Pulmonary Pathology Society

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December, 2024
Case of the Month

Clinical History:
A 35-year-old man, former light smoker (2 pack-years), with a history of tuberous sclerosis and amyloidosis with associated end-stage renal disease, presented with multiple bilateral ground glass pulmonary nodules detected on a chest-CT scan, which was done as part of renal transplant work-up. A right upper lobe wedge resection was performed (see figures 1 through 4).

Q1. What is the nature of this lesional process?

Neoplastic-benign
Infectious
Hamartomatous
Neoplastic - malignant

Q2. Which finding is commonly associated with this diagnosis?

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)
Lymphangitic carcinomatosis
Bronchiolocentric non-necrotizing granulomas
Lymphangioleiomyomatosis

Q3. Which of the following best describes the histologic features of this lesion?

Enlarged cells with increased nuclear-to-cytoplasmic ratio
Cuboidal cells with minimal cytologic atypia
Cuboidal-to-columnar cells with apical snouts
Lack of elastic fibers within septae

Answers to Quiz

Q1. C
Q2. D
Q3. B

Diagnosis

Multifocal micronodular pneumocyte hyperplasia

Discussion

Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare hamartomatous pulmonary disease characterized by the presence of multiple, scattered atypical pneumocyte proliferations. It is associated with tuberous sclerosis (TS) and can be seen both with or without lymphangioleiomyomatosis (LAM), a more classic pulmonary manifestation of TS. Few cases have been reported in the literature; however, radiographic evidence suggests the low incidence may be due to limited screening.

Though MMPH is typically asymptomatic, some patients may report non-specific respiratory symptoms or present with pneumothorax. More commonly, the diagnosis is incidental, with the lesions first described during imaging performed for other reasons. The condition is generally indolent and lung lesions are not progressive. Treatment or follow-up imaging are therefore unnecessary.

On high resolution chest CT imaging, MMPH is characterized by scattered sub-centimeter ground glass opacities with no regional predilection. This radiographic finding is not diagnostic of MMPH and can be seen in multiple malignant and non-neoplastic processes, including multifocal atypical adenomatous hyperplasia, lymphangitic pulmonary metastases, and granulomatous reactions. However, in the correct clinical setting, particularly with a known history of TS, the radiologic picture of multiple randomly distributed ground glass nodules should raise the consideration of MMPH.

Histologically, MMPH consists of multicentric, nodular, well-defined proliferations of cuboidal pneumocytes along the alveolar walls (figures 1 and 2). The pneumocytes exhibit only mild cytologic atypia with preserved nuclear to cytoplasmic ratios (figures 3 and 4). Septal thickening associated with increased elastic fibers is a characteristic finding and can be highlighted with the use of elastic fiber staining. TTF-1 and Napsin A immunohistochemical stains are positive, consistent with the pneumocytic origin of MMPH, but melanocytic (HMB45, MelanA, MITF) and hormonal (ER, PR) markers are negative, unlike in LAM.

MMPH has a significant radiographic and histologic overlap with atypical adenomatous hyperplasia (AAH). Therefore, the clinical presentation is a key factor in distinguishing the two entities; while MMPH should be suspected in TS patients, AAH is commonly seen in the background or setting of a lung neoplasm. Though there is a certain degree of histologic overlap, essentially, type II pneumocytes in MMPH show abundant cytoplasm with unremarkable nuclei, whereas the pneumocytes in AAH exhibit higher nuclear to cytoplasmic ratio and worse nuclear atypia. Additionally, the septal thickening in MMPH is often characterized by elastic fiber hyperplasia.

Take home message for trainees: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a hamartomatous pneumocyte proliferation associated with tuberous sclerosis. The lesions classically present as multifocal ground glass opacities and microscopically consist of nodular pneumocyte proliferations with mild cytologic atypia. The morphologic overlap with atypical adenomatous hyperplasia is a potential diagnostic pitfall.

References

Kobashi Y, Sugiu T, Mouri K, et al. Multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis: differentiation from multiple atypical adenomatous hyperplasia. Jpn J Clin Oncol 2008;451-4.

Konno S, Shigemura M, Ogi T, et al. Clinical Course of Histologically Proven Multifocal Micronodular Pneumocyte Hyperplasia in Tuberous Sclerosis Complex: A Case Series and Comparison with Lymphangiomyomatosis. Respiration. 2018; 310-316.

Popper HH, Juettner-Smolle FM, Pongratz MG. Micronodular hyperplasia of type II pneumocytes--a new lung lesion associated with tuberous sclerosis. Histopathology 1991; 347-54.

Ristagno RL, Biddinger PW, Pina EM, et al. Multifocal micronodular pneumocyte hyperplasia in tuberous sclerosis. AJR Am J Roentgenol. 2005; 184(3 Suppl):S37-9.

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