WORKUP

Lab Studies:

• No single investigative method is adequate to diagnose bronchial tumors in all patients, but most tumors are detectable. Laboratory, radiographic, and procedural techniques are required to locate lesions.

• Complete blood count

• Generally not helpful in initial evaluation

• Must be obtained to aid in differentiation of an infiltrate as potential pneumonia

• Useful to help quantify volume of hemoptysis associated with endobronchial lesions

• Electrolytes, BUN, creatinine, calcium - Not useful, except in evaluating for paraneoplastic involvement

• Liver function tests - Insensitive as indicators of hepatic metastases

• Arterial blood gases (ABGs) - Useful in detection of respiratory failure (eg, acidosis, hypercarbia, hypoxia)

• Sputum culture/cytology

• Rarely helpful in diagnosing bronchial adenomas

• Sensitivity approximately 74% if central airways are involved

• Tumor markers

• Carcinoid

   

  • ACTH

     

  • Antidiuretic hormone

     

  • Calcitonin

     

  • Bombesin

     

  • Neuron-specific enolase

     

  • Serotonin

     

  • Synaptophysin

     

  • Note: All above-mentioned markers also can be identified in small cell lung cancer; therefore their presence offers no diagnostic value in distinguishing between these 2 tumor types.

• Biochemical testing: Neither blood nor urine screening for serotonin or 5-hydroxyindoleacetic acid is of diagnostic value, unless carcinoid syndrome is present clinically. In this case, the presence of these biochemical abnormalities portends a more adverse prognosis.

• Immunohistochemical staining

   

  • May detect differences in secretory products between typical carcinoids and tumorlets

     

  • Controversial regarding tumorlet etiology due to similar staining patterns between tumorlets and normal bronchial epithelium (see Special Concerns).

Imaging Studies:

• Chest x-ray

• Findings may include a nodule, a mass, infiltrate (unilateral hyperlucency, mediastinal or hilar enlargement, and pleural effusion.

   

• Mass or parenchymal changes may be present secondary to tracheobronchial obstruction.

• Findings frequently are nondiagnostic.

• Oblique-view radiographs provide improved detectability of central lesions and may delineate an occult endobronchial component.

• Computed tomography scan

• CT scan is the criterion standard imaging tool.

• Upon nodule discovery, obtain 10-mm CT cuts through the chest and upper abdomen. Fine cuts (ie, 1-2 mm) should be obtained through nodules, looking for calcifications. Tracheobronchial obstruction is suggested by compression of structures in close proximity to the trachea on chest CT scan.

• CT scan further delineates both endobronchial and parenchymal tumor components. Prior to the development of CT scan, hilar tomography and bronchography were used to delineate endobronchial obstruction and irreversible bronchiectasis distal to the mass. CT scan supplants both of these tests; neither is indicated currently.

• Central lesions are observed as well-defined masses that narrow, deform, or obstruct adjacent airways. Diffuse punctate calcifications are observed in 30% of cases and are characteristic but not diagnostic of carcinoid.

• Peripheral parenchymal atelectasis or bronchiectasis is common.

• Peripherally located lesions usually lie adjacent to the airway.

• Typical carcinoid is marked by homogeneous contrast enhancement.

• Atypical carcinoid is associated with less contrast enhancement and frequent irregular contours; regional adenopathy is common.

• Stromal osseous metaplasia due to tumor-induced necrosis of bronchial cartilage is observed on CT scan as intratumoral calcification.

• Magnetic resonance imaging generally is used when CT scan findings are equivocal.

• None of these radiologic techniques accurately differentiates these tumors from other neoplasms.

• Nuclear imaging may include bone scanning when applicable.

Other Tests:

• Spirometry: Peak expiratory flow is a good bedside detector of significant airflow obstruction. Flow volume loops indicate truncation of the expiratory limb.

Procedures:

• Transbronchoscopic fine-needle aspiration

• Fine-needle aspiration (FNA) biopsy of peripheral lesions may yield a basis for diagnosis, including revision of incorrect interpretations (eg, bronchial carcinoid misinterpreted as small cell carcinoma); therefore, histologic confirmation is the only definitive means of diagnosis.

• FNA biopsy is a routine part of the bronchoscopic examination of submucosal lesions.

• Frozen section examination of FNA biopsy specimens may be misleading because of the tumors' similarity to small cell carcinoma.

