 The specificity of computed tomography, however, is low for pulmonary lesions, except for the pathognomonic “popcorn-like” calci- Benign lesions fications of hamartomas12 and the minority of carcinoid 13,14 tumors that are calcified (26%). Magnetic resonance Inflammatory myofibroblastic tumor (IMT) imaging for pulmonary hamartomas15 and carcinoid tu- mors16,17 has been described, but it is not widely employed. IMT is a myofibroblastic spindle cell soft tissue tumor with Furthermore, carcinoid tumors can also be diagnosed by infiltrative plasma cells, lymphocytes, and eosinophils as de- functional imaging techniques that rely on radiolabeled pep- fined by the World Health Organization (WHO)29 (Figure 2). tide analogues that react with specific somatostatin recep- It has been given many other names in the last half-century tors found in increased number on carcinoid tumors with a 18,19 in the medical literature, the most well-recognized names high degree of sensitivity and specificity. Although flu- being inflammatory pseudotumor and plasma cell granu- orodeoxyglucose (FDG) positron emission tomography has loma. It was first described in 1939 as a primary pulmonary a high sensitivity and specificity in identifying increased lesion,30 and theory has held that it forms as a reaction to a metabolic activity, and hence malignancy in solitary pul- previous tissue insult.31 Various antecedent infections have 20 21 monary nodules, carcinoid tumors are not avid. Further- been described in many reports with rates varying from 5% more, neither magnetic resonance nor functional imaging to 37%.32-35 Furthermore, viral etiologies for these lesions studies have gained widespread applicability or acceptabil- have also been proposed after molecular constructs of the ity in the pediatric population in the evaluation and man- Epstein–Barr and Human Herpesvirus-8 viruses were recov- agement of pulmonary lesions. ered from these lesions,36-40 but these theories are as yet Bronchoscopy, rigid or flexible, is useful in examining unproven. Though traditionally considered benign, recent patients with persistent symptoms and/or radiographically molecular analysis has cast doubt on this assumption. The 22,23 defined lesions, especially if centrally located. Although WHO has defined this tumor as an intermediary lesion that the possibility exists for macroscopic inspection, pathologic has been characterized by a molecular rearrangement on sampling, and therapeutic treatment of these lesions, only chromosome locus 2p23 involving the tyrosine kinase re- gross inspection is readily recommended in treating pediat- ceptor anaplastic lymphoma kinase (ALK) involved in other ric lesions. Bronchoscopic biopsy can be employed as well, forms of malignancy.41 Although this genetic lesion has but again only for endobronchial lesions, and the possibil- been associated in some IMTs,42-44 it has not been uni- ities of indeterminate pathologic analysis from small sample formly documented in all lesions, and debate continues on size and poor sample quality as well as the risk of hemor- the true nature and malignant potential of this lesion. rhage with fatal outcome from this approach are signifi- It is the most common benign pediatric pulmonary lesion cant.7,24,25 Therapeutic bronchoscopic resection and treat- representing more than 50% of all documented benign le- ment using a combination of mechanical, thermal, radiation, sions.4,5 It is predominantly a peripheral lesion that has a and photobiologic therapies can be performed,26,27 but only tendency to grow slowly, but it can invade local structures Weldon and Shamberger Pediatric Pulmonary Tumors 19

