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In the three-quarters of a century that have elapsed since the first description of a bronchial carcinoid, the field has progressed from serendipitous radiological or bronchoscopic diagnosis to computed tomography, magnetic resonance imaging, and somatostatin receptor imaging identification. Similarly, pathologic techniques have advanced from a naïve assessment of neoplasia to a delineation of several tumor subtypes and an understanding of the neuroendocrine basis of the disease process.
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A Historical Appreciation of Bronchopulmonary Neuroendocrine Neoplasia: Resolution of a Carcinoid Conundrum
Section snippets
Key points
From Gnosis to Sunesis
In the eighteenth and nineteenth centuries, lung disease was difficult to diagnose and even more difficult to treat. Visualization of the lung was only possible postmortem and operative intervention was impossible in the absence of anesthesia and positive pressure ventilation. The stethoscope described by Laennec (1781–1826) in 1816 had replaced the percussive technique of Auenbrugger (1722–1809) as a clinical tool but neither yielded great insight into pulmonary pathology (Fig. 1). Diseases of
Early observations on lung tumors
Early literature indicates that the first description of a neoplastic lesion of the lung emanates from Morgagni (1682–1771), who in 1761, described an ulcus cancrosum of the right lung in an autopsy on a 60-year-old man (Fig. 2).1 In 1821, Andral2 suggested that examination of the color of sputum could facilitate diagnosis of lung lesions; he associated green sputum with blood and lung disease. It was, however, Laennec’s description of an unusual lung mass, a “crude yellow tubercle,” in 18313
Radiology
The precise localization of lung tumors was greatly facilitated at the turn of the nineteenth century by the advent of the new discipline of radiology. In May 1897, Williams7 of Boston at the meeting of the Association of American Physicians provided an early comprehensive discussion of the use of radiographs in thoracic diseases, including pulmonary TB, pneumonia, and pleural effusions. He particularly stressed the correlation of radiographic appearances with the pathologic findings, which he
Bronchial adenomas
Although a bronchial adenoma was initially recognized at the necropsy of a woman who suffered from hemoptysis and chronic cough by Muller in 1882,35 it was Heine,36 in 1927, who documented the first series of these tumors. In 1930, Kramer37 became the first to clinically diagnose the condition and noted that although these were slow growing, in general, there existed a propensity in some for malignant change. This finding encapsulated the prevailing concept that bronchial adenomas were benign,
Carcinoid tumors and the diffuse neuroendocrine system
In the nineteenth century, Langhans (1839–1915), Lubarsch (1860–1933), and Ransom (1860–1909) described unusual tumors in the small bowel but each failed to adequately investigate these novel entities (Fig. 9).31 This responsibility fell to Oberndorfer, who became the first to adequately characterize the nature of the lesions and refer to them as “benign carcinomas.” During his tenure at the Pathologic Institute of the University of Munich, Oberndorfer32 noted that these tumors were distinct
Early recognition of a neuroendocrine cell genesis
In 1926, about the same time that a consensus was being reached on the relationship between enterochromaffin or NEC and carcinoids, a hitherto unreported small-cell tumor (“oat-celled sarcoma”) of the mediastinum was reported by Barnard.27 Thereafter, although Hamperl would describe the specific entity of bronchial carcinoid (1937),30 misperceptions existed in the pathologic community between the precise terminology and the differences or similarities between oat-cell and small-cell cancers,
The APUD concept and bronchial carcinoids
With the evolution of more sophisticated biochemical techniques, the genesis of oat-cell lesions and lung carcinoids was proposed to include the ubiquitous polypeptide hormone–producing cells of the APUD system, which had been devised by Pearse in 1968.53 Pearse had concluded that all such tumors (neural crest–related) comprised cells capable of secreting a variety of polypeptide hormones, including catecholamines and 5-hydroxytryptamine and possessed the common cytochemical characteristics
The role of immunohistochemistry in the delineation of bronchopulmonary NETs
Initial attempts to assess pulmonary NETS and define neuroendocrine differentiation were based on the use of standard hematoxylin and eosin (H&E) morphology. Introduction of staining techniques enabled a further classification into argentaffin and argyrophilic lesions. However, the subsequent development of immunohistochemical techniques greatly augmented the ability to define neuroendocrine lesions.
