Pulmonary preneoplasia.
Abstract: Context.--Improved screening techniques for lung cancer have resulted in detection of lesions that are considered to represent precursors of invasive lung carcinomas. These lesions may cause a diagnostic dilemma particularly on small biopsy or cytology specimens. Ancillary studies are usually not helpful, and diagnosis is based on morphology alone. Recognition of these lesions is very important to prevent potential diagnostic mistakes that may result in inadequate patient management. Future molecular studies may provide clinically useful diagnostic and prognostic gene markers.

Objective.--To review currently proposed morphologic criteria for precursor lesions of non-small cell lung carcinomas including squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic neuroendocrine cell hyperplasia. Major molecular abnormalities are briefly discussed.

Data Sources.--Published literature and recent World Health Organization classification of lung tumors.

Conclusions.--Practicing surgical pathologists must be familiar with morphology of recognized pulmonary preneoplastic lesions that are more frequently detected radiographically and subjected to diagnostic procedures. Future understanding of underlying molecular abnormalities associated with progression of these lesions into invasive lung carcinoma may result in a development of molecular assays with potential diagnostic and prognostic importance.
Article Type: Clinical report
Subject: Dysplasia (Development and progression)
Lung cancer, Non-small cell (Development and progression)
Cancer (Diagnosis)
Cell research
Medical research
Medicine, Experimental
Medical errors
Author: Dacic, Sanja
Pub Date: 07/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: July, 2008 Source Volume: 132 Source Issue: 7
Product: Product Code: 8000200 Medical Research; 9105220 Health Research Programs; 8000240 Epilepsy & Muscle Disease R&D NAICS Code: 54171 Research and Development in the Physical, Engineering, and Life Sciences; 92312 Administration of Public Health Programs
Accession Number: 230247089
Full Text: Lung cancer consists of 4 major types including squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma. The sequential preneoplastic changes have been well defined for centrally arising squamous cell carcinomas. Similarly, preneoplastic changes have been documented in peripheral adenocarcinomas, while no preneoplastic lesions have been defined for small cell lung carcinoma. Recent advances in imaging, improved bronchoscopic techniques, increased interest in lung cancer screening techniques, and new molecular markers for early detection of lung cancer have resulted in the need to recognize precursor lesions of lung carcinoma. High-resolution computed tomography can now detect very small lung lesions, frequently measuring less than 1.0 cm in diameter. These lesions are frequently indeterminate for malignancy by positron emission tomography scan. Pathologists often find themselves being pressured to make a definitive diagnosis on a very small specimen with many processing artifacts, which can lead to potential errors.

Grading of premalignant lesions, particularly squamous preneoplasia, has been described for many years in research studies investigating bronchial neoplasms. However, there was no consensus classification system until 1999 when the criteria for diagnosing squamous premalignant lesions were first defined in the World Health Organization (WHO) histologic typing of lung and pleural tumors. (1) Nicholson et al (2) showed that this grading scheme has an acceptable low level of interobserver and intraobserver variation, and therefore this grading system was recommended for future clinical and research use. In contrast to squamous cell carcinoma, less was known about the development of lung adenocarcinoma. Atypical adenomatous hyperplasia (AAH) is considered to be the preinvasive lesion of nonmucinous type bronchioloalveolar carcinoma (BAC) and a subset of peripheral invasive adenocarcinoma. Our knowledge about precursor lesions of other lung tumors is relatively poor, and although some entities are included in the latest WHO classification, more work needs to be done to completely understand the biology of these lesions and their potential clinical significance.

Although there has been great progress in our understanding of carcinogenesis of lung carcinoma, this review does not focus on the molecular biology of preneoplastic lesions. Rather, the purpose of this review is to summarize potential diagnostic problems that practicing pathologists may face in a daily practice while dealing with preneoplastic lesions particularly on small biopsy specimens.


The spectrum of mucosal abnormalities associated with squamous cell carcinoma has been known for many years. (3-5) These include basal cell hyperplasia, squamous metaplasia, dysplasia, and carcinoma in situ, which are all usually seen in the background of invasive squamous cell carcinoma of the large airways. However, the same mucosal abnormalities may be detected in smokers without evidence of carcinoma. The frequency of these lesions in smokers correlates with the number of cigarettes smoked. These lesions are preinvasive and reversible, which means that they may not necessarily progress into invasive carcinoma and may regress if an individual quits smoking.