Figure 1 This algorithm demonstrates the proposed evaluation of a patient with respiratory symptoms. A baseline workup should be undertaken as a first step, including a history and physical examination (H/P), chest radiograph (CXR), and laboratory evaluations (LABS) (A). The most likely underlying disease process should be treated with the appropriate medical therapy, and then there should be close follow-up within 2 to 4 weeks. If symptoms persist (B), then a repeat workup should be performed with the addition of a chest computed tomogram (CT) and pulmonology consult (C). If this workup, including the chest CT and pulmonology consults, is nondiagnostic, then further medical therapy should be administered with close follow-up (D). If the patient becomes asymptomatic, then no further therapy is warranted (E). But if the symptoms persist (F), then a repeat workup should be ordered, including a bronchoscopy and another chest CT (G). If this workup is again negative, then medical management should be continued with close follow-up (H). If the chest CT (I) and/or bronchoscopy (J) demonstrate a lesion, then the workup should proceed as if these studies were positive from the first encounter (C). If the lesion is peripheral (K) on a CT scan and amenable to a biopsy (M), then this should be considered before resection (N) and disease-specific treatment (O). If the lesion is centrally located, then a bronchoscopy should be performed (J), before resection (N) and further disease-specific treatment (O). producing a variety of symptoms in the pediatric popula- Hamartoma tion. Furthermore, multiple deaths have been documented as 4,33,45 a result of local invasion by this tumor. It is far more Hamartomas are benign lesions that are described in many likely to recur locally than metastasize, with reported fre- organs, but especially the lung and liver. First described in 46,47 quency of 3% to 24%. The largest and most compre- 1904 by Albrecht,54 it is a tumor primarily composed of hensive review demonstrated a 14% recurrence rate with normal cells ordered in an abnormal pattern. Pulmonary 48 pulmonary IMTs. The presence of local invasion was hamartomas are composed of cartilage and gland-like for- highly correlated with local recurrence; IMTs confined to mations in an irregular and haphazard orientation. These the lung at the time of resection recurred in 1.5%, whereas tumors grow slowly.55,56 Macroscopically, they are de- those with extension beyond the lung recurred in 46% of scribed as well demarcated, but without a defined capsule, cases. This latter figure is important since 27% of patients and they are composed of lobules of glandular tissue with have locally invasive disease at the time of resection. Treat- deep septa of connective tissue. The reported incidence in ment should be complete surgical resection, including pos- an autopsy series is 0.25%.57 Hamartomas represent 8% of sible pneumonectomy. Fat-laden macrophages signify pos- all pulmonary neoplasms in all ages,58 and it is the most itive margins on pathological analysis.4 Enucleation as common benign pulmonary lesion in adults, most com- opposed to resection resulted in the only cases of a recur- monly diagnosed in the fourth to seventh decades in rence of an IMT localized to the lung.49 Adjuvant therapies life.55,59 However, this is not the case in pediatric patients, have employed both radiotherapy50 and chemotherapy (includ- where it is the second most common benign pulmonary ing nonsteroidal antiinflammatory drugs)51-53 with some sus- lesion (18-23%).4,5 Radiographically, hamartomas can have tained success, but no specific regimen has gained wide- a pathognomonic stippled, “popcorn” calcification on chest spread acceptance. radiographs, but this finding is only present in 10% to 25% 20 Seminars in Pediatric Surgery, Vol 17, No 1, February 2008

