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Published: 2022-09-22
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Alveolar adenoma and coexisting atypical adenomatous hyperplasia: a case report and literature review

Department of Pathology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
Department of Pathology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Department of Chest Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
Alveolar adenoma atypical adenomatous hyperplasia lung carcinoma

Abstract

Alveolar adenoma is a rare tumour of the lung. It is typically found in asymptomatic adults as a peripheral or subplerual nodule on imaging examination. Microscopically, the tumour is composed of admixture of epithelial and mesenchymal component in variable sized cystic or alveolar structures. The tumour shows a benign nature. There have been no reported recurrences or metastases. Malignant transformation of alveolar adenoma and coexisting with lung carcinoma have been rarely described. In this article, we report a case of an alveolar adenoma and coexisting atypical adenomatous hyperplasia. This case, contributing to the limited numbers of cases described to date, illustrates the importance of awareness on the possibility of alveolar adenoma being associated with lung carcinoma and its precursor lesions especially when diagnosed by small biopsy specimens.

Introduction

Alveolar adenoma (AA) is a rare pulmonary tumour with proliferation of alveolar epithelium and septal mesenchyme. Yousem and Hochholzer described the first six cases of AA in 1986 1. To date, approximately 57 cases have been reported in the literature. AA represents one type of adenoma of lung in the 2021 World Health Organization classification 2. There are only few articles about coexistence of AA with other neoplasms 3-6. Here, we report a rare case of an AA coexisting with atypical adenomatous hyperplasia (AAH). We also review the clinical, radiologic, pathologic and molecular features of AAs.

Case report

A 52-year-old woman, a non-smoker, was incidentally found to have a solitary pulmonary nodule during a regular medical examination. The computed tomography (CT) of the chest revealed a 1.2 cm subpleural nodule in the right upper lobe. The positron emission tomography (PET) scan showed no definite uptake in the nodule. She underwent a wedge resection of the right upper lobe lesion. Frozen section analysis indicated a benign lesion.

The pathological examination of the wedged lung tissue showed a well-demarcated grey white nodule grossly. Microscopic examination disclosed a well-fined tumour containing multiple cystic spaces filled with eosinophilic granular material and lined by flattened to cuboid epithelial cells without significant atypia (Fig. 1A). The associated stroma between the cystic spaces consisted of bland spindle cells, inflammatory cells and myxoid matrix (Fig. 1B).

Immunohistochemically, the lining epithelial cells were positive for pan-cytokeratin (CK), CK7 and thyroid transcription factor 1 (TTF-1) (Fig. 1C). The interstitial cells were focally positive for cluster of differentiation 34 (CD34) (Fig. 1D), while negative for TTF-1 and CK. Both the histopathological and immunohistochemical studies confirmed the lesion to be an AA.

Incidentally, an AAH, 1 mm in size, was identified in the surrounding lung parenchyma. Cytological atypia was found (Figs. 1E, F). There was no parenchymal inflammation or fibrosis in the background. No recurrence or metastasis was observed after 3-year follow up.

Discussion

AAs occur more commonly in women than in men (M:F ratio about 1:2) (Tab. I). The tumour usually presents in the five to sixth decade of life. Most often, patients are asymptomatic. Other symptoms, such as cough, chest pain, dyspnoea and haemoptysis, have been reported. Chest plain film and computed tomography typically show a peripherally or subpleurally located, well circumscribed nodular lesion with occasional central cavitation. There is usually no or minimal, thin-rim contrast enhancement 4,7. More central location of the lesions has been described 8-9. The most common location was the left lower lung field. The reported size ranges from 2 mm to 98 mm (average 24 mm). Most of the cases are solitary; however, two cases of multiple occurrences have been reported 7,10. Few reported cases with follow-up imaging studies have shown slight size enlargement 11-16. Positron emission tomography (PET) scan often shows no or faint uptake 8,17.

