Pulmonary sclerosing pneumocytoma (PSP) is a rare benign tumor in the lung (1). This disease was firstly described by Liebow and Hubell1 as sclerosing hemangioma of the lung owing to prominent sclerotization and vascularization of the tissue. Pathologically, sclerosing hemangioma (SH) is typically composed of solid, papillary, sclerotic, or hemangiomatous components (2). The term “sclerosing hemangioma” was recently changed in 2015 by the WHO Classification of Lung Tumors as “pulmonary sclerosing pneumocytoma” (3). PSP was thought to be a vascular tumor but greater knowledge of this disease has led scientists to reconsider PSP as derived from primitive respiratory epithelium of the pulmonary alveolus, principally in type II alveolar cells (4). However, vascularization of this tumor is one of the main characteristics (4). PSP is difficult to recognize due to the lack of significant clinical or imaging features and at first glance appears to be a benign nodule such as hamartoma, tuberculoma, bronchial cysts, or certain lung cancer nodules (5). Although the etiology and pathogenesis of PSP are still unclear, recently it has been clarified that PSP is derived from the epithelial part of the lung, which gives rise to the name sclerosing pneumocytoma of the lung (6). PSPs are composed of four major histologic patterns, which are hemangiomatous, papillary, sclerotic, and solid, as well as different radiological characteristics made apparent by computed tomography (CT) findings according to their composition (6–14). It has been described that PSP typically presents as a well-defined, juxta-pleural nodule with strong and homogeneous enhancement (14–16) on CT, while several studies have analyzed CT findings of PSP and its pathologic correlation (14, 15). However, there is a limitation due to the small number of patients and the preoperative imaging modalities used in clinical practice to diagnosis PSP (16–18). In addition, a few studies investigated PSP using 18F-fluorodeoxyglucose positron emission tomography (FDG PET) (19, 20). The interval between the PET and CT study was a mean of 3.2 months (5–10); however, the hypermetabolism in pneumocytoma has not yet been defined or correlated with the possibility of developing into a malignant disease.

Patients are usually asymptomatic in which the PSP is detected coincidentally. Moreover, a cough, chest pain, and haemoptysis may also occur (6). PSP is often a solitary, well-defined, round or oval, homogeneous nodule, or mass (14–16); however, there are also cases of metastases to the lymph nodes, pleura, and bones (14, 17, 18). Patients may present with a mass lesion of up to 7 cm although 73% of lesions measure under 3 cm (8, 10). Marginal pseudocapsules (50%), overlying vessels (26.3%), air gap (2.6%), and halo sign (17.1%) are among thoracic CT findings (12). Occasionally, pleural-based, polypoid lesions may mimic a solitary fibrous tumor. Often the tumor consists of superficial cuboidal and round interstitial cells with a combination of four patterns. In the case of a biopsy with a predominance of papillary components of the sclerosing pneumocytoma, diagnosis may be difficult. In addition, both superficial cuboidal cells and round interstitial cells are positively immunoreactive for TTF1 and EMA (10, 19). TTF1 is used in the diagnosis of lung adenocarcinoma and may be misleading for diagnosing PSP. Napsin A, a human aspartic proteinase, shows immunohistochemical reactivity in type II pneumocytes with a granular and cytoplasmic staining pattern (18). It has been widely used in the panel for diagnosis of lung adenocarcinoma along with TTF-1 (17). Recently it has been demonstrated that Napsin A preferentially stains cuboidal surface cells, rather than stromal round cells, in sclerosing pneumocytoma (20, 21). Round cells are generally uniformly negative for pan-cytokeratin and positive for cytokeratin-7 and CAM 5.2 in few cases (10). However, markers related to possible malignancy transformation have not yet been identified.

The idea to test ALDH and SOX2 markers derives from the consideration of the pathological characteristics of this tumor constituted by an abundant vascularized component, and for the roles that ALDH and SOX2 may have in the process of endothelial vascular tumor progression. In particular, it has been shown that ALDH is able to detect endothelial stem-like cells in tumor with a role into the angiogenetic process (22), although SOX2 is involved into the endothelial differentiation process since this transcription factor have been shown to be essential mediators in vascular development (23, 24).

For these considerations, the aim of our study is to highlight the elevated expression of ALDH in the pneumocytoma of the lung as described, as well as the presence of SOX-2 markers in patients with a lymph node recurrence, and in one with a PET-positive nodule. However, we are conscious of the limitation of our study for the low number of patients. If the presence of these two markers will be confirmed in a larger cohort, it would be helpful for the setting of future target therapies, which may avoid the patient from lung resection for a benign disease.