dominal pain, diarrhea, bronchospasm, and endomyocardial valvular disease. These tumors arise from Kulchitsky cells of the amine precursor uptake and decarboxylation (APUD) system that are found in many organs in the body, including the bronchi and lungs. These cells are involved in the synthesis and metabolism of tryptophan and other vasoac- tive amines, and the primary way to diagnose carcinoid tumors is by urinary analysis for the primary degradation product of tryptophan metabolism (5-hydroxyindoleacetic acid, 5-HIAA). Molecular analysis has determined that p53 mutations and disordered expression of anti- and pro-apop- totic member proteins of the Bcl-2 family may contribute to both disease oncogenesis and aggression.65 Carcinoid tumors may occur in isolation, or infrequently (4%) as part of the Multiple Endocrine Neoplasia syndromes (MEN I).66,67 Figure 2 CT scan of an 18-year-old girl who presented with They may present infrequently with Cushing’s syndrome68 left-sided chest pain. Scan revealed a mass causing collapse of the or carcinoid syndrome (1-7%).69,70 The carcinoid syndrome lower lobe with some areas of calcification. Initial percutaneous biopsy was consistent with an inflammatory pseudotumor of the in pulmonary tumors generally signifies extrapulmonary lung. She subsequently underwent resection with a left pneumo- metastatic disease (hepatic or regional and/or local lymph nectomy. nodes). Carcinoid tumors are separated into two subsets, typical (90%) and atypical (10%); the latter, defined by histopathological criteria suggestive of a more aggressive 12,59 of cases. The vast majority are isolated tumors located phenotype, includes the presence of necrosis or an elevated in the periphery of the lung, and though described as asymp- mitotic index. However, regardless of this distinction, both tomatic in adults, they are frequently symptomatic in chil- variants may metastasize. Surgery is the mainstay of treat- 4 dren owing to their size and anatomic location. In fact, four ment; the goal is to remove all microscopic and macro- deaths have been reported secondary to significant pulmo- scopic disease, including associated lymph nodes. The nary compromise. Conservative surgical resection is recom- 5-year survival rates for local, regional, and disseminated mended for treatment of these lesions. Finally, pulmonary disease are 81%, 77%, and 26%, respectively.62 Typical hamartomas have been found in association with extra- carcinoid lesions have fewer lymph node metastases (5- adrenal paraganglioma and gastric smooth muscle tumors in 71 72 60 10% versus 30-75% ) and a more favorable prognosis adolescent females (the Carney triad), and if one of these (stage for stage) in comparison to atypical lesions. Finally, tumors is discovered, a thorough attempt should be made to metastatic disease in adult patients, especially to liver, has determine whether the others tumors are present. been treated with adjuvant radio- and chemotherapy, hepatic artery embolization, hepatic transplantation, and primary and secondary metastasectomy in combination with Malignant lesions the administration of either short- or long-acting somatostatin analogues for symptomatic control of carcinoid syn- Bronchial adenoma drome. However, none of these modalities have been proposed in children, except for the medicinal control of Bronchial adenomas have been cohorted into a single entity, carcinoid syndrome. although they are really several distinct tumors. They are the Mucoepidermoid tumors are the second most common 4,5 largest group (40%) of malignant lung lesions in the pedi- lesion in this cohort, and they represent about 10% of all 1 atric population.4,5 The three most common tumors in this pulmonary tumors in pediatric patients. They originate group are carcinoid tumor, mucoepidermoid carcinoma, and from mucous glands in the submucosa and respiratory mu- 73,74 adenoid cystic carcinoma (cyclindroma) in decreasing order cosa. They are centrally located and infrequently me- of frequency. tastasize to lymph nodes or distant sites. Histopathologi- Carcinoid tumors are the most common malignant pul- cally, these tumors are divided into high- and low-grade monary neoplasm in pediatric patients2,4,5,61 (Figure 3). An lesions, with the overwhelming majority of lesions defined analysis of over 10,000 patients from the SEER database of as low-grade in children.1,7-9,28 In fact, there have only been the National Cancer Institute documented that bronchial or three high-grade lesions reported in children,28 and the only pulmonary carcinoid tumors accounted for 28% all of car- death noted in this entire cohort was in this subset. Man- cinoid lesions diagnosed.62 The term “carcinoid” was first agement of mucoepidermoid tumors involves the complete used by Obendorfer in 1907,63 whereas the term “carcinoid resection of all gross and microscopic disease. High-grade syndrome” was coined by Thorson in 195464 to describe the lesions carry a dismal prognosis in the adult population with associated symptoms of flushing, palpitations, fainting, ab- all patients being dead within 16 months in one series.75 Weldon and Shamberger Pediatric Pulmonary Tumors 21

Figure 3 Lateral chest radiograph (A) of an 11-year-old boy who presented with intermittent cough. It revealed collapse of the middle lobe which was confirmed on the computed tomogram. (B) Subsequent bronchoscopy (C) revealed a lesion obstructing the bronchus intermedius, presumed to be a carcinoid tumor which was confirmed (D) on subsequent pathology. (Color version of figure is available online.)

Adenoid cystic carcinomas are the least frequently iden- node basins. Treatment is extirpation with negative surgical tiﬁed bronchial adenoma in children,4,5 and this tumor is margins and lymphadenectomy, but late recurrences up to described as being a salivary gland-type tumor. They are 10 years have been described.76,77 slow growing, submucosal masses with a high incidence of local recurrence and dissemination.72 The tumors tend to Bronchogenic carcinoma grow radially into the pulmonary parenchyma as opposed to the tracheobronchial tree.72 Hence, frozen section analysis The second most common malignant pulmonary cancer in at the margin of resection is mandatory to determine com- the pediatric population is bronchogenic carcinoma (16.8%)5 pleteness of resection in light of these insidious growth with adenocarcinoma and undifferentiated carinomas ac- patterns. They also have a penchant to have perineural counting for the majority of lesions4,5 (Figure 4). It was ﬁrst spread and direct extension into local and regional lymph described in 1876,78 and it is far more common in adults 22 Seminars in Pediatric Surgery, Vol 17, No 1, February 2008

onset respiratory papillomatosis and carcinomas found in isolated papillomas.94-96

Pleuropulmonary blastoma (PBB)

