Pulmonary sclerosing pneumocytoma: Cytomorphology and immunoprofile.

BACKGROUND: Sclerosing pneumocytoma (SP) is a rare, benign pulmonary neoplasm. To the authors' knowledge, the current study is the first to evaluate the cytomorphology and immunoprofile of SP in a series. METHODS: A total of 9 fine-needle aspiration cases of SP (7 of which were computed tomography guided and 2 of which were endobronchial ultrasound guided) including histopathology and immunohistochemistry were collected from 5 institutions. RESULTS: The female-to-male ratio was 3.5:1, and the mean age of the patients was 54 years (range, 27-73 years). All cases presented as lung nodules, with a mean size of 2.2 cm (range, 1.1-5 cm), and were interpreted as atypical on rapid on-site evaluation. The final diagnoses were favor adenocarcinoma (1 case), well-differentiated lung adenocarcinoma (2 cases), low-grade epithelial neoplasm (2 cases), and sclerosing pneumocytoma (4 cases). Samples were moderately cellular, and consisted of round epithelioid cells with clear cell features, columnar cells, and spindle cells. A papillary arrangement with prominent hyalinized fibrovascular cores was the most common architectural pattern, followed by flat sheets and acinar formations. Tumor cells demonstrated mild, focally moderate nuclear pleomorphism with prominent nucleoli, hyperchromasia, nuclear elongation, nuclear overlap, and occasional nuclear inclusions and grooves. The background consisted of foamy macrophages (9 cases), hemosiderin pigment (6 cases), and lymphoid aggregates (3 cases) with no mitoses and/or necrosis. The surface cells and underlying round cells were positive for both thyroid transcription factor 1 and epithelial membrane antigen in all cases, which was the most notable immunohistochemical finding. CONCLUSIONS: Cytomorphological findings of SP overlap with those of well-differentiated lung adenocarcinoma. Awareness of these cytomorphologic findings and the distinct immunoprofile of the 2 cell types found in SP should prevent a misdiagnosis and aggressive treatment.

A 33-Year-Old Woman With a Fluorodeoxyglucose-Avid Left Lower Lobe Mass.

A 33-year-old woman of Latin American origin was referred to our department by her primary care physician for a left lower lobe mass, which was incidentally found on a CT scan of her abdomen. The patient had complaints of abdominal pain for which she underwent imaging of her abdomen. Review of systems was negative for any respiratory complaints, and she denied any history of cigarette smoking or recreational drug use.

Histogenesis of pulmonary sclerosing hemangioma and significance of P63 expression.

OBJECTIVE: To investigation of the histogenesis and the significance of expression of P63 in pulmonary sclerosing hemangioma (SH). METHODS: Eighteen cases of SH were retrospectively studied, and P63, surfactant protein B (SPB), thyroid transcription factor-1 (TTF-1), epithelial membrane antigen (EMA), cytokeratin (CKpan), vimentin, SMA, chromagranin (CgA), Syn and CD34 were immunohistochemically labelled with EnVision method. RESULTS: There are mainly four types of structures in SH tissue: solid, papillary, angiomatous (haemorrhagic), and sclerotic pattern. The tumour cells are composed mainly of two types of cells: cuboidal tumour cells and polygonal cells. The immunohistochemistry showed that cuboidal tumour cells expressed P63 (+++) in 16 cases of SH (16/18 cases). Polygonal cells and cuboidal cells of all cases express both TTF-1 and EMA at the same time (18/18 cases); cuboidal tumour cells express SPB (18/18 cases); polygonal tumour cells express vimentin (18/18 cases). In one case, a polygonal tumour cell weakly expressed Chromogranin (CgA) and Syn. CONCLUSION: The P63 positive cuboidal tumour cells may be pluripotent original respiratory epithelial cells, with multidirectional differentiation capacity. Immunohistochemically labelling of P63 may have important value for SH diagnosis.