We describe five patients (all female with a mean age of 54 years) who underwent surgery in our department between 1994 and 2011 for a pulmonary sclerosing pneumocytoma of the lung. All patients were subjected to major lung resection. The diagnosis of pneumocytoma has been carried out by morphological evaluation and immunostaining of transcription termination factor 1 (TTF-1), pan-citocheratine (MNF116), and epithelial membrane antigen (EMA) (3). No postoperative complications were noted. Patients have been checked by the oncologist for the definition of signs or symptoms for the disease and for the follow-up. Data analysis was carried out by reporting descriptive statistics of the study sample.

Pulmonary sclerosing pneumocytoma (PSP) is a rare benign tumor typically occurring in women with a favorable prognosis. Recurrence for this disease is infrequent, although not impossible to find. The nomenclature for this benign disease (8–10) has recently been renamed “pulmonary sclerosing pneumocytoma” (6).

It is extremely difficult to obtain an accurate diagnosis for PSP due to its low incidence and the impossibility of establishing a clinical and radiological differential diagnosis from other diseases. This is well-documented in the scientific literature where surgery is the gold standard treatment and the most common immunohistochemistry markers are used for diagnosis (Table 2) (15). Moreover, due to the frequent expression in females, estrogen receptors have been studied using immunohistochemistry, which has revealed an overexpression of ERbeta in 91.9% of patients affected by the disease (19, 20). The frequent markers used for diagnosis indicate positivity for EMA (epithelial membrane antigen), TTF-1 (transcription termination factor 1), and CK-7 (cytokeratin-7) staining (Table 2) (18, 26–35). However, currently no specific markers in this type of benign tumor have been identified.

Our study is the first attempt to show the presence of ALDH and SOX-2 in pulmonary sclerosing pneumocytoma of the lung. In particular, we decided to test ALDH and SOX2 in our PSP samples for the well-known vascular aspect of this tumor which may be associated with the role that these two markers have into the tumor vascularization process. Recently, it has been revealed that tumor endothelial cells were different from normal endothelial cells in various aspects such as gene expression profiles and for the activities of the ALDH, enzyme that plays a key role in the metabolism of aldehydes. Several studies showed that different type of stem cell types including hematopoietic stem cells and neural stem cells possess high ALDH activities. Thus, ALDH is used extensively as a stem cell marker, also for endothelial stem-like cells (22). Scientific advantages have shown that ALDH is upregulated in human endothelial cells in vivo and may be involved in tumor angiogenesis in cancer patients (36). There is likely an important role for ALDH in the formation of this tumor, which derives from vascular endothelial cells. On this marked trail, our results show a very high expression of ALDH (score of 4) in three patients and a high expression (score of 3) in the other two patients. Additionally, we found that the positivity of ALDH was sparsely distributed within the tumor, which may support endothelial cell heterogeneity. This concept may be attributed to the fact that ALDH expression levels are linked to the tumor microenvironment or tumor malignancy, which may affect ALDH expression in the endothelial cells themselves (37). Furthermore, the evaluation of SOX-2 in our patients' tumors derived from the knowledge that SOX-2 is known to play an important role in vascular development and disease, since its transcription factors have been shown to be essential mediators in vascular development, and in the developing endothelium (23). The involvement of SOX-2 may be crucial also for the angiogenesis in this type of tumor, synergistically participating with ALDH positive cells in the vascular impairment of pneumocytoma (22). Interestingly, SOX-2 was found to be highly expressed (score of 3) in only one patient: the same patient showing an ALDH score of 4 and lymph node recurrence, which is highly uncommon for this disease (24).

Although we are conscious of the fact that our study focuses on a small number of patients, due to the rarity of this benign disease of the lung, we strongly believe that the presence of ALDH and SOX-2 in pneumocytoma of the lung requires deeper analysis, especially in patients who show recurrence. This will be helpful for understanding the molecular mechanisms behind the phenomenon, and for developing future targeted therapies, which may be more effective than surgery in removing or controlling the disease.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This Study has been approved by the Ethics Committee at University Hospital of Modena, MODENA, Italy, on 4 June 2019, Prot. N. 395/2019/OSS/AOUMO. The patients/participants provided their consent to participate in this study.

The idea for the manuscript was conceived in February 2019 by BA and was further developed by VM, DB, BM, FBa, RD'A, FBe, MD, UM, and AM was involved in histopathological diagnosis. BA and VM wrote the first draft of the manuscript. BA and UM have been involved in surgery and tissue collection. VM performed laboratory experiments. BA, VM, FBa, MD, FBe, RD'A, AM, and UM all reviewed the manuscript and were involved in its critical revision before submission. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.