PBB is the third most frequent (15.5%) pediatric primary pulmonary cancer as previously described in the seminal series on this topic4,5 (Figure 7). The lesion was first characterized in 1945,97 revised in 1953,98 modified by Spencer in 1961,99 and finally defined by Manivel in 1988100 who coined the term pleuropulmonary blastoma to anatomically and histologically define this lesion and distinguish it from a similar cancer commonly seen in adults. It is comprised of mesenchymal elements and embryonic stroma without a neoplastic epithelial component and is Figure 4 An 8-year-old boy presented with a persistent cough and tachypnea. Chest radiograph shows mediastinal widening and thought to arise from somatopleural mesoderm or thoracic the CT scan with IV contrast showed an extensive central lesion which can be seen compressing the pulmonary artery to the left lung. Biopsy revealed bronchogenic carcinoma. than in children. Certain bronchogenic carcinoma subtypes, squamous cell and bronchioloalvelor subtypes, are known to arise from parenchymal cystic lesions in infants and children, including bronchogenic cysts and cystic adenomatoid malformation.4,79,80 The incidence in children is 0.16% in the first decade of life, 0.9% in the second decade, and only 1.2% in all people less than 40 years old.81,82 The incidence peaks in the sixth to seventh decades of life. Similar to the adult population, surgical intervention is the primary mode of therapy with ipsilateral lymphadenectomy for localized disease.83 Adjuvant therapy for local disease and disseminated disease at diagnosis combines both radio- and chemotherapy and will vary depending on the specific histologic subtype and disease stage. Unfortunately, these tumors are generally metastatic at diagnosis, and the patients often present with symptoms (bone pain, weight loss4,84,86) suggestive of this disease burden. The mortality rate mirrors that of the adult population with one large series documenting those pediatric patients with disseminated disease at diagnosis live less than 7 months.4 The recently described basaloid variant85 bronchioloalvelor subtype87 (Figure 5) has a more favorable prognosis as described by Ohye and colleagues.88 Special consideration should be made for squamous cell variant (Figure 6) which account for 12% of described lesions,4,89 and unlike adults, environmental exposures, including tobacco products, are not a known risk factor. How- ever, Human Papilloma Virus (HPV) has been postulated to function as an inciting factor for the development of squamous cell carcinoma (SCC) as it has been found in meta- plastic SCC pulmonary lesions90 and in tracheobronchial lesions91,92 from squamous papillomas or papillomatosis, but there is not convincing evidence to make a definitive Figure 5 Chest radiograph (A) showing the extensive nature of 93 etiologic link. Regardless of this debate, HPV 6 has been the disease, and CT scan (B) showing multiple lesions with the found in benign lesions, and HPV 11, 16, and 18 have been characteristic cavitary centers of a patient with bronchial alveolar found in both the malignant transformation of juvenile- carcinoma. Weldon and Shamberger Pediatric Pulmonary Tumors 23

determining when metastasectomy is appropriate. Before attempting metastasectomy, however, four criteria should be met: (1) primary tumor diagnosis; (2) primary tumor local control; (3) effective adjuvant treatment modalities; and (4) removal of all evident disease.