• Permanent hematoxylin and eosin preparations usually lead to the correct diagnosis, although confusion regarding atypical carcinoid still may lead to an inaccurate diagnosis.

• Bronchoscopy (fiberoptic or rigid)

• Eighty percent of bronchial adenomas are visible by bronchoscopy, which usually is successful in localization within and proximal to segmental orifices.

   

• Endoscopic bronchoscopy helps visualize 75% of carcinoids.

   

• Accurate identification requires bronchial biopsy. Biopsy should be performed despite reports of massive hemorrhage associated with biopsy of these tumors. Most episodes of postbronchoscopic hemorrhage follow attempts at partial or complete removal rather than simple biopsy. The submucosal location necessitates a slightly deeper than usual biopsy. Dilute epinephrine is a helpful adjunct.

   

• General anesthesia and rigid bronchoscopy may be required for airway control if severe hemorrhage occurs with fiberoptic technique.

   

• Bronchoscopy should be performed in all candidates for a bronchoplastic procedure to precisely define the limits of the planned bronchial resection. This can be performed with local anesthesia and sedation or with general anesthesia. The procedure usually is performed under general anesthesia because bronchial adenomas, owing to their propensity to bleed, are evaluated best with rigid ventilating bronchoscopy.

• Because massive hemoptysis may develop, strict airway control is maintained best with rigid bronchoscopy in the setting of bleeding or constricting bronchial lesions. The scope can be attached directly to the anesthesia circuit. Intermittent ventilation is performed while the eyepiece is closed. When the eyepiece is opened to suction, a biopsy sample is taken and the site is then packed. Avoid use of nitrous oxide because the patient may be apneic for a long period.

• Severe tracheal injury may occur if the patient bucks during rigid bronchoscopy; therefore, patient paralysis may be necessary to achieve the best results. Typically, anesthesia is induced, the patient is ventilated and then paralyzed, and the surgeon places the rigid scope directly. The patient is intubated only after the scope is removed at the completion of the procedure.

• Be aware that within seconds of completing the bronchoscopy, the patient is either awakened (eg, if the tumor is unresectable) or reintubated with a double-lumen tube.

• Occasionally, fiberoptic bronchoscopy is performed under minimal anesthetic concentration. In these situations, the patient is given antisialagogue preoperatively to dry out the bronchial mucosa, thus enhancing the effectiveness of topical anesthetics and making the procedure easier.

• Mediastinoscopy

• Previously, this was used routinely in evaluating bronchial adenomas.

• It is of little value in preoperative nodal staging in typical carcinoid tumors, unless mediastinal involvement suspected.

• It is beneficial in atypical carcinoid and when unresectability is suggested by evidence of mediastinal involvement on radiographic imaging.

• Mediastinotomy

• Needle thoracentesis

• This can aid in diagnosis via cytology studies.

• It can be therapeutic and is useful when large pleural effusions cause respiratory insufficiency.

• Ultrasound guidance may be used for small effusions.

Microscopically, morphology usually involves uniform, round-polygonal cells, unless the cells are located peripherally, and then a spindle shape predominates. Nuclei are small and oval. Finely granular chromatin is observed, with abundant eosinophilic cytoplasm. Cells undergo infrequent mitoses. The cellular arrangement usually involves small clusters, interlacing cords, or both, separated by well-vascularized connective tissue. Stromal osseous metaplasia secondary to central tumor necrosis or necrosis of compressed bronchial cartilage with secondary ossification may be present. Ultrastructurally, closely packed cells with small but well-formed desmosomes and numerous heterogeneous neurosecretory granules are observed.

Typical carcinoids appear through microscopy as noted above. The overlying bronchial epithelium may undergo squamous metaplasia. Nodal metastases are present in only 10-15% of patients. These are tumors of Kulchitsky cell type I.

Atypical carcinoids exhibit aggressive behavior and malignant histologic features. These are well-differentiated neuroendocrine carcinomas, also known as Kulchitsky cell II tumors. The age of onset is later than that of the typical variety. More than 50% occur in a peripheral location. Nodal metastases at presentation occur in 50-70% of cases. This subtype is difficult to differentiate from small cell carcinoma. Tumors exhibit a poor response to chemotherapy. Histologically, the tumors exhibit pleomorphism with more mitotic activity, nuclear abnormalities, prominent nucleoli with peripheral palisading, and necrosis. Note that Kulchitsky III cell tumors are small cell carcinomas.

