Atypical Adenomatous Hyperplasia: Lung
Because of the difficulties in identifying these lesions, their true prevalence is difficult to gauge. Although confounded by a number of possible factors, limited autopsy data have shown AAH in 2–4% of noncancer bearers but in 10% of cancer bearers. Lesions have mostly been described in lung specimens resected for primary carcinoma. In resection specimens bearing squamous cell carcinoma, AAH have been described in 3–11% of cases; in adenocarcinoma resections, the prevalence is higher ranging from 16% to 56% of cases.
Lesions are mostly described in a population ranging from 50 to 80 years, but this reflects the circumstances in which they are found, namely, cancer resections. Lesions are described occasionally in younger patients, but the true age distribution of AAH remains unclear.
Lesions appear to be commoner in female lung cancer patients, than in males, and especially more frequent in females with adenocarcinoma
Other than recognizing that these are lesions of the peripheral, parenchymal lung compartment and that microscopically they tend to be centriacinar in location, there are no further data on location.
There is no specific treatment for AAH. As a putative precursor of invasive adenocarcinoma, identification of a patient with AAH would suggest some follow-up strategy. Small ground-glass opacities (GGO) identified during high-resolution computed tomographic lung screening (HRCT) may correspond to AAH and may trigger closer follow-up, depending on other risk factors.
AAH is considered to be a precursor lesion for adenocarcinoma in situ (AIS), which is a precursor of invasive adenocarcinoma. The risk of progression of AAH to invasive carcinoma is not known and AAH-bearing patients are only identified after lung resection. Outcome is then usually determined by the primary cancer, rather than the presence of AAH. There are no convincing data to suggest a resection bearing AAH confers a poorer prognosis than one without. However, anecdotally, very small GGO identified during HRCT lung screening have been observed, in some instances, to grow, progress, and develop into invasive adenocarcinoma. It is not possible to know for certain, in such a case, whether the initial small GGO was AAH or adenocarcinoma in situ (AIS) or some other lesion.
AAH lesions are usually incidental findings at microscopy. However, AAH may be recognized on gross examination of the cut surface of lung parenchyma as rather ill-defined pale gray-white to tan-colored patches of a few millimeter across. They are best viewed in fixed and inflated lung tissue, with the cut surface washed under running water. This appearance is in no way specific; sampled lesions may be inflammatory, fibrotic, or even adenocarcinoma in situ.
Foci of AAH comprise a collection of contiguous alveoli, often close to a terminal or respiratory bronchiole, lined by a population of enlarged, cuboidal, or low columnar cells. These cells may be rounded or oval and frequently have apical snouts consistent with a Clara cell phenotype. Nuclei are mild to moderately atypical and show a rather dense chromatin. Nucleoli are rarely seen, mitoses are unusual, but nuclear inclusions may be present. Nuclei are occasionally apical and multinucleate cells occur. Occasionally individual cells are much larger than their neighbors. There is usually relatively little eosinophilic cytoplasm. Ciliated cells are not found in AAH.
The cells are characteristically arranged with gaps between the large columnar or peg-type cells. Cellularity varies although when multiple AAH lesions are present, the cytomorphology is often quite similar between lesions. These epithelial cell changes are associated with mild thickening of the alveolar walls themselves. Marked, rather hyaline interstitial fibrosis may occur but is relatively uncommon. There is a tendency for alveolar macrophages to accumulate in the airspaces of AAH.
AAH lesions are usually multiple in a lung resection specimen, especially one bearing adenocarcinoma, and lesions vary from tiny foci affecting a few alveoli to examples measuring 5 mm or more. Lesions over 10 mm in diameter are exceptional but not impossible – larger lesions tend to be more cellular and atypical, and there is a point where the larger and more cellular lesions become classifiable as adenocarcinoma in situ (AIS).
AAH lesions express TTF1, as would be expected, given their origin from the terminal respiratory unit epithelium. Expression of p53, HER2, and CEA has been related to their preneoplastic status, but none of these markers are useful in diagnosis. Other molecules such as napsin A, surfactant proteins, and cytokeratin (CK) 7 are also expressed in AAH.
There are no characteristic or unique molecular features in AAH, but changes have been described which are commensurate with their position as an earlier precursor in a proposed AAH-AIS-adenocarcinoma sequence, as a stepwise process of adenocarcinogenesis.
A variety of studies using nuclear morphometry, cytofluorimetry, and genetic markers have demonstrated that at least some AAH lesions are clonal proliferations with evidence of aneuploidy and changes in nuclear DNA content consistent with neoplastic change.
