Elsevier

Thoracic Surgery Clinics

Volume 24, Issue 3, August 2014, Pages 235-255
Thoracic Surgery Clinics

A Historical Appreciation of Bronchopulmonary Neuroendocrine Neoplasia: Resolution of a Carcinoid Conundrum

https://doi.org/10.1016/j.thorsurg.2014.05.008Get rights and content

Section snippets

Key points

  • 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.

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.

First page preview

First page preview
Click to open first page preview

References (105)

  • W.D. Travis et al.

    Reproducibility of neuroendocrine lung tumor classification

    Hum Pathol

    (1998)
  • Morgagni G. De sedibus et causis morborum per anatomen indagatis libri quinque. Venetiis: Thypographia Remondiniana,...
  • G. Andral

    Recherches sur l'expectoration dans les différentes maladies de poitrine

    (1821)
  • R. Laennec

    Traite de l’auscultation mediate et des maladies des poumons et du coeur

    (1831)
  • I. Adler

    Primary malignant growths of the lungs and bronchi

    (1912)
  • F.H. Harting et al.

    Lung cancer, the disease of miners in the Schneeberg mines

    Vjschr gericht Med off Sank

    (1879)
  • H. Rottmann

    Über Primäre Lungencarcinome

    (1898)
  • F.H. Williams

    The roentgen rays in thoracic diseases

    Trans Assoc Am Physicians

    (1897)
  • F.D. McMahon et al.

    The roentgenologic diagnosis of primary carcinoma of the lung

    Am J Med Sci

    (1918)
  • C. Jackson

    The bronchial tree: its study by insufflation of opaque substances in the living

    Am J Roent

    (1918)
  • J.A. Sicard et al.

    The radiologic examination of the bronchopulmonary cavities by means of intra-tracheal injections of iodized oil

    J Med Franc

    (1924)
  • H.E. Martin et al.

    Biopsy by needle puncture and aspiration

    Ann Surg

    (1930)
  • P. Kerley

    Neoplasms of the lungs and bronchi

    Br J Radiol

    (1925)
  • H.O. Peterson

    Benign adenoma of the bronchus

    J Roentgenology

    (1936)
  • I.V. Allen

    Bronchial adenoma

    Can Med Assoc J

    (1946)
  • S. Zellos

    Bronchial adenoma

    Thorax

    (1962)
  • S. Dahlgren

    Needle biopsy of intrapulmonary hamartoma

    Scand J Respir Dis

    (1966)
  • G. Killian

    Ueber directe Bronchoskopie

    MMW

    (1898)
  • C. Jackson

    The bronchoscope as an aid in general diagnosis

    Tr Am Laryngol Assoc NY

    (1914)
  • H.H. Hopkins et al.

    A flexible fibrescope, using static scanning

    Nature

    (1954)
  • H.D. Becker et al.

    History of the rigid bronchoscope

    (2000)
  • H.M. Davies

    Recent advances in the surgery of the lung and pleura

    Br J Surg

    (1913)
  • L. Grimelius

    A silver nitrate stain for alpha-2 cells in human pancreatic islets

    Acta Soc Med Ups

    (1968)
  • A.G. Pearse

    The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept

    J Histochem Cytochem

    (1969)
  • J.M. Polak et al.

    Immunofluorescent localization of secretin and enteroglucagon in human intestinal mucosa

    Scand J Gastroenterol

    (1971)
  • W. Barnard

    The nature of the ‘oat-celled sarcoma’ of the mediastinum

    J Pathol

    (1926)
  • F. McKeown

    Oat-cell carcinoma of the oesophagus

    J Pathol Bacteriol

    (1952)
  • P. Geipel

    Concerning our knowledge of benign bronchial tumors

    Frankf Z Pathol

    (1931)
  • H. Hamperl

    Ueber gutartige Bronchialtumoren (Cylindrome und Carcinoide)

    Virchow’s Arch (Pathol Anat)

    (1937)
  • S. Oberndorfer

    Karzinoide Tumoren des Dünndarmes

    Frankf Z Pathol

    (1907)
  • J.G. Azzopardi

    Oat-cell carcinoma of the bronchus

    J Pathol Bacteriol

    (1959)
  • K.G. Bensch et al.

    Oat-cell carcinoma of the lung. Its origin and relationship to bronchial carcinoid

    Cancer

    (1968)
  • H.L. Muller

    Zur Entstehungsgeschichte der Bronchialerweiter ungen (inaugural dissertation)

    (1882)
  • J. Heine

    Ueber eine primare gestielte Bronchialgeschwulst

    Verh Dtsch Ges Pathol

    (1927)
  • R. Kramer

    Adenoma of bronchus

    Ann Otol Rhinol Genol

    (1960)
  • S.W. Holley

    Bronchial adenomas

    Mil Surg

    (1946)
  • F. Feyrter

    Ueber das Bronchuscarcinoid

    Virchow’s Arch (Pathol Anat)

    (1959)
  • E.D. Williams et al.

    Tumours of the lung and the carcinoid syndrome

    Thorax

    (1960)
  • A. Liebow

    Tumors of the lower respiratory tract. Atlas of Tumor. Pathology (section 5, fascicle 17)

    (1952)
  • J.T. Goodner et al.

    The nonbenign nature of bronchial carcinoids and cylindromas

    Cancer

    (1961)
  • Cited by (6)

    • Neuroendocrine neoplasms of the lung

      2022, Practical Pulmonary Pathology: A Diagnostic Approach
    • Neuroendocrine Neoplasms of the Lung

      2018, Practical Pulmonary Pathology: A Diagnostic Approach A Volume in the Pattern Recognition Series
    • Neuroendocrine Neoplasms of the Lung

      2017, Practical Pulmonary Pathology: A Diagnostic Approach A Volume in the Pattern Recognition Series

    The authors have nothing to disclose.

    View full text