AAs are grossly well-circumscribed, grey-white or yellow-brownish nodules with a soft, spongy or glistening cut surface. Occasionally they may be cystic or haemorrhagic. Prominent cystic change had been reported 18-20. Microscopic examination typically shows a well-defined lesion that contains admixture of epithelial and mesenchymal component in variable sized cystic or alveolar structure. Proteinaceous, eosinophilic granular material can be observed in the cysts, some of which may also contain macrophages, fresh blood with cholesterol clefts or hemosiderin-laden macrophages. The larger cysts tend to be concentrated towards the centre of the lesion. Small lymphoid aggregates could be seen at the periphery of the lesion 21. Microcystic formation and follicular growth pattern, morphologically mimicking thyroid tissue, has been described 19.

The cystic spaces are separated by varying thickness of stroma containing mostly bland spindle cells, loose or myxoid matrix, capillaries and scattered inflammatory cells including lymphocytes, plasma cells, and eosinophils. Round-shaped cells as well as spindle-shaped interstitial cells over the septal mesenchyme has been mentioned in one report 22. Foci of interstitial haemorrhage and hemosiderin deposition can be observed 23. One reported case showed presence of mature adipocytes within the tumour 24. High power examination of the cystic lining shows single layer of flat, cuboidal or hobnail epithelial cells. Nuclear atypia, mitotic activity, and necrosis are absent.

Immunohistochemical analysis of AAs typically shows positive immunoreactivity for CK, CK7, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), TTF-1 and surfactant apoprotein in the epithelial component with expression of CK20 in one reported case 25-26. There is variable immunoreactivity for CD34, smooth muscle actin and S100 in the mesenchymal component 23-24. The eosinophilic granular material within the cysts is PAS-positive. The proliferation index (Ki-67) is less than 1%. Absence of p53 immunohistochemical expression is found 3,5,15-16,22,27. Based on the immunohistochemical profiles and some ultrastructural studies, the epithelial component of AA is considered to be type II pneumocytes. Additionally, the interstitial cellular component is thought to made up of fibroblasts or fibroblast-like cells 1,11,25,28.

The exact histogenesis of AA is uncertain. It is unclear if both the epithelial and mesenchymal components are neoplastic. It has been postulated that the cell origin of AA is probably primitive mesenchymal cells with the capacity to differentiate towards type II pneumocytes. Some authors thought of the CD34 immunoreactivity in the interstitial cells as a manifestation of the primitive mesenchymal nature being able to differentiate into specific lineages, such as adipocytes 23-24. By contrast, the hypothesis that the mesenchymal proliferation is secondary to the epithelial proliferation and stimulated by the epithelial growth has also been proposed 3,11,29. Limited studies have described the molecular alterations of AA. Cavazza et al. used microsatellite instability analysis to show that the stromal and epithelial components are genetically unrelated, suggesting the dual nature of the lesions 24. Flow cytometric studies of the AAs in some reports showed a diploid DNA pattern 27-29. Roque et al. reported a non-balanced translocation demonstrated by fluorescence in situ hybridisation analysis 30. The importance of the chromosomal abnormality on the pathogenesis of AA is still unknown. Lack of EGFR mutation and anaplastic lymphoma kinase (ALK) protein expression was shown in one report 16.

The differential diagnosis of AA comprises both benign and malignant lesions, including sclerosing pneumocytoma (SP), lymphangioma, AAH, adenocarcinoma in situ (AIS) and lepidic predominant adenocarcinoma. Proliferation of both epithelial and stromal component of SP can resemble AA. The absence of diverse growth patterns as well as negative TTF-1 and EMA staining in the mesenchymal component in AA can help one distinguish between these two considerations. Lymphangioma might be confused with AA because both tumours contain cystic structure and proteinaceous material. The flat lining cells of AA may resemble endothelial cells 27. However, unlike AA, lymphangioma does not contain the mesenchymal component. The absence of CK immunoreactivity in the lining cells of lymphangioma also helps to differentiate. Other diagnostic considerations include AAH, AIS and lepidic predominant adenocarcinoma. Areas of small cystic or glandular spaces with regular lining cells in AA might simulate these three entities 14. Lack of cytologic atypia and infiltrative growth in AA can be helpful features in the differential diagnosis.

