Malignant neuroendocrine tumor of endodermal origin arising from Kulchitsky cells.

Neuroendocrine and salivary gland tumors of the tracheobronchial tree were previously referred to as bronchial adenomas [1]. This potentially confusing terminology has fallen out of favor secondary to the variable glandular component and malignant potential of these tumors [33].

Bronchial carcinoid is the most common malignant endobronchial tumor and the second most common primary malignancy of the lower respiratory tract in children (after PPB) [5]. Carcinoids are most commonly seen in the gastrointestinal tract, with only 10–32 % occurring in the tracheobronchial tree [34, 35]. The average age of presentation of bronchial carcinoid is 45–56 years [34, 35]. This is a decade younger than the average age of presentation for other lung malignancies, but carcinoid is still uncommon in the pediatric age range. When it occurs in children, it tends to affect older children and adolescents with the youngest reported patient being 8 years of age [34]. There is no known smoking association, or sex or racial predilection.

Presentation is varied. Post-obstructive atelectasis and pneumonitis are common [35]. Nonspecific respiratory symptoms and signs, including pleuritic pain, dyspnea, cough, wheeze, and hemoptysis, are also seen. The tumor is incidentally detected in up to half of patients. Carcinoid tumors can synthesize a variety of neuroamines and peptides leading to more specific presentations. Overproduction of adrenocorticotropic hormone (ACTH) leads to Cushing syndrome in up to 4 % of patients. Overproduction of serotonin leading to carcinoid syndrome is rare in bronchial carcinoid outside of the setting of metastatic disease (2–5 %). Up to 4 % of carcinoid tumors are associated with other endocrine neoplasias [34]. The most common association is with pituitary tumors, seen in half of this patient subset.

In addition to imaging, detection and follow-up of lesions can be aided by serum and urine 5-hydroxyindolacetic acid (5-HIAA), a serotonin metabolite that is relatively specific though not sensitive for the diagnosis [34].

The typical appearance of a bronchial carcinoid is that of a single round or lobulated mass that is at least partially endobronchial [35, 36]. The mass is typically 2–5 cm in size. Endoscopy can underestimate the size of the mass as the endobronchial component can represent just the “tip of the iceberg.” The mass is seen within the main, lobar, and segmental bronchi in 80 % of cases with a preference for branching sites (Fig. 8.3). The remaining 20 % of bronchial carcinoids are peripheral in location and indistinguishable from intraparenchymal pulmonary masses [35].

In up to 30 % of cases, bronchial carcinoids demonstrate calcification that is best appreciated on CT. The masses demonstrate high signal intensity on T2-weighted MRI images and typically exhibit homogeneous avid enhancement [35]. However, heterogeneous or minimal enhancement does not exclude the entity. Bronchial carcinoids demonstrate octreotide uptake on somatostatin receptor scintingraphy in greater than 86 % of cases [35, 37] (Fig. 8.3).

Associated findings include post-obstructive atelectasis or pneumonitis, bronchiectasis, and mucous plugging. Local or distal recurrence occurs in up to a fifth of cases with 15 % presenting with metastases [35]. Metastases are most commonly seen in the liver, bone, adrenals, and brain.

In the current molecular model [38], bronchial carcinoids originate from bronchial Kulchitsky-type neuroendocrine cells. These cells are capable of producing precursor lesions such as diffuse idiopathic pulmonary cell hyperplasia or tumorlets. Small invasive foci break through the basal lamina and invade locally, producing small lesions termed tumorlets, which are by definition <5 mm in diameter. The most common chromosomal aberrations in pulmonary carcinoids include −11p, +19p, −13q, +19q, +17q. −11p, −6q, +16p, +2-p, and −3p, although these occur at a frequency of <25 % in typical lesions. However, as bronchial carcinoids assume atypical features and undergo carcinomatous transformation, the frequency of these changes rises to as high as 75 % for −3p and −13q. Approximately 18 % show sporadic mutations and loss of heterozygosity of MEN1, the multiple endocrine neoplasia 1 gene.

Pulmonary carcinoids generally contain a uniform population of monotonous round cells with regular, central nuclei, granular chromatin, inconspicuous nuclei, and a relatively high nuclear-to-cytoplasmic ratio. The cytoplasm is generally lightly eosinophilic but on occasion is more abundant and resembles that of rhabdoid cells. Rarely, it is clear, and melanin or mucus may be present. Some tumors show marked nuclear pleomorphism, a feature not reliable in predicting behavior. The cells usually grow in an organoid or trabecular pattern, forming nests or cords, but sometimes they form spindle cells or rosettes. The intervening stroma is vascular and collagenous and is capable of producing amyloid, hyaline, bone, or cartilage (Fig. 8.3).

Atypical carcinoids are characterized by the presence of focal necrosis or conspicuous mitotic activity (2–10 mitoses/2 mm²) [33].

Prognostic factors in bronchial carcinoids include stage and the presence of atypical features (atypical carcinoid). Pediatric bronchial carcinoids generally have an excellent long-term outcome with adequate surgery and lymph node excision. Long-term follow-up is required, as relapse may occur years after the initial excision, but usually can be successfully treated with additional surgery [39].

Pleuropulmonary blastoma (PPB) is a rare primitive mesenchymal, embryonal type neoplasm of the lung and pleura of young children.

PPB has been previously termed pulmonary embryoma, pulmonary blastoma, mesenchymal cystic hamartoma, and sarcoma arising in congenital cystic malformations [5]. PPB was described as a tumor distinct from adult pulmonary blastoma in 1988 by Manivel et al. [46]. PPB is a rare neoplasm with approximately 25–50 cases occurring annually in the USA, 500–600 cases reported in the literature, and 370 centrally reviewed cases in the International Pleuropulmonary Registry (Personal communication, Dr. Yoav Messinger, on July 17, 2013). In spite of its rarity, it is likely the most common primary malignancy of the lung in children. Epidemiological data is largely derived from the largest reported case series of 50 patients from the Registry [47]. The average age of presentation is 38 months with the cystic types presenting earlier and rarely presenting at more than 6 years of age. Prenatal presentation of cystic PPB has been reported [48].