Adrenocortical carcinoma

Pulmonary metastasectomy for adrenocortical carcinoma should be considered since effective adjuvant therapies are not available. A recent review of the International Pediatric Adrenocortical Tumor Registry revealed that the 5-year, event-free survival was 54%, and the incidence of pulmonary metastases was 7% at presentation.120 Prognosis was Figure 6 CT scan of an 18-year-old boy who had suffered from improved for younger patients with completely resected, respiratory papillomatosis for many years. He ultimately devel- small, early-stage tumors with virilizing symptoms, but sep- oped squamous cell carcinoma of the lung related to the papilloma arate analysis of the patients with lung metastases could not virus. This scan shows the extensive and invasive nature of his be performed because of the small number of cases. How- advanced disease. ever, reports in the literature document long-term survival in patients (predominantly adults) who underwent pulmonary 121,122 splanchnopleura.101,102 Hence, it has pulmonary, pleural, metastasectomy for adrenocortical carcinoma. In fact, and mediastinal lineages. These lesions have been micro- Kwauk and colleagues documented that complete surgical scopically and macroscopically categorized by Dehner ac- excision of all metastatic disease provided for a 5-year survival of 71% versus 0% for those with unresected dis- cording to the proportion of cystic and solid components 123 within the lesion (Type I, only cystic components; Type II, ease. Furthermore, Schulick and colleagues echoed these results and sentiments and advocated for repeat metastasec- cystic and solid components; Type III, solid compo- 124 nents).103 Regardless of the histological evaluation, the tomies. They reported that, for every reoperation, the prognosis is poor with mortality rates ranging from 60% to median survival was longer for the complete versus incom- 95% at 5 years4,104-107 and only 8% at 10 years.101 Negative plete resection cohort, which may be a function of the prognostic factors are size Ͼ5 cm, metastatic diseases, and biology of the tumor involved as opposed to the operation positive thoracic lymph nodes.108-112 Treatment consists of performed. surgical resection for locally confined lesions with adjuvant chemotherapy postoperatively, or in the presence of meta- Differentiated thyroid cancer static disease at diagnosis, neoadjuvant chemotherapy, and radiotherapy.113 For those patients with recurrent or residual Pulmonary metastasectomy should only be performed in disease, chemotherapy and radiotherapy are also recom- differentiated thyroid cancer where there is indecision about mended as described by several groups.113,114 Finally, similar the nature of a pulmonary lesion, especially after treatment. to bronchogenic carcinoma, these lesions have been noted to Disseminated pulmonary disease is found in up to 25% of patients,125-131 but it does not confer a dismal prognosis arise from congenital anomalies of the lung, including cys- 125-131 tic adenomatoid malformation, sequestrations, and broncho- with survival rates of greater than 94% reported. A 115-118 comprehensive review on the treatment of thyroid cancer in genic cysts. Weinblatt first described this relationship 131 in 1982,115 and Tagge and colleagues later documented that children has recently been published. Of the 740 cases 31% arise from cystic pulmonary lesions.117 documented, 131 (17.7%) had evidence of pulmonary disease, and they were treated with radioactive iodine. The 5- and 10-year survival rates were 99.5% and 98.8%, respectively, with only 5 children dying of distant metastases with Metastatic tumors a mean follow-up of 115 months. With therapeutic radioactive iodine administration for pulmonary metastases, Metastatic pulmonary tumors are more frequently encoun- 28.9% had a complete response (negative nuclear imaging tered in the pediatric population than primary lesions. Kay- and thyroglobulin level Ͻ1 ng/mL), 47.7% had a partial but ton has recently published an excellent review of the utility stable response (negative nuclear imaging and thyroglobulin of pulmonary metastasectomy in children,119 but there is a level 1-10 ng/mL), and 23.4% had a partial response. lack of tumor-specific, prospective, randomized clinical tri- als critically evaluating this therapeutic intervention in the Germ cell tumors (gonadal) pediatric population. The data that do exist are generally retrospective small studies that span many years and treat- Pulmonary metastasectomy for germ cell tumors (gonadal) ment regimens, and they can only serve as a guide to should be considered, especially if present after adjuvant 24 Seminars in Pediatric Surgery, Vol 17, No 1, February 2008

Figure 7 (A) Chest radiograph of a 3.5-year-old boy who presented with a cough and some dyspnea on exertion showed opacification of most of the right hemithorax. (B) CT scan showed a multi-lobulated lesion in the lung with cystic and solid components. Percutaneous biopsy did not establish the diagnosis of pulmonary blastoma, but an open wedge biopsy did. (C) Chest radiograph following four cycles of multimodal chemotherapy showed a remarkable regression of the tumor, although the MRI scan (D) showed significant residual tumor within the lung. He subsequently underwent a right upper and middle lobectomy and completion of his chemotherapy. therapy is completed to determine the presence or absence primarily to define the presence of viable tumor in lesions of viable tumor within the lesion and the need for further after chemotherapy and for determining further treatment adjuvant therapy. Germ cell tumors are chemosensitive le- regimens. sions with a long-term survival rate of 90%.132 However, residual radiographic lesions after adjuvant therapies may Hepatoblastoma harbor viable tumor,132-136 with the lung being the most frequent site of distant metastasis.133 Several groups132-136 Pulmonary metastasectomy for hepatoblastoma should only have examined their data concerning the role and utility of be performed for radiographically persistent lesions after pulmonary metastasectomy in these patients, and the results adjuvant therapy. Data to support this concept have been demonstrate that over 40% of patients harbored viable tu- published by Feusner and colleagues137 representing the mor cells within radiographically visible lesions post- Children’s Cancer Group and two reports from the Interna- therapy. Therefore, the role of pulmonary metastasectomy is tional Society of Pediatric Oncology on Childhood Liver Weldon and Shamberger Pediatric Pulmonary Tumors 25