Serial bronchoscopies and biopsies in patients with bronchial dysplasia showed that approximately 25% of the dysplastic lesions progress to invasive carcinoma during a mean period of 36 months. More than 50% of patients with carcinoma in situ were found to progress to invasive carcinoma within 30 months. (6,7) Several studies have shown that the use of fluorescent bronchoscopy improves the detection rate of high-grade squamous preneoplasia compared with standard white light bronchoscopy. (8-10)


Morphology is the gold standard in diagnosing premalignant squamous lesions, and no ancillary studies (eg, immunohistochemistry) can be used as a diagnostic aid. The following histologic criteria are used to assist in the recognition and grading of mucosal lesions of the airways: (1) thickness of the epithelium, (2) cell size, (3) cell maturation/orientation, and (4) nuclear characteristics. Overlap between different components does exist. A common feature of squamous preneoplasia is an intact and usually variably thickened basement membrane.

The following morphologic entities are considered to represent squamous preneoplasia:

1. Goblet cell hyperplasia may be seen in a background of carcinoma but is also seen in inflammatory diseases. It consists of an increased number of goblet cells in the bronchial mucosa. In goblet cell hyperplasia, the goblet cells are frequently adjacent to one another and may appear multilayered, the nucleus is basally located, the chromatin is dense, and the cytoplasm is abundant (Figure 1).

2. Basal cell (reserve cell) hyperplasia is characterized by expansion of the basilar zone of bronchial mucosa. Nuclei are small, round, and stratified in the lower levels of the mucosa. Cytoplasm is scant. Goblet cells and cilia are maintained at the luminal surface (Figure 1).

3. Immature squamous metaplasia is similar to basal cell hyperplasia except that the metaplastic epithelium occupies nearly the full thickness of the epithelium. In comparison to mature squamous metaplasia, cells have less cytoplasm and are nonkeratinized. Ciliated cells may be retained on the epithelial surface, but goblet cells are usually depleted.

4. Squamous metaplasia is characterized by replacement of columnar ciliated respiratory epithelium by mature squamous epithelium. A progressive maturation of epithelial cells from the basal layer through a well-defined intermediate cell zone to a desquamating superficial zone is seen. Keratinized epithelial cells are oriented parallel to the basement membrane. Cellular pleomorphism or cytologic atypia are absent or minimal.

Squamous metaplasia and reactive epithelial changes may be seen in inflammatory processes related to infection or prior surgical procedures. They are usually associated with a significant inflammatory component and various artifacts related to the procedure (eg, foreign material, hemorrhage). Squamous metaplasia and reactive epithelial changes need to be differentiated from squamous dysplasia.

5. Mild squamous dysplasia is characterized by mildly increased epithelial thickness, with slightly enlarged cells showing mild anisocytosis and pleomorphism. The basilar zone is expanded with cellular crowding in the lower third. The intermediate zone is intact and distinct, and cells show superficial flattening. The nuclear-cytoplasmic (N/C) ratio is not significantly altered and is only mildly variable. Chromatin is finely granular. Nuclei show minimal angulation and are vertically oriented in the lower third. Nucleoli are absent or inconspicuous. Mitoses are absent or very rare (Figure 2, A).

6. Moderate squamous dysplasia is characterized by moderately increased epithelial thickness, with moderately enlarged cells, although in some cases cells may be small. Moderate anisocytosis and pleomorphism are common features. The basilar zone is expanded with cellular crowding in the lower two thirds. The intermediate zone is confined to the upper third of the epithelium, and cells show superficial flattening. A moderate variation of N/C ratio is present. Similar to mild dysplasia, chromatin is finely granular and nucleoli are absent or inconspicuous. However, nuclei are angulated with grooves and lobulations and are vertically oriented in the lower two thirds. Mitoses are present in the lower third (Figure 2, B).

