Multifocal Micronodular Pneumocyte Hyperplasia
These lesions are benign, multifocal proliferations of type 2 pneumocyte or Clara cells in a nodular distribution with a marked interstitial stromal response, having a strong association with tuberous sclerosis complex (TSC)-related pulmonary disease.
Multifocal micronodular pneumocyte hyperplasias (MMPH) are rare lesions which are found in up to 50% of patients with TSC. Of the remainder, half of the patients have lymphangioleiomyomatosis. The others have neither TSC nor lymphangioleiomyomatosis.
Most patients with MMPH range from 30 to 40 years old.
Most patients are premenopausal women, but cases in men are reported.
Lesions are found diffusely scattered in the pulmonary parenchyma. There are no other localizing features. They may be encountered as small, so-called “ground glass” nodules on computed tomography (CT) scanning of the chest. These radiographic changes may accompany other TSC-associated phenomena such as lymphangioleiomyomatosis or spontaneous pneumothorax associated with the latter.
There is no active treatment. Diagnosis would require excision of a lesion for pathological examination.
The lesions are entirely benign. They are usually incidental findings, and follow-up has revealed that lesions were stable. Occasionally dyspnea, especially on exercise, and cough have been attributed to lesions that are numerous.
These lesions appear as small, pale nodules on the cut surface of well-prepared and sectioned lung. The margins are indistinct. They appear relatively solid lesions and range from 1 to 10 mm in size.
Most lesions are of a few millimeters in diameter and appear relatively solid and well demarcated when compared to the surrounding lung. The lesions comprise thickened alveolar walls lined by plump, cuboidal, or rounded type 2 pneumocytes with abundant eosinophilic cytoplasm which may appear somewhat granular. Crowding of the cells may lead to simple papillary projections of the epithelial cells into the attenuated alveolar air spaces. Nuclei are regular and vesicular and may have small inclusions typical of proliferating type 2 pneumocytes. Multinucleate cells are sometimes seen, but mitoses are not a feature of MMPH.
The alveolar walls show collagenization and an increase in reticulin fibers but no increase in smooth muscle cells. All of these changes make the alveoli of the lesion appear small or collapsed, such that the alveolar spaces appear like slits or clefts. These residual spaces show an excess of alveolar macrophages, replacing much of the remaining alveolar air in the lesions. All of these features combine to minimize the alveolar air space and make the lesions appear solid. The epithelial proliferation is confined to the nodular area with no tendency to lepidic spread.
The epithelial lining cells of MMPH have an immunophenotype in keeping with their origin from type 2 pneumocytes (keratins (e.g., pan- and CK7), EMA, TTF1, and surfactant protein positive). Neither these lining cells nor the interstitial cellular population, which is not very distinctive, stains with any of desmin, smooth muscle actin, S100, or HMB45. Estrogen and progestogen receptor staining is also negative. The PEC cell phenotype (HMB-45) is absent in these lesions, while it is seen in other lesions related to TSC, such as lymphangioleiomyomatosis and angiomyolipoma. Proliferation markers such as Ki67 show a very low positive nuclear staining index of less than 5%, and p53 expression is not seen, all in keeping with a nonneoplastic proliferation.
Mutations of the hamartin-encoding TSC1 gene (chromosome 9q34) and the tuberin-encoding TSC2 gene (chromosome 16p13.3) are responsible for the development of tuberous sclerosis complex. These mutations have been found in MMPH. In relation to this, expression of tuberin can be shown by immunohistochemistry, and upregulation of TSC2 mRNA can also be detected. Loss of homozygosity at TSC2-related loci in 16p has also been reported. Consistent with this loss of a tumor suppressor gene, the mTOR-related proteins may be activated. These findings are of interest since many of these molecular findings have also been described in other abnormal proliferative lesions of the terminal respiratory unit epithelium, namely, atypical adenomatous hyperplasia, adenocarcinoma in situ, and early invasive adenocarcinomas, in patients without TSC (see “Differential Diagnosis” below).
The main differential diagnoses involve localized lesions where there is proliferation of type 2 pneumocytes and Clara cells. The rarity of MMPH makes the diagnosis challenging, and awareness of the MMPH entity is required. Recognition of these lesions is also dependent to a large extent on the adequate preparation and sectioning of the lung tissue since artefactual collapse or compression will hamper lesion identification.
Localized reactive type 2 pneumocyte hyperplasia is actually not very common, but associated features of chronic inflammation or scarring should help with diagnosis. More often, this reactive process is more diffuse, at a microscopic as well as gross level, without a tendency to form nodules.
References and Further Reading
- Flieder, D. B. (2013). Benign epithelial neoplasms and tumour-like proliferations of the lung. In P. S. Hasleton & D. B. Flieder (Eds.), Spencer’s pathology of the lung. Cambridge: Cambridge University Press.Google Scholar