During the first half of the twentieth century, silver stains attained significance in the
Pulmonary neuroendocrine cells and neuroepithelial bodies
As early as 1949, it was apparent to Froelich that clear cells, or “Helle Zelle,” were present in the bronchial mucosa of man and other animals arranged singly or in corpuscular aggregates, termed, “Knoetchen.”67 He proposed that they were of neuroectodermal origin and might subserve a chemoreceptive function. Shortly thereafter in 1956, Feyrter55 confirmed the existence of these cells and concluded that they represented the pulmonary component of the DNES that he had originally described in
The continuum of bronchopulmonary neuroendocrine tumors
The lesions have been identified to range from central in location to peripheral and the cells of origin variously considered as components of the DNES, APUD in origin, or specifically Kulchitsky in type. The spectrum of tumors ranges from modest hyperplasias and tumorlets via adenomas and carcinoids to atypical lesions and highly aggressive malignancies typified as carcinomas. Although many are benign or low-grade malignant neoplasms without evident cause and with few significant clinical
Peripheral carcinoids—a topographic concept
Gmelich and coworkers71 described Kulchitzky-type cells proliferating in the periphery of the lung in association with multiple peripheral carcinoid tumors in 1967 and suggested that these cells were the origin of peripheral pulmonary carcinoids. Subsequently, in 1976, Bonikos, working with the same group at Yale, described 5 cases of peripheral carcinoid tumors, which they distinguished from the more usual type of bronchial carcinoid by location in distal airways.72 In 1980, Ranchod and Levine
Bronchial carcinoids (typical)
Although the classical description of a bronchial carcinoid was first provided by Hamperl in 1937,30 more recent appreciations of broncho-pulmonary carcinoid (BPC) were provided by DeLellis and colleagues in 1984.74 They noted that BPC most closely resembled the “benign” carcinoid lesions of the gut first described by Oberndorfer, who had described their characteristic insular, trabecular, or mixed pattern histologic appearance. DeLellis observed that this fundamental description still served
Atypical bronchial carcinoid
In 1972, Arrigoni and colleagues75 from the Mayo Clinic recognized that although carcinoids generally have a good prognosis, some metastasized and a rare few progressed to systemic spread and death. They undertook a classic surgical pathology study to identify predictive histologic factors of more aggressive behavior in 215 carcinoid tumors of the lung. In 23 carcinoid tumors, they identified a series of features that allowed them to describe the entity of the atypical carcinoid. These features
Pulmonary neuroendocrine hyperplasia
The recognition of the entity of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) was initially described by Aguayo and colleagues in 1992.77 It is now considered to be a precursor lesion that culminates in the development of BPCs. The cause of pulmonary neuroendocrine hyperplasia is unclear but environmental stress (eg, high altitudes) and injuries (eg, chronic cough or obstruction) are associated with the proliferation of both PNECs and NEBs. The consequences of such
Chemodectoma (paraganglioma)
In 1958, Heppleston described a carotid-body-like tumor of the lung in a Welsh coal worker who was found by screening chest radiograph to have a small rounded opacity that slightly increased in size over 6 years.79 This opacity was demonstrated to be a paraganglioma-like carcinoid. The distinction of carcinoids, especially from the periphery of the lung, from paragangliomas and chemodectomas is of historical interest and continuing debate. Most peripheral tumors with the histologic appearance
Large-cell neuroendocrine carcinoma
In 1985, Hammond and Sause81 described a group of 8 histologically large-cell undifferentiated carcinomas, which were shown to have neuroendocrine differentiation by immunohistochemistry. They were compared with 9 bronchial carcinoids and 9 atypical carcinoids. All of the typical carcinoids were recognized by light microscopy, and all of these patients were alive and free of disease at the end of the follow-up period.
Carcinoid, well-differentiated neuroendocrine carcinoma, intermediate neuroendocrine carcinoma, and small-cell neuroendocrine carcinoma
In 1985, Warren and coworkers82 proposed a 4-step classification of the neuroendocrine carcinomas: typical carcinoids, well-differentiated neuroendocrine carcinomas, intermediate neuroendocrine carcinomas, and small-cell neuroendocrine carcinomas. The typical carcinoids were usually centrally placed, displayed little or no pleomorphism, were richly granulated by electron microscopy, and were strongly positive by immunohistochemistry. The hormones they displayed were indigenous to their site of
The classification conundrum
As the delineation of bronchopulmonary NETs moved from descriptive pathologic abnormality to morphologic detail and then embraced histochemistry, a variety of progressive perceptions of the nature of neuroendocrine lung neoplasms emerged over time. The steady addition of information predictably therefore has led to the development several classification systems. Although logical in their individual construct, there remains a need to establish a definitive system to categorize this complex group
Summary
In the three-quarters of a century that have elapsed since the first description of a bronchial carcinoid, the field has progressed from serendipitous radiological or bronchoscopic diagnosis to computed tomography, magnetic resonance imaging, and somatostatin receptor imaging identification. Similarly, pathologic techniques have advanced from a naïve assessment of neoplasia to a delineation of several tumor subtypes and an understanding of the neuroendocrine basis of the disease process.
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Cited by (6)
Neuroendocrine neoplasms of the lung
2022, Practical Pulmonary Pathology: A Diagnostic ApproachNeuroendocrine Neoplasms of the Lung
2018, Practical Pulmonary Pathology: A Diagnostic Approach A Volume in the Pattern Recognition SeriesDiffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)
2015, Seminars in Diagnostic PathologyNeuroendocrine Neoplasms of the Lung
2017, Practical Pulmonary Pathology: A Diagnostic Approach A Volume in the Pattern Recognition SeriesSomatostatin receptor PET/CT in restaging of typical and atypical lung carcinoids
2015, EJNMMI Research
The authors have nothing to disclose.