The reported cases of AA have had an indolent clinical course. Regardless of the type of surgical intervention, no rrecurrences or metastases have been reported with up to 15 years of follow-up. However, one patient presented with malignant transformation of an AA to an adenocarcinoma in one report 16. Borderline and transitional areas between the AA and adenocarcinoma has been shown in the case. There are two reported cases of AA with a concurrent lung carcinoma or AIS 3,6. To the best of our knowledge, our case is the first description of coexisting AA and AAH. AAH is a putative precursor of AIS or lung adenocarcinoma 2. The above-mentioned cases including ours, albeit in limited numbers, remind us of the possibility of AA with the potential for malignant transformation or being associated with lung carcinoma and its precursor lesions especially when diagnosed by small biopsy specimens.

Conclusion

In summary, AA is a rare pulmonary tumour often found in asymptomatic adults in their five to sixth decade of life. No recurrences or metastases have been reported to date. It should be considered in the differential diagnosis of a solitary pulmonary nodule. Our case demonstrates the rare occurrence of coexisting AA and AAH. Further molecular analyses might assist in clarifying its pathogenesis and nature.

Figures and tables

Figure 1.(A) In low-power view, the tumour was well defined, containing multiple variable-sized cystic spaces filled with eosinophilic granular material. (haematoxylin-eosin, original magnifications 40X) (B) The epithelial cells lining the cystic spaces were bland, flat to cuboidal. The stroma between the cysts consisted of inflammatory cells, bland spindle shaped cells and loose, myxoid matrix. (haematoxylin-eosin, original magnifications 200X) (C) TTF-1 immunoreactivity was observed in the epithelial cells and negative in the interstitial cells. (original magnifications 200X) (D) The interstitial cells were partially immunoreactive for CD34. (original magnifications 200X) (E) An atypical adenomatous hyperplasia was incidentally identified in the surrounding lung parenchyma. (haematoxylin-eosin, original magnifications 100X) (F) In high-power view, the atypical adenomatous hyperplasia revealed cytological atypia of the proliferative pneumocytes. (haematoxylin-eosin, original magnifications 400X)