There is no apparent sex or racial predilection. About 40 % of patients with PPB or their relatives manifest certain other dysplasias and neoplasms as part of the PPB Family Tumor Dysplasia Syndrome (PPB-FTDS). Conditions associated with PPB-FTDS include PPB, cystic nephroma, pineoblastoma, pituitary blastoma, embryonal rhabdomyosarcoma (especially of the uterine cervix), medulloblastoma, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, multinodular goiter, intestinal juvenile hamartomatous polyp, and ovarian stromal sex-cord tumor (especially Sertoli-Leydig tumors) [49–51]. The clinical presentation of PPB ranges from an incidental finding in an asymptomatic patient to nonspecific respiratory or systemic symptoms, such as respiratory distress, fever, chest pain, cough, anorexia, and malaise [47].

PPB has been categorized into three main types based on gross morphology. Type I is entirely cystic, type II is mixed cystic and solid, and type III is entirely solid [52]. Age of presentation, malignant behavior, and mortality increase with type number. If untreated, progression of type I to type II and III can occur. CPAMs do not transform into PPB [47]. Type I PPB may also spontaneously regress, leading to categorization as type Ir PPB for type I-regressed PPB [49].

Types I and Ir PPB appear as an air-filled unilocular or multilocular thin-walled cyst with delicate septations, and are indistinguishable from the more common large cyst form of CPAM (Fig. 8.5). Findings that favor type I PPB over large-cyst CPAM include the presence of multifocal or bilateral cysts or spontaneous pneumothorax [47–49, 53]. Type II and III PPB usually appear as a large, heterogeneously enhancing mass in the hemithorax with associated mediastinal mass effect and pleural effusion and lack of chest wall invasion [9] (Fig. 8.6). PPB is slightly more common in the right hemithorax than the left, and bilateral tumors may be synchronous or metachronous [54].

Aggressive local invasion of the bronchi, great vessel, and heart is unusual but has been reported [54, 55]. Metastases occur in 11 % and 55 %, respectively, of types II and III cases [49]. The most common location for distal metastasis is the brain, followed by bone. Cerebral metastases are much more frequent in PPB than in other childhood sarcomas [56]. Metastases to the liver, adrenal glands, and ovary have also been reported [47, 49].

Comparative genomic hybridization identifies aberrations (amplifications, gains, losses) in PPB tumors, with DNA gains involving chromosome 8q being the most frequent abnormality. Losses of 9p and 11q are also reported [57]. The sites of gains and losses may contain oncogenes or tumor suppressor genes, respectively.

Children with PPB-FTDS discussed above frequently have heterozygous, germline loss-of-function mutations in the DICER1 gene that codes for a protein involved in microRNA (miRNA) processing. Loss of DICER 1 function in the epithelium of the developing lung may alter the regulation of diffusible factors that results in mesenchymal proliferation and sarcomatous transformation [58]. DICER1 mutations are inherited by an autosomal dominant mechanism with variable expressivity, and are thought to be present in 60–70 % of cases of PPB [49].

PPB is composed of a malignant mesenchymal component but no malignant epithelial component. It is postulated that PPB originates in mesenchymal elements resembling fetal lung at 10–16 weeks of gestation. Three types (I, II, and III) based on gross morphology are described [59].

A unilocular or multilocular cyst with thin fibrous septa characterizes type I PPB. The cysts are lined by ciliated epithelium with small subepithelial “buds” containing aggregates of primitive mesenchymal cells or nodules of immature cartilage (Fig. 8.5). These small, round-to-spindled, subepithelial mesenchymal cells may display rhabdomyoblastic differentiation. In type Ir (regressed cystic), the small primitive mesenchymal cells are not seen, and the wall or septa of the cyst may be hyalinized or necrotic.

In type II PPB, cystic and plaque-like areas mingle with solid areas with overgrowth of rhabdomyoblasts, spindle cell sarcoma, or blastematous elements. Type III PPB consists of a solid tumor with mixed sarcomatous (fibrosarcoma, rhabdomyosarcoma, pleomorphic undifferentiated sarcoma) and blastematous features (Fig. 8.6). Foci of muscle and chondroid differentiation are frequent, as are foci of anaplasia with giant bizarre pleomorphic tumor cells (Fig. 8.6a). Malignant epithelium is not seen, differentiating PPB from pulmonary blastoma. Immunohistochemical staining is variable from one tissue type to another. Myogenin, desmin, and MyoD1 are useful for the identification of rhabdomyoblasts [49].

As was mentioned, PPB is histologically and clinically distinct from pulmonary blastoma, a rare subtype of malignant biphasic sarcomatoid carcinoma typically seen in adults. However, a recent case report of a neonate described histology distinct from PPB and more similar to adult PB [60]. PB is occasionally reported in adolescents [61].

Overall survival rate is estimated at 90 % for type I and 40–60 % for types II and III [49]. Progression of type I to type II and III is well recognized. Tumors do not regress from type III to type II or from type II to type I. Local recurrence develops in fewer than 15 % of type I but is seen in over 45 % of types II and III [49]. Recurrence can affect the ipsilateral or contralateral lung [47]. Sex, tumor side, tumor size, preexisting lung cysts, and extent of surgical resection at the time of diagnosis do not impact prognosis, whereas incomplete resection and extrapulmonary involvement at diagnosis result in a significantly worse prognosis [62].