The melanocytic variety is a rare pigmented carcinoid that is differentiated from pulmonary melanoma.

The oncocytic type is a rare subtype of typical lesions with mixed cellular content, including typical carcinoid cells and large eosinophilic oncocytes. True oncocytic differentiation occurs.

Tumorlets/multiple peripheral lesions are isolated foci of atypical hyperplastic bronchial epithelium. These lesions are seen especially in patients with restrictive pulmonary pathology. Most often, these lesions are an incidental finding during autopsy or in a resected specimen.

The malignant potential depends on whether the carcinoid is typical or atypical and on the stage at presentation.

Adenoid cystic carcinomas are slow-growing masses with the propensity for submucosal invasion, perineural invasion, and distant metastasis. Numerous prominent mitochondria and serous secretory granules are observed through electron microscopy.

Staging:

• Carcinoids

• No correlation is shown to standard tumor, node, metastases (TNM) classifications.

• Most typical lesions present as stage 1 tumors.

• More than 50% of atypical lesions present as stage 2 or 3 tumors with bronchopulmonary or mediastinal nodal involvement.

• Intraoperative biopsies of hilar and lobar nodal tissue and tissue in the involved bronchopulmonary segment, with frozen section analysis, are required.

TREATMENT

Medical Care:

• Carcinoid

• In the absence of distant metastases, the treatment principle is complete removal of primary carcinoid with maximal parenchymal preservation, based on the principle that the majority is only locally invasive.

   

• In the past, as many as 62% of patients with bronchial adenomas required conventional lobectomy or pneumonectomy. These patients often had significant delays in their diagnosis, and most were observed to have either total obstruction of a bronchus or parenchymal destruction due to recurrent infections.

• Emergency therapy

• Treatment is symptom based.

   

• If upper airway obstruction is present, prepare for intubation, cricothyrotomy, and/or tracheostomy.

   

• If hemoptysis is present, supplemental oxygen/suctioning may be necessary. In the threat of imminent demise, consider using a double-lumen endotracheal tube. Place the patient with the bleeding side down. Rigid bronchoscopy may be required. Perform ABG determination, CBC count, type and crossmatch, and coagulation profile if bleeding is significant.

   

• Pain control may be necessary.

• Chemotherapy

   

  • Combination therapy as in small cell carcinoma is effective in treating metastatic carcinoids. Response is only 50% at best, which is lower than in small cell carcinoma.

     

  • Adjuvant chemotherapy along with postoperative radiation are advocated for atypical lesions associated with mediastinal nodal extension.

   

• Radiation

• Carcinoid tumors are resistant to irradiation, making this an inappropriate mode of primary therapy.

   

• Anecdotal reports exist of tumor response in inoperable cases. Radiation is recommended for postoperative management of incompletely resected atypical lesions and in cases of mediastinal nodal metastasis. Data supporting the efficacy of this treatment currently are lacking.

   

• Adenoid cystic tumors are radiosensitive, and postoperative radiotherapy is indicated.

   

• Provide follow-up.

Surgical Care:

• Endoscopic resection

   

  • Bronchoscopic resection

     

    • This procedure is plagued by incomplete tumor removal, with frequent recurrence due to extraluminal tumor bulk, often with limited tumor visibility and accessibility via the bronchoscope.

       

    • It carries a high risk of hemorrhage.

       

    • Bronchoscopic resection is warranted to alleviate bronchial obstruction in patients in whom thoracotomy is prohibitive.

       

    • Occasional preoperative use of this technique may allow assessment of the reversibility of distal parenchymal damage.

     

  • Neodymium-yttrium-aluminum-garnet laser

     

    • Neodymium-yttrium-aluminum-garnet (Nd: YAG) laser reduces the risk of hemorrhage-related complications by means of photocoagulation.

       

    • It is not recommended as a primary mode of tumor removal.

       

    • Rarely, Nd: YAG laser is applicable to a polypoid, easily accessible lesion on a narrow uninvolved stalk.

• Surgical resectional therapy

   

  • Complete tumor removal with maximal parenchymal preservation is the goal of surgical therapy.

     

  • Note that removal of all functionless necrotic/destroyed parenchyma distal to the lesion is required. Complete nodal dissection also is required, including all accessible mediastinal nodes.