Tumors.138,139 Feusner and colleagues137 reported on six modality approach that addresses synchronous pulmonary patients with pulmonary recurrence who were treated me- lesions at the time of local control; (2) repeated resections tastasectomy and chemotherapy with four patients having a for metachronous lesions; (3) operative evaluation of sus- complete remission; three had a survival of greater than 5 pected masses since computed tomographic imaging does years. Perilongo and colleagues138 documented the results not identify all pulmonary lesions; (4) continued screening of SIOPEL1, where 20% of patients with hepatoblastoma for pulmonary lesions after the first occurrence as a majority presented with pulmonary metastases, and the 5-year event- of patients will have at least one more pulmonary recurrence free survival was 28%. A sustained remission from chemo- within 12 months of the first resection; and (5) the under- therapy alone in these patients was achieved in only standing that other criteria—disease free interval and per- 26%. Schnater and colleagues139 analyzing the same non- centage of tumor necrosis on histopathological evalua- randomized data emphasized that only 41% of patients who tion—in addition to tumor burden are important prognostic presented with pulmonary metastases were long-term sur- factors. vivors, but all patients who underwent surgery and chemotherapy to treat their pulmonary metastases were alive at data analysis. References Neuroblastoma 1. Welsh JH, Maxson T, Jaksic T, et al. Tracheobronchial mucoepidermoid carcinoma in childhood and adolescence: case report and re- Pulmonary metastasectomy for neuroblastoma should not view of the literature. Int J Pediatr Otorhinolaryngol 1998;45:265-73. be performed. However, if there is concern about the nature 2. Cohen MC, Kaschula ROC. Primary pulmonary tumors in childhood: of a pulmonary lesion after or during treatment, then it a literature review of 31 years; experience and the literature. Pediatr should be biopsied. The incidence of pulmonary metastases Pulmonol 14:222-232, 1992. Ͻ 3. Crisei KL, Greenberg SB, Wolfson BJ. Cardiopulmonary and tho- from neuroblastoma has been reported from 1% to racic tumors of childhood. Radiol Clin North Am 1997;35:1341-66. 140-144 23% ; however, most large studies report rates of 5% 4. Hartman GE, Shochat SJ. Primary pulmonary neoplasms of child- or less.142-144 These patients with pulmonary metastases hood: a review. Ann Thor Surg 1983;36:108-19. from neuroblastoma have a poor prognosis, a higher asso- 5. Hancock BJ, DiLorenzo M, Youssef S, et al. Childhood primary ciation of unfavorable Shimada histology, MYCN amplifi- pulmonary neoplasms. J Pediatr Surg 1993;28:1133-6. 143-144 6. Lack EE, Harris GBH, Eraklis AJ, et al. Primary bronchial tumors in cation, and a lower event-free survival. Hence, the childhood: a clinicopathologic study of six cases. Cancer 1983;51: utility of performing resections except to confirm the diag- 492-7. nosis are not warranted. 7. Hause DW, Harvey JC. Endobronchial carcinoid and mucoepidermoid carcinoma in children. J Surg Oncol 1991;46:270-2. 8. Al-Qahtani AR, Dilorenzo M, Yazbeck S. Endobronchial tumors in Nephroblastoma children: institutional experience and literature review. J Pediatr Surg 2003;38:733-6. Pulmonary metastasectomy for nephroblastoma should not 9. Curtis JM, Lacey D, Smyth R, et al. Endobronchial tumors in child- be resected, and suspected lesions should only be biopsied. hood. Eur J Radiol 1998;29:11-20. 145,146 10. Manninen MP, Paakkala TA, Pukander JS, et al. Diagnosis of tra- Some authors have advocated for primary pulmonary cheal carcinoma at chest radiography. Acta Radiol 1992;33:546-7. 147 metastasectomy to spare the effects of radiotherapy on 11. Kwong JS, Adler BD, Padley SPG, et al. Diagnosis of diseases of the patients, but other reports have demonstrated the efficacy of trachea and main bronchi: chest radiography vs CT. AJR Am J chemotherapy and radiotherapy in the treatment of pulmo- Roentgenol 1993;161:519-22. nary metastases over chemotherapy and surgical excision, 12. Eggli KD, Newman B. Nodules, masses, and pseudomasses in the 148-150 pediatric lung. Radiol Clin North Am 1993;31:651-66. regardless of pathological subtype or stage. The 13. Zweibel BR, Austin JH, Grimes HH. Bronchial carcinoid tumors: importance of biopsy for suspicious pulmonary lesions, assessment with CT location and intratumoral calcification in 31 especially if small (Ͻ1 cm) and found only on computed patients. Radiology 1969;93:1013-9. tomography was confirmed recently by Ehrlich and col- 14. Shin MS, Berland LL, Meyers JL, et al. 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