Pulmonary sclerosing hemangioma: a unique epithelial neoplasm of the lung (report of 26 cases).

BACKGROUND: Pulmonary sclerosing hemangioma (SH) is an uncommon tumor. The aim of this study was to identify the origin of pulmonary SH and summarize its clinicopathologic features. METHODS: Data of 26 cases of pulmonary SH were collected and reviewed, including their clinical symptoms, chest radiological examinations, treatments, and pathological findings. RESULTS: Female patients of pulmonary SH were markedly frequent (n=23, 88.46%). Solitary mass or nodule in the lung fields was the most common manifestation (n=24, 92.31%), especially in the right middle lobe (n=9, 34.62%). There were two kinds of tumor cells: lining cells and round cells. All tumors contained a mixture of papillary, solid, sclerotic, and hemorrhagic patterns. Immunohistochemistry with a variable number of antibodies was performed for some cases. All of the detected specimens revealed strong reaction of lining cells with epithelial markers, such as thyroid transcription factor-1 (TTF-1), epithelial membrane antigen (EMA), cytokeratin (CK), pancytokeratin (PCK), and cytokeratin 7 (CK-7), while round cells were positive with TTF-1 and EMA. Until the end of last contact, none of the patients died or suffered from the recurrence of the disease after surgical treatment. CONCLUSIONS: Pulmonary SH is a unique neoplasm of the lung with a characteristic solitary mass or nodule. Pulmonary epithelium might be the primary origin of the tumor cells.

Napsin A is differentially expressed in sclerosing hemangiomas of the lung.

CONTEXT: Sclerosing hemangiomas (SH) are lung tumors characterized by surface cuboidal cells and round stromal cells. The cell of origin remains controversial, though immunohistochemical and ultrastructural studies suggest primitive respiratory epithelium. Napsin A, a human aspartic proteinase found primarily in type II pneumocytes and alveolar macrophages, is emerging as a helpful immunohistochemical marker in characterizing the origin of lung neoplasms, and may be of use in evaluating SH. OBJECTIVE: To evaluate napsin A immunohistochemical staining in SH to further characterize the cell of origin. DESIGN: Six cases of SH were stained for napsin A, as well as thyroid transcription factor 1 and cytokeratin in selected cases. RESULTS: Surface and round cells were positive for thyroid transcription factor 1 in all cases stained with this marker. Cytokeratins were positive in surface cells in all cases stained with this marker; 2 cases had focal cytokeratin staining in round cells. Round cells had focal napsin A staining in 1 case (17%); surface cells were napsin positive in all cases. CONCLUSIONS: The observation of thyroid transcription factor 1 positivity in both surface and round cells in all SH suggests primitive respiratory epithelium as the cell of origin of SH. Our napsin A findings support this, with positivity in surface cells of all tumors (100%), and focal round cell staining in only 1 (17%). In fact, surface cells may represent entrapped type II pneumocytes, which normally express napsin A in a granular cytoplasmic pattern, similar to surface cells. The coexpression of thyroid transcription factor 1 and napsin A also introduces a caveat in differentiating primary pulmonary adenocarcinomas from SH in small biopsy specimens.

[Histogenesis of pulmonary sclerosing hemangioma].