     

  • Occasional use of bronchoscopic tumor removal prior to formal resection allows for reversal of distal parenchymal damage with preservation of this tissue.

   

• Procedures employed

• Lobectomy with/without sleeve resection: Lobectomy is the most commonly employed technique because most tumors occur in or near the origin of lobar bronchi. Concomitant sleeve resection of the mainstem is required if the orifice of the lobar bronchus or the adjacent mainstem bronchus is involved. Bronchoplastic adjunct permits preservation of normal parenchyma distal to the lesion. This procedure is preferable to pneumonectomy.

   

• Endobronchial resection: Preoperative laser photoresection may be employed prior to complete resection.

   

• Bronchotomy/simple wedge: Polypoid tumors are accessible by bronchotomy, excised with the attached bronchial wall. Bronchotomy ensures complete resection as compared to endoscopic removal. Tumor is rarely amenable to this technique. Wedge resection is appropriate only for small peripheral typical lesions. The procedure must be accompanied by nodal sampling with frozen sectioning of segmental and hilar nodes.

   

• Bilobectomy

   

  • Bronchoplastic sleeve resection alone is useful for mainstem bronchial tumors and, occasionally, tumors involving the bronchus intermedius. Parenchymal preservation is an advantage of this technique, which is preferable to bilobectomy or pneumonectomy. Carinal resection occasionally may be useful.

     

  • Segmental resection is the procedure of choice for tumors arising distal to the origins of tertiary bronchi. Tumor originating from the superior segment of the lower lobe is treated by a combination of segmental resection and lower lobe bronchial sleeve resection. This allows complete basal segmental preservation in the absence of regional nodal involvement on frozen sectioning.

     

  • Pneumonectomy rarely is required and is useful only in cases of complete destruction of all lobes by a proximal lesion.

• Preoperative risk assessment

• History

   

  • Severe COPD

     

  • Chronic renal failure

     

  • Cor pulmonale

     

  • Diabetes

     

  • Myocardial infarction within 6 months

     

  • Congestive heart failure

   

• Electrocardiogram

   

  • Baseline testing - Differentiates between chest pain and dyspnea

     

  • ECG patterns - Often are altered by changing pulmonary hemodynamics

• Preoperative planning

• Determine the approach (ie, thoracoscopic vs thoracotomy) based on tumor location, cell origin, and other variables.

   

• Surgical options include bronchoplastic techniques. A portion of the bronchus is removed, with or without lobectomy, as a sleeve resection and a primary bronchial reanastomosis. Parenchymal preservation is the advantage of this.

   

• Bronchial hygiene: Preoperative preparation for bronchoplastic procedures must include measures to improve bronchial hygiene, using bronchodilators, nebulizers, and perioperative antibiotics.

   

• Pulmonary functional status: Preoperative assessment must evaluate pulmonary functional status and includes the following: exercise tolerance, spirometry, and diffusing capacity of lung for carbon monoxide.

   

• Pulmonary reserve criteria include the following:

   

  • Forced expiratory volume in 1 second (FEV₁): Mortality rate is inversely proportional to FEV₁. With low FEV₁, expect the need for prolonged postoperative mechanical ventilation. Contraindication includes FEV₁ of less than 50%.

     

  • Forced vital capacity (FVC): FVC 3-times tidal volume is necessary for an effective cough. Mortality rate also is inversely proportional to FVC. Contraindication includes an FVC of less than 2 liters.

     

  • Ratio of residual volume (RV) to total lung capacity (TLC): A value of greater than 50% suggests near-terminal COPD with airway closing volumes approaching TLC. Surgery reduces the remaining reserve. Contraindication includes an RV-to-TLC ratio of greater than 50%.

     

  • Maximum breathing capacity (MBC): Contraindication is MBC of less than 50% of predicted.

     

  • PaCO₂: Contraindication is a PaCO₂ of greater than 40.

     

  • Split-function testing

     

  • Maximum voluntary ventilation

   

• Pulmonary artery/bronchial artery occlusion testing rarely is used today to predict whether patients with known pulmonary hypertension will tolerate resection without developing right ventricle failure.

• Operative preparation

   

  • Monitor central venous/arterial pressure.