AAH lesions show increased proliferative activity as measured by a modest increase in the expression of proteins associated with increased cell cycle activity (Ki67 and MCM2). Other studies have also demonstrated changes promoting cell proliferation and reduced apoptosis through changes in cyclin D1, bcl2, BAX, and survivin expression. Disruption in telomerase biology has been demonstrated supporting the promotion of decreased cell senescence.
A variety of genomic alterations have been shown which imply disruption or loss of tumor suppressor gene activity. Although elevated p53 protein has been demonstrated in a range of AAH lesions, this does not appear to be associated with P53 gene mutation. Several studies have demonstrated loss of heterozygosity in a number of chromosomal loci (including 3p, 9p, 9p, 10q, 11q, 13q, 16p, 17p), but there is a lack of consistency between studies. Hypermethylation is a recognized mechanism of gene downregulation during carcinogenesis, and studies on AAH have shown alterations in several candidate genes including P16.
Given the emergent therapeutic importance of EGFR mutation and a mutual exclusivity of this mutation with KRAS mutation in lung adenocarcinoma, the identification of these mutations in some AAH lesions is clearly of interest. EGFR mutations have been described in anywhere between 3% and 44% of AAH lesions. Higher prevalence, and most studies, has concerned Japanese patients, in keeping with this higher prevalence of both AAH and EGFR-mutated adenocarcinoma in this population. KRAS mutation has been described in 0–39% of cases, and higher levels have tended to be described in Caucasian subjects. There is not necessarily any relationship between these mutations in AAH and the status of any associated adenocarcinoma in the same patient. This is in keeping with AAH being independent precursor lesions and field carcinogenesis theory.
Both benign, reactive conditions and neoplastic lesions potentially enter the differential diagnosis of AAH. As ever, which of these lesions that may be considered in an individual case will depend on individual prevailing features.
Reactive type 2 pneumocyte hyperplasia may be mistaken for AAH. Features that may help in differential diagnosis include the fact that a reactive epithelial cell population is often a regular, even layer of cuboidal cells, lacking Clara cell features and the interrupted appearance seen in AAH with intercellular gaps. The accompanying features are also helpful. Inflammation and fibrosis favor a reactive process, and the latter may extend in the lung beyond the limits of the reactive epithelial population. There may be organizing intra-alveolar exudate. Reactive lesions are rarely distinctly focal or localized. However, one localized lesion it is important to be aware of is peribronchiolar metaplasia, where reactive bronchiolar epithelium lines alveolar walls adjacent to the parent bronchiole. Scarring is more usual than active inflammation. The epithelial component is quite distinct from that of AAH, representing bronchial epithelium with a subtle basal layer and prominent ciliated cells.
Micronodular pneumocyte hyperplasia is a rare lesion associated with tuberous sclerosis. Markedly thickened alveolar walls helps distinction from AAH, while the cellular component may closely resemble AAH, although cells are often rather rounded and may be relatively crowded. Rare neoplasms such as alveolar adenoma or papillary adenoma might be considered in a differential diagnosis although any resemblance is hard to equate.
Given that AAH is thought to progress in some cases into adenocarcinoma in situ (AIS) and the transition point is a rather subjective decision, the distinction between the more cellular and atypical forms of AAH and AIS can be difficult. On the other hand, in practical terms, the distinction carries little implication for the patient (after all the lesions have been removed) apart from a potential diagnostic label of “cancer,” albeit noninvasive. AIS lesions are generally larger than AAH, but lesions under 5 mm in diameter may be encountered. The cell population lining the alveolar walls is consistently columnar and continuous (no gaps) and often shows overlapping. Nuclear features are commensurate with low-grade carcinoma. To assist with the distinction, it has been proposed that AIS lesions usually demonstrate at least three of the following: (a) average cell height exceeding that of the columnar cells in adjacent bronchioles, (b) a continuous proliferation of cells in a “picket fence” arrangement, (c) marker cellular stratification, (d) high cell density leading to overlapping, and (e) coarse chromatin with prominent nucleoli. Occasionally transition lesions with features of AAH in one or more areas and AIS in others may be encountered – these are best regarded as AIS.
References and Further Reading
- Kerr, K. M. (2013). Pulmonary pre-invasive disease. In P. S. Hasleton & D. Flieder (Eds.), Spencer’s pathology of the lung. Cambridge, UK: Cambridge University press.Google Scholar
- Travis, W. D., Brambilla, E., Noguchi, M., et al. (2011). International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. Journal of Thoracic Oncology, 6(2), 244–285.CrossRefPubMedPubMedCentralGoogle Scholar
- Travis, W. D., Brambilla, E., Burke, A. P., Marx, A., & Nicholson, A. N. (Eds.). (2015). WHO classification of tumours of the lung, pleura, thymus and heart. Geneva: WHO Press.Google Scholar