OBJECTIVE: To investigate the histogenesis of pulmonary sclerosing hemangioma (PSH). METHODS: Tissue microarray and immunohistochemical technique were used to detect the expression of pan-cytokeratin, epithelial membrane antigen(EMA), vimentin, thyroid transcription factor (TTF)-1, napsin A, synaptophysin, chromogranin A, CD56, E-cadherin, ß-catenin, CD117, CD68 and transforming growth factor(TGF)-ß1 in 49 cases of PSH. RESULTS: Immunohistochemistry revealed that all cuboidal surface cells expressed pan-cytokeratin, EMA, TTF-1 and napsin A. The polygonal cells expressed EMA, TTF-1, napsin A (positive rate 16.3%, 8/49), but not pan-cytokeratin. Both types of cells were negative for synaptophysin, chromogranin A and CD56. Strong positive staining for E-cadherin and ß-catenin appeared on the membrane of cuboidal cells in all PSH, with cytoplasm staining for ß-catenin as well. The expression levels of these adhesion molecules decreased in the polygonal cells, with the staining localized to the cytoplasm. E-cadherin staining was not detected or was weak. ß-catenin staining was not detected on the cell membrane but partially in the cytoplasm. The polygonal cells stained strongly for vimentin, while only a few cuboidal cells were positive. CD117 and CD68 positive inflammatory cells were scattered between the polygonal cells, which was consistent with the distribution of TGF-ß1 positive cells. CONCLUSIONS: PSH originates from the primitive respiratory epithelium, and polygonal stromal cells may be derived from epithelial-mesenchymal transformation of the cuboidal cells. TGF-ß1 may play an important role in the formation of sclerosing hemangioma.

Expression and significance of stem cell markers in pulmonary sclerosing haemangioma.

AIMS: The two major types of cells of pulmonary sclerosing haemangioma (PSH) with the same origin show significant differences in morphological phenotype. Whether these differences are caused by their different differentiation status is still uncertain. The aim of this study was to analyse their differentiation status by detecting the expression of several stem cell markers in PSH. METHODS AND RESULTS: The expression of stem cell markers was examined by using streptavidin peroxidase (SP) immunohistochemisty in 45 PSH specimens. Also, the two types of cells were, respectively, captured by laser capture microdissection (LCM) from 28 PSH specimens, and total RNA was then extracted followed by reverse transcription-polymerase chain reaction (RT-PCR). The results demonstrated that the expression rates of ABCG2, Notch1 and Notch3 in polygonal cells were significantly higher than those in cuboidal cells (P < 0.05), and the expression levels of ABCG2, Notch3 and Jagged1 in polygonal cells were clearly higher than those in cuboidal cells (P < 0.05). CONCLUSION: The data obtained provided evidence that the two types of cells in PSH may be different in differentiation status. The differentiation difference between the two types of cells might lead to variation in their morphological phenotype.

In pulmonary sclerosing hemangioma expression of ß-catenin, Axin, and C-myc differs between the two cell types.

Previous studies have shown that pulmonary sclerosing hemangioma is a tumor derived from primitive respiratory epithelium, but its character and the differentiation status of the two cell types (polygonal and cuboidal) composing the lesion are still controversial. We hypothesize that the polygonal cells are immature compared with cuboidal cells and have higher proliferative activity. To further study this question, we examined the expression of ß-catenin, Axin, and C-myc by immunostaining in 45 primary sclerosing hemangioma (PSH) specimens. The two cell types were captured by laser capture microdissection from 28 PSH specimens, and total RNA was extracted. Messenger RNA (mRNA) expression of Axin and C-myc was examined by reverse transcription polymerase chain reaction (RT-PCR). By immunostaining, ß-catenin was predominantly strongly expressed on the cell membrane of cuboidal cells, while in polygonal cells, ß-catenin was predominantly expressed in the cytoplasm and significantly decreased on cell membranes. Axin was expressed in cuboidal cells in 93 % of our 45 cases, but only expressed in 18 % of these in polygonal cells. C-myc expression in polygonal cells was significantly stronger than in cuboidal cells (P < 0.05). RT-PCR showed that the expression level of Axin mRNA in cuboidal cells was significantly higher than in polygonal cells (P < 0.05), and expression level of C-myc mRNA in polygonal cells was significantly higher than in cuboidal cells (P < 0.05).The two PHS cell types have distinct expression of ß-catenin, Axin, and C-myc, suggesting that their differentiation status may be different. The higher expression of C-myc in polygonal cells suggests that these cells might have higher proliferative activity.

So-called sclerosing hemangioma of lung: current concept.