7. Severe squamous dysplasia is characterized by markedly increased epithelial thickness. The basilar zone is expanded with cellular crowding into the upper third. Cells are large with marked anisocytosis and pleomorphism. No or little maturation is seen from base to luminal surface. Intermediate zone is attenuated, and cells show superficial flattening. N/C ratio is usually high and variable. In contrast to mild and moderate dysplasia, the chromatin is coarse and uneven. Prominent nuclear angulation and folding are present with nuclei vertically oriented in the lower two thirds. Nucleoli are frequently present and conspicuous. Mitoses are present in the lower two thirds (Figure 2, C).

8. Squamous carcinoma in situ may not be necessarily associated with increased epithelial thickness. Cells are usually markedly increased in size and may show marked anisocytosis and pleomorphism. Usually there is no progression of maturation from base to luminal surface, and the epithelium has a monotonous appearance. The basilar zone is expanded with cellular crowding throughout the epithelium. The intermediate zone is absent and surface flattening is confined to the most superficial cells. The N/C ratio and the nuclear and chromatin features are identical to those seen in severe squamous dysplasia, except that nuclei do not show consistent orientation in relation to the epithelial surface. Nucleoli may be present or inconspicuous. Mitoses are present through the full thickness of the epithelium.

In the last decade, several studies provided molecular characterization of the premalignant changes involved in squamous cell carcinoma. The current knowledge indicates that allelic losses (loss of heterozygosity) at multiple 3p chromosome sites are the earliest change, followed by loss of heterozygosity at 9p21. (6,7,11) Later changes include alterations at 8p21-23, 13q14, and 17p13. (6) These changes are progressive and advanced tumors frequently show complete or partial loss of chromosomal arms, whereas precursor lesions tend to show more focal losses. Several studies demonstrated p53 protein expression in bronchial preinvasive lesions but not in normal bronchial mucosa. (12,13) The pattern of p53 protein expression in precursor lesions suggests gene alterations, but the detection of gene mutation seems to be more important. (14,15) Loss of heterozygosity and p53 changes may be seen in histologically normal bronchial mucosa of smokers and may not indicate an increased risk for development of invasive carcinoma but rather indicate smoking-related genetic damage. (7) A similar observation was made in respect to methylation of CDKN2A ([p16.sup.Ink4a])/ARF locus at 9p21. Methylation of [p16.sup.Ink4a] was demonstrated in 75% of in situ carcinoma adjacent to invasive squamous cell carcinoma of the lung. There is an increasing frequency of this event during disease progression from basal cell hyperplasia (17%) to squamous metaplasia (24%) to carcinoma in situ and invasive carcinoma (50%-75%). (16,17) The significance of aberrant methylation detected in clinical specimens should be interpreted with caution because aberrant methylation can be also detected in cancer-free individuals who are long-term tobacco smokers.


Recently, substantial attention has been paid to AAH that is considered to represent the adenoma in a putative "adenoma-carcinoma" sequence in the lung periphery leading to the development of nonmucinous BAC and invasive peripheral adenocarcinoma. These lesions are detectable on high-resolution computed tomography scan as small, ground glass densities. (18) In resected lungs, the incidence of AAH is between 9% and 21% in patients with primary lung cancer and between 4% and 10% in patients without known lung cancer. (19) The first descriptions of this lesion and its association with lung adenocarcinoma were made independently by Shimosato and by Miller. (20-22) The WHO defines AAH as a localized proliferation of mild to moderately atypical cells lining involved alveoli and sometimes respiratory bronchioles, resulting in focal lesions in peripheral alveolated lung, usually less than 5 mm in diameter. (1) Most of these lesions are incidental microscopic findings in lungs resected for other reasons, primarily lung cancer and especially adenocarcinoma. Atypical adenomatous hyperplasia may be visible on gross inspection as discrete, grey to yellow foci. Histologically, AAH is a discrete parenchymal lesion arising often in the centriacinar region (Figure 3, A). The alveolar septa are lined by rounded, cuboidal, low columnar cells with round to oval nuclei showing either Clara cell or type II pneumocyte differentiation. Intranuclear inclusions are a frequent feature and may be seen in up to 25% of the cells (Figure 3, B). Ciliated and mucin producing cells are absent. Mitoses are extremely rare. Cellularity and atypia are variable. The majority of the lesions show a discontinuous lining of the alveolar septa with cells showing minimal atypia, whereas in some cases cells may be more continuous exhibiting moderate atypia. Pseudopapillae and tufts may be present. These cytologic differences resulted in separation of AAH into low and high grade by some authors. However, it has been shown that this difference has no known clinical significance, and the WHO classification does not recommend it. The alveolar septa may be thickened by collagen, occasional fibroblasts, and lymphocytes.