     

  • Management of airway compromise: Recall the 2 components of bronchial obstruction: dynamic and static. The dynamic component often is not unmasked until the patient is supine, general anesthesia is induced, or the patient is given paralytics. It is suggested by a history of orthopnea or dyspnea. In the absence of contraindications (eg, aspiration risk), slow airway conductance (general anesthesia) induction maintains spontaneous ventilation until effective positive-pressure ventilation is instituted and the patient is positioned. Airway compression can be overcome with rigid bronchoscopy and a long endotracheal tube.

     

  • Blood conservation includes typing and crossmatching.

     

  • Positioning

     

    • This depends on the operative approach.

       

    • The head should be maintained in a neutral position.

       

    • An axillary roll maintains arm perfusion and prevents suprascapular nerve stretch.

       

    • The table break should be at the hips.

       

    • Use a bean bag for the lateral decubitus position.

       

    • Lower-extremity pillows help protect against skin necrosis.

       

    • The arms should be in a natural position.

     

  • Ventilation mode should be single lung.

     

  • Endotracheal tubes should be of the double-lumen type (eg, Carlens; Robertshaw).

     

  • Fiberoptic evaluation should include bronchial blockers.

     

    • The catheter used should have a high-pressure cuff at one end.

       

    • It should be placed directly into the main stem to be occluded (bronchoscopically).

       

    • The cuff should be inflated.

       

    • It tends to dislodge during manipulation.

     

  • Endobronchial intubation

     

    • A Univent tube is an endotracheal (ET) tube with a built-in occlusive catheter.

       

    • An advantage is that it can be stabilized by the cuff of the ET tube.

     

  • Management of one-lung ventilation

     

    • Use 100% fraction of inspired oxygen.

       

    • Tidal volume should be 10-12 mL/kg.

       

    • Set the respiratory rate to maintain a PCO₂ of less than 40.

       

    • A tidal volume (VT) greater than 15 can increase the amount of zone 2 in the dependent lung, causing increased blood flow to the unventilated lung.

       

    • Atelectasis and decreased functional residual capacity (FRC) occur with VT less than 8 mL/kg. Peak end-expiratory pressure to the ventilated dependent lung improves oxygenation by increasing the FRC and decreasing atelectasis.

       

    • Continuous positive airway pressure (CPAP) to the nondependent lung is the most effective way to treat hypoxia during one-lung ventilation. Recall that carbon dioxide can be ventilated adequately by the dependent lung, and a continuous supply of oxygen to the unventilated up-lung replaces what little oxygen is removed. CPAP also may divert blood from the unventilated up-lung to the ventilated dependent lung.

• Intraoperative details

   

  • The margin of resection for endobronchial lesion requires frozen section examination.

     

  • The presence of microscopic tumor at the resection margin mandates more proximal resection.

     

  • Nodal staging by frozen section method is mandatory, with complete mediastinal nodal dissection reserved for instances of atypical carcinoid or extensive nodal involvement identified by frozen section analysis.

   

• Postoperative details

• Planning the postoperative course includes the following:

   

  • Postoperative thoracic surgical patients may experience various postoperative pulmonary complications, including abnormal ventilatory mechanics, pneumonia, and respiratory failure.

     

  • Reinstitution of nebulized bronchodilators may be needed.
•  
  • Aggressive chest physiotherapy may be needed.

   

• Pain control includes the following:

   

  Pain leads to a restrictive pulmonary defect, severely impairing patients' ability to ventilate and/or clear secretions. A significant decrease in vital capacity and FVC results.
• Thoracic epidural patient-controlled analgesia (PCA), in combination with local analgesia and narcotics, may provide excellent pain relief. PCA enables the use of a less-potent general anesthetic. Usually, PCA is run as an infusion of 10 mcg/cc fentanyl with 0.1% bupivacaine. Risk of respiratory depression from epidural anesthetics is increased in patients with significant COPD and in patients with morbid obesity. These agents generally remain in use for 3 days until removal of the chest tube.

• Nonsteroidal anti-inflammatory drugs complement narcotic analgesia, unless contraindicated (eg, allergies, asthma, renal dysfunction, peptic ulcer disease). These may be given intraoperatively near completion of the procedure.
• Following thoracoscopy, port sites and sites for tube thoracostomies are the most painful. PCA may be required for patients undergoing open procedures. Postoperative intercostal nerve blocks also provide excellent foramina and should be performed with 0.25% bupivacaine with epinephrine.

For this group of tumors, no drugs are effective.