Author Cases Age (y) /Sex Imaging Location Size (cm) Treatment F/U (mo.)
Yousem1 6 45/F Solitary nodule LLL 2 Wedge 13
54/F Solitary nodule RUL 2.5 Lobectomy 12
59/F Solitary nodule RUL 1.3 Lobectomy 13
74/F Solitary nodule RML 2.5 Lobectomy 120
58/M Solitary nodule LLL 1.5 Wedge 56
64/M Solitary nodule RUL 1.2 Lobectomy N/A
Al-Hilli31 1 60/F Solitary nodule LUL 1 Wedge N/A
Semeraro11 1 67/F Solitary nodule RML 2.8 Enucleation 3
Oliveira29 1 55/F Solitary nodule RLL 6 Segmentectomy 32
Böhm32 1 52/F Solitary nodule LLL 2 Wedge 12
Burke28 10 41/F Solitary nodule LLL 1.1 N/A N/A
41/F Solitary lesion LLL 2.5 N/A N/A
46/F Round shadow N/A N/A N/A N/A
52/F Solitary lesion LLL 3 N/A N/A
39/M Solitary nodule RLL 2 N/A N/A
45/M N/A LUL 1.5 N/A N/A
50/M Solitary lesion LLL N/A N/A N/A
58/M Solitary nodule LLL 1.9 N/A N/A
68/M Coin lesion LLL 1.8 N/A N/A
N/A Shadow Right 3 N/A N/A
Fujimoto7 1 47/F Three nodules LLL*2, RUL 2,1,1 Wedge (largest nodule) 15
Yilmaz33 1 51/F Solitary nodule RUL 1.8 Wedge 24
Cakan12 1 34/F Solitary nodule LUL 1.6 Wedge 12
Palpa34 2 54/M Solitary nodule Right 2.5 Wedge 144
66/F Solitary nodule RML 1.4 Resection N/A
Hartman9 1 51/F Solitary nodule RUL 3.4 Wedge 18
Golubovic13 1 64/F Solitary nodule LUL 4 Resection N/A
Cavazza24 1 69/M Solitary, cystic nodule RUL 3.5 Wedge 13
Halldorsson25 1 43/M Solitary nodule LLL 1.1 Wedge 18
Saito35 1 35/F Solitary nodule RUL 2 Wedge N/A
Sak27 2 62/M Solitary nodule LLL 1.5 Wedge 22
54/M Solitary nodule LLL 4 Wedge 32
Nakamura36 1 58/F Solitary nodule LUL 0.8 Wedge 3
Gonza´lez37 1 71/M Solitary nodule RLL 1.7 Segmentectomy N/A
Petrella18 1 38/F Giant cystic mass LUL 9.8 Resection N/A
Kondo15 1 61/F Solitary nodule LUL 2.4 Segmentectomy 12
Bhavsar3 1 59/M Undetected RUL 0.2 Lobectomy N/A
Panagiotou38 1 42/F Solitary nodule RLL 1.5 Wedge 12
Nosotti8 1 54/F Solitary nodule LLL 2 Lobectomy 12
De Rosa23 2 24/M Solitary nodule LLL 1.8 Wedge 7
35/F Solitary nodule RUL 5 Wedge 132
Wang X14 1 60/F Solitary nodule RLL 7.3 Wedge 6
Wang L39 1 48/F Solitary nodule RLL 4 Lobectomy 48
Kazerouni21 1 41/F Solitary nodule LLL 1.2 Lobectomy N/A
Lee10 1 57/F Two nodules LLL 1.6 N/A N/A
RML 0.8
Yamamoto6 1 65/F Double barrel -shaped nodule LLL 1.3 Wedge 11
Tang4 1 47/F Solitary nodule RLL 4 Segmentectomy 52
Hsieh19 1 67/M Solitary, cystic RLL 4 Wedge N/A
Okada16 1 83/M Solitary nodule LUL 1.8* Segmentectomy 48
Gan5 1 48/F Solitary nodule LLL 3.5 Lobectomy 60
Zhang22 1 40/M Solitary nodule LLL 5.2 Lobectomy 26
Kavas40 4 36/M Solitary nodule LLL 2.6 Resection 34
38/F Solitary nodule RUL 1.3 Wedge 120
51/F Solitary nodule RUL 1.8 Wedge 180
59/F Solitary nodule LLL 2 Wedge 96
Volk20 1 26/F Multicystic LUL N/A Lobectomy N/A
Roshkovan17 1 48/F Solitary nodule LUL 1.2 Wedge N/A
Present case 1 52/F Solitary nodule RUL 1.2 Wedge 36
Total 58 Median age = 52 (24-83) Solitary (including cystic*3): multiple = 53:2 RUL:RML:RLL = 13:4:8 Right = 2 Mean = 2.4 (0.2-9.8) Lobectomy = 11 Mean = 41.5(3-180)
F:M = 38:19 Multicystic = 1 LUL:LLL = 10:23 N/A = 3 Wedge = 26 N/A = 23
N/A = 1 Undetected = 1 N/A = 1 Segmentectomy = 5
N/A = 1 Enucleation = 1
Resection = 4
N/A = 11
Table I.Clinical features of reported cases of AA. (Continues)

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Affiliations

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Yen-Wen Lu

Department of Pathology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
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$authorString->getOrcid() =>

$authorString->getFullName() => Shih-Lung Chang

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Shih-Lung Chang

Department of Pathology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
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$authorString->getOrcid() =>

$authorString->getFullName() => Yi-Chen Yeh

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Yi-Chen Yeh

Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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$authorString->getOrcid() =>

$authorString->getFullName() => Yei-San Hsieh

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Yei-San Hsieh

Department of Chest Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
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Copyright

© Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology , 2022

How to Cite

[1]
Lu, Y.-W., Chang, S.-L., Yeh, Y.-C. and Hsieh, Y.-S. 2022. Alveolar adenoma and coexisting atypical adenomatous hyperplasia: a case report and literature review. Pathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology. 114, 4 (Sep. 2022), 326-331. DOI:https://doi.org/10.32074/1591-951X-755.
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