Sclerosing hemangioma of the lung is a rare neoplasm with polymorphic histologic features. Despite various patterns, there are 2 unifying cellular components: "surface cells" and "round cells." Although histogenesis has been debated for decades, most ultrastructural, immunocytochemical, and molecular studies strongly indicate a neoplastic epithelial derivation for both cellular components. Herein, we present a review of sclerosing hemangioma and summarize the essential data regarding histologic, cytologic, and ancillary findings of this distinctive pulmonary neoplasm.

Role of the PI3K/Akt, mTOR, and STK11/LKB1 pathways in the tumorigenesis of sclerosing hemangioma of the lung.

Although the histogenesis of sclerosing hemangioma (SH) of the lung is now thought to be respiratory epithelial in origin, the genetic abnormalities that mediate its development are not known. Because pathophysiology of several syndromes associated with benign tumors may converge on the tuberous sclerosis complex (TSC), serine/threonine kinase 11 (STK11), and mammalian target of rapamycin (mTOR) pathways, the purpose of the present paper was to investigate their roles in the development of SH. Semiquantitative immunohistochemical analysis was done to assess the expression of phospho-mTOR, phospho-S6 ribosomal protein, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phospho-Akt, STK11, tuberin, hamartin, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1alpha (HIF-1alpha) in 19 cases of typical SH. To determine whether genetic alteration of STK11 is involved in the development of SH, all encoding exons of STK11 were analyzed by polymerase chain reaction (PCR) amplification and direct sequencing of genomic DNA of six specimens. The six specimens were also investigated for whether promoter hypermethylation exists as an alternative inactivating mechanism for STK11. All specimens showed moderate to marked reaction to phospho-S6 ribosomal protein and PTEN; 16 specimens (84%) showed slight to moderate reaction to phospho-mTOR, negative reaction to STK11, and slight to moderate reaction to hamartin; 11 (58%) showed slight to moderate reaction to phospho-Akt; 18 (95%) showed slight to moderate reaction to tuberin and positive reaction for HIF-1alpha; and 17 (90%) showed moderate reaction to VEGF. No somatic mutation of STK11 was found and the six specimens were unmethylated in the promoter region. These data imply that aberrant mTOR signaling may play a role in the development of SH, and its vascular nature may be due partially to high levels of VEGF caused by dysregulation of mTOR signaling.

p53 protein expression and genetic mutation in two primary cell types in pulmonary sclerosing haemangioma.

AIMS: To investigate the significance of p53 protein expression and genetic mutations in two primary cell types in pulmonary sclerosing haemangioma (PSH). METHODS: p53 protein expression in polygonal cells and cuboidal cells in 19 patients with PSH was detected using immunohistochemistry. The two major cell types were captured using laser capture microdissection technology. Mutations in the p53 gene (exons 5-8) were examined using single-stranded conformation polymorphism and DNA sequencing analysis. RESULTS: p53 protein expression and gene mutations were observed in 15.8% (3/19) of cases. In these cases, p53 protein was expressed in the nucleus of both cell types, with higher expression levels and mutation rates in polygonal cells than in surface cuboidal cells. Two cases showed mutation only in the polygonal cells, while one case showed double (separate) mutations in both the polygonal and cuboidal cells. CONCLUSIONS: p53 mutation was exhibited in PSH. The mutation rate in polygonal cells was higher than that in surface cuboidal cells.

Frequent nuclear expression of beta-catenin protein but rare beta-catenin mutation in pulmonary sclerosing haemangioma.