The differential diagnosis of AAH includes reactive pneumocyte hyperplasia, bronchiolar metaplasia, non-mucinous BAC, and micronodular pneumocyte hyperplasia. Certain features may be helpful in separating these possibilities. Reactive pneumocyte hyperplasia is very common and is usually seen in parenchymal inflammation and fibrosis. Reactive pneumocyte hyperplasia does not form discrete lesions such as the case in AAH but is rather more diffusely distributed. There is an obvious associated injury, such as pneumonia or acute lung injury. This assists in classifying the pneumocyte abnormality as reactive rather than neoplastic, as generally AAH cannot be identified in the presence of inflammatory or fibrosing lung disease. Cytologic characteristics of the cells are also very helpful. Cells in reactive processes usually do not show atypical cytologic characteristics, except in cases of chemotherapy when large, bizarre pneumocytes may be identified. Individual large, bizarre cells with abundant cytoplasm and bizarre nuclei in an inflammatory background suggest a reactive process rather than a neoplasm.

Peribronchiolar metaplasia is a nonspecific reaction to bronchiolar or peribronchiolar injury that results in fibrosis. Similar to AAH, peribronchiolar metaplasia may appear as a discrete lesion at the low scanning power, but distinction between these 2 entities should not be difficult because alveolar septa adjacent to airways in peribronchiolar metaplasia are lined by ciliated, bronchiolar type epithelium.

Separation of AAH from micronodular pneumocyte hyperplasia in patients with tuberous sclerosis may be difficult. Cells in AAH usually have a greater degree of nuclear atypia and higher N/C ratio than in micronodular pneumocyte hyperplasia. Clinical history is very helpful in difficult cases.

Because of morphologic and genetic overlap between AAH and BAC, it has been proposed that these 2 lesions represent a spectrum of bronchioloalveolar neoplasias analogous to the adenocarcinoma sequence in colon cancer. The WHO defines BAC as a growth of neoplastic cells along preexisting alveolar structures (lepidic growth), without evidence of stromal, vascular, or pleural invasion. (1) The distinction between AAH (particularly more cellular and atypical) and BAC could be very difficult, especially on small biopsy specimens or frozen sections. Helpful features in separating AAH from BAC include size, low-power appearance of the lesion, cytology, and presence of goblet cells. (23) Bronchioloalveolar carcinoma measures more than 5 mm in diameter. At low power, BAC appears as a monotonous cellular proliferation of homogenous columnar cells, which show overlap and mild stratification (Figure 4, B). Usually there is a more abrupt transition to adjacent lung parenchyma. In contrast, AAH measures less than 5 mm in diameter. At low power, the lesion appears as a polymorphic cellular proliferation of variably sized and shaped cuboidal cells that respect each other's borders. Frequently gaps between the cells can be appreciated (Figure 4, A). Although AAH is a well-defined lesion, usually there is blending with normal alveolar lining cells peripherally. The presence of goblet cells strongly argues against the diagnosis of AAH, and the possibility of BAC must be excluded. Size of the lesion is often unhelpful because in many instances lesions smaller than 5 mm are composed of columnar-shaped cells with nuclear hyperchromasia and nuclear crowding. In such cases, regardless of size, the lesion should be classified as malignant (BAC) because the previously mentioned cytologic characteristics argue against AAH.


From a practical standpoint, AAH can be a source of confusion on a small biopsy specimen, and pathologists should be careful not to overcall these lesions as malignant, which may result in unnecessary surgical procedures. Similarly, a conservative approach is reasonable in frozen section interpretation. Identification of AAH in wedge biopsies or lobectomy specimens is usually not a problem. The standard for reporting of AAH incidentally identified in larger resection specimens outside of an academic environment has not been established. Several studies failed to show any difference in postoperative survival in groups of patients with adenocarcinoma with and without AAH in the background lung. (24) There is no indication for surgical or medical therapy in patients without cancer who are incidentally found to have AAH, and current understanding about risk of progression of these lesions into invasive adenocarcinoma is controversial.