FOLLOW UP

Transfer:

• If the endoscopist is not prepared to deal with airway bleeding, biopsy should be deferred until the patient has been sent to an appropriate facility.

Complications:

• Delayed hemorrhage

• Bronchial anastomotic leak

• Coagulopathy

• Myocardial ischemia

• Need for persistent mechanical ventilation

• Mucoepidermoid carcinoma - Known to result in intracranial metastases, even in cases of minimal bronchial wall involvement

• Carcinoid - Solid organ metastases (eg, to the liver) possible

Prognosis:

• The overall 5-year patient survival rate for bronchial adenoma is excellent (96%).
• A few reports exist of local recurrence or distant metastases following adequate resection.
• Overall, the long-term prognosis is excellent for these patients, and thus, limited resection should be used whenever possible.
• The mean duration before metastases is 2 years.

   

• Carcinoid

• The slow growth pattern often prolongs the natural history of pulmonary carcinoids over many years, with or without treatment.
• Patient survival rates depend on tumor aggressiveness. Complete resection of a typical lesion, with or without nodal metastases, usually is curative.
• A 5-year patient survival rate of at least 90% should be expected in this subgroup and has been confirmed in several series.

• The 10-year patient survival rate for uncomplicated typical carcinoids has been reported to be as high as 88%.

• Complete excision with nodal dissection in metastatic typical lesions (N2 disease) should allow a 5-year disease-free patient survival rate of nearly 100%.

• N2 disease in atypical carcinoid is associated with a 5-year disease-free patient survival rate of 60% or lower. Distant metastases are a common form of recurrence in this subgroup.

• Adenoid cystic carcinoma

• Patients with adenoid cystic carcinoma have an excellent prognosis because this tumor is radiosensitive and grows very slowly. The best prognosis is achieved when complete resection is possible. However, prolonged patient survival is possible even with incomplete resection.

• The 5-year survival rate is approximately 83%, while the disease-free survival rate after surgery is approximately 60%.

• Mucoepidermoid carcinoma

• The 5-year patient survival rate is 11.1%.
• Chemotherapy and radiation are reserved mainly for palliation and do not add to overall 5-year patient survival rates.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to diagnose

• The most common legal hazard is failure to diagnose. The patient with bronchial adenoma may present with hemoptysis, chronic cough, recurring pneumonia, or simple chest discomfort. While the x-ray may show segmental or lobar atelectasis or infiltrate, the tumor itself rarely is large enough to be visible and the x-ray findings may be completely normal.

• The way to avoid this is to have a very low threshold for bronchoscopy. Hemoptysis almost always prompts bronchoscopy, but the general clinician should remember that chronic cough and recurring pneumonia also are indications. No physician should be sued successfully if an honest effort is made to diagnose the problem, but that effort often should include bronchoscopy.

• Bleeding

• Bronchoscopic biopsy may lead to bleeding, which can be severe and life-threatening. Occasional reports of spontaneous severe bleeding have been made; however, once the tumor has been biopsied, bleeding may be severe. Any bleeding in the airway can be life-threatening.

• Bleeding following bronchoscopy is the most dangerous pitfall. If the endoscopist is not prepared to deal with airway bleeding, a biopsy should be deferred until the patient has been sent to an appropriate facility. Some surgeons feel that the bronchoscopy always should be performed through a straight bronchoscope, but this probably is overly cautious. Nonetheless, a straight bronchoscope permits better control of a bleeding biopsy site than a flexible bronchoscope. To successfully deal with bleeding, a rigid bronchoscope should be available and the operator should have the ability to intubate and to use an ET tube to tamponade the bleeding tumor, or at least to block off the bronchus on the bleeding side to permit ventilation through the nonbleeding side.

• Failure to perform a biopsy

• Because of the risk of bleeding, many clinicians have fallen into an associated pitfall, which is a failure to perform a biopsy on anything in the tracheobronchial tree that looks as if it may be a bronchial adenoma.

• To avoid this, perform the biopsy but be prepared to handle any hemorrhage.

Special Concerns:

Future/controversies - Tumorlet etiology
Hyperplastic proliferation of neuroendocrine cells, rather than neoplasms as proposed by Cutz et al
True neoplasm because D'Agati et al have reported peribronchial nodal metastases
Diffuse form as possible etiology of small airway obliterative disease as proposed by Aguayo et al