Microdissection-based polymerase chain reaction analyses have made possible studies of AAH at the molecular level. Initial studies focused on the KRAS mutations, which are detected in 24% to 50% of lung adenocarcinomas and are considered to represent an early event that precedes malignant growth. (25) KRAS codon 12 mutations are reported in 15% to 39% of AAH lesions, and most of the time the patterns of base substitutions are different, suggesting that AAH is an independent lesion. (26,27) More recent studies suggest that AAH could develop by either KRAS or EGFR gene mutation pathways, but AAH harboring a KRAS gene mutation might not progress further to an invasive cancer. (28) Atypical adenomatous hyperplasia was also evaluated for the key genetic alterations that are frequently present in lung adenocarcinomas including loss of heterozygosity on chromosomes 3p (FHIT gene) and 9p (p16 gene). (29) Not surprisingly, loss of heterozygosity of these chromosomal arms has been identified in 18% and 13%, respectively, of AAH. Loss of heterozygosity and mutations of the p53 gene are very rare in AAH compared with adenocarcinoma; however, p53 protein expression is common in AAH. p53 mutation has been demonstrated with increasing frequency in the progression from AAH through BAC to invasive adenocarcinoma. (30,31)


Diffuse idiopathic neuroendocrine cell hyperplasia was first described in the early 1950s but was not fully recognized and named until 1992. (32) It may be arranged as a diffuse proliferation of scattered single neuroendocrine cells, small nodules (neuroendocrine bodies), or a linear proliferation of pulmonary neuroendocrine cells confined to the epithelium of large and small airways. When there is extension of neuroendocrine cells beyond the basement membrane that measures less than 5 mm in diameter, the term carcinoid tumorlet is appropriate. Proliferations larger than 5 mm are classified as carcinoid tumors and may be associated with diffuse idiopathic neuroendocrine cell hyperplasia. Neuroendocrine cell hyperplasia and carcinoid tumorlets are often seen in association with chronic inflammation and fibrosis, where they are considered reactive. However, they may be seen in a background of pure neuroendocrine neoplasms, and therefore it is tempting to speculate that such focal hyperplasia might represent a precursor lesion of benign and malignant neuroendocrine neoplasms. These lesions are most frequently an incidental microscopic finding. Radiographically, plain chest x-rays are often normal, but computed tomography scan may show a mosaic pattern of air trapping sometimes with nodules and thickened airway walls. (33) On gross inspection of lung specimens, these early proliferations are invisible. Carcinoid tumorlets can be seen as small, grey-white nodules. Larger carcinoid tumors form well-defined, firm, grey or yellow-white masses. Microscopically, proliferation of neuroendocrine cells confined to the bronchial or bronchiolar epithelium is present (Figure 5). Larger lesions may protrude into the lumen occasionally causing bronchiolar occlusion. The bronchiolar wall may show fibrotic thickening that may result in airway obstruction. The main differential diagnosis is to separate reactive pulmonary neuroendocrine cell proliferations from neoplastic proliferations. Therefore, it is very important to closely examine the background lung. There are presently no genetic markers that could separate neoplastic from nonneoplastic proliferations. Genetic or histogenetic knowledge about these lesions is minimal, and much work needs to be done before we begin to understand the significance of these lesions.


A careful morphologic examination of lung specimens using established histologic criteria is necessary for diagnosing preneoplastic lesions of lung carcinoma. Histologic examination together with improved techniques of molecular biology will help us to improve our understanding of lung carcinogenesis. In the future, we might possibly be able to use a combination of histology and molecular biology within the clinical arena, resulting in earlier detection and decreased mortality of lung carcinoma.

Accepted for publication February 8, 2008.


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From the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pa.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Sanja Dacic, MD, PhD, Department of Pathology-PUH A610, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213 (e-mail: dacics@upmc.edu).
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