BACKGROUND: Pulmonary sclerosing haemangioma (PSH) is an uncommon tumour that is composed of glandular/papillary lining cells and polygonal cells. The biological behaviour of this tumour has been investigated; however, the molecular pathogenesis of PSH remains unknown. AIMS: To characterise the role of the Wnt/beta-catenin pathway in the genesis of PSH. METHODS: 37 PSH samples were investigated immunohistochemically for detection of the beta-catenin protein and direct sequencing of exon 3 of the beta-catenin gene. RESULTS: Nuclear expression of beta-catenin was found in the lining component of 23 tumours (62%) and in the polygonal component of 11 tumours (30%). The expression of beta-catenin was stronger in the lining component, but weaker in the polygonal component. Interestingly, all the tumours with expression of beta-catenin in the polygonal component also expressed beta-catenin in the lining component. However, mutation of exon 3 of the beta-catenin gene was detected in only one tumour that expressed nuclear beta-catenin in lining and polygonal components. CONCLUSIONS: The Wnt/beta-catenin pathway is involved in the genesis of PSH, but mutation of exon 3 of the beta-catenin gene rarely contributes to the activation of the Wnt/beta-catenin pathway in PSH.

Microsatellite and EGFR, HER2 and K-RAS analyses in sclerosing hemangioma of the lung.

Sclerosing hemangioma (SH) is an uncommon pulmonary tumor thought to derive from primitive respiratory epithelium consisting of 2 cell populations (cuboidal surface and polygonal stromal cells) and sharing some clinical characteristics (frequent occurrence in nonsmoking women of Asian ethnicity) with bronchioloalveolar carcinoma with which it has been suggested a possible common origin. We investigated 11 cases of SH by immunohistochemistry, fluorescence in situ hybridization, and polymerase chain reaction-based microsatellite and mutational analyses with particular emphasis on possible alterations of microsatellite loci located at tumor suppressor genes (FHIT, p16, Rb, and p53) involved in lung adenocarcinoma genesis and EGFR, HER2, and K-RAS genes. Although EGFR expression was observed in all tested cases, none showed HER2 immunostaining. Fluorescence in situ hybridization and mutational analysis of EGFR and HER2 and also K-RAS sequencing did not reveal molecular alterations, whereas allelic losses at p16 and Rb loci (4 and 2 out of 9 tested cases, respectively) with an identical microsatellite allelic loss pattern in both cuboidal and polygonal cells were observed. The finding of microsatellite alterations in chromosomal regions related to genes deeply involved in early stage lung adenocarcinoma could suggest a possible link between SH and bronchioloalveolar carcinoma, but tumor pathway promoted by EGFR, HER2, and K-RAS does not represent a common molecular mechanism of tumorigenesis. Microsatellite alterations identified in cuboidal and polygonal cells further confirm the clonal and neoplastic nature of both components of SH.

Pulmonary sclerosing hemangioma detected by fluorodeoxyglucose positron emission tomography in familial adenomatous polyposis: report of a case.

We present a 53-year-old female suffering from familial adenomatous polyposis, who was found to have a positive nodus, lateral to the hilus of the left lung, on routine FDG-PET scan. This lesion was found to be a sclerosing hemangioma. We found an aberrant beta-catenin expression on immunohistochemical staining, suggesting that sclerosing hemangioma and familial adenomatous polyposis share the same pathophysiology. It is important to be aware of the association of familial adenomatous polyposis and sclerosing hemangioma.

Expression of E-cadherin, beta-catenin and p120ctn in the pulmonary sclerosing hemangioma.

BACKGROUND: The major two types of cells in pulmonary sclerosing hemangiomas (PSH) may be not equally maturity, but this viewpoint needs more evidences. AIM: To determine E-cadherin, beta-catenin and p120(ctn) expression phenotype in cuboidal and polygonal cells, which are the two major cell types in pulmonary sclerosing hemangiomas. METHODS: Specimens were obtained from 25 patients with PSH and 8 patients with pulmonary inflammatory pseudotumors. The expression levels of E-cadherin, beta-catenin and p120(ctn) were detected using a streptavidin peroxidase (SP) immunohistochemical method. RESULTS: E-cadherin, beta-catenin and p120(ctn) were expressed strongly on the cuboidal cell membranes, while beta-catenin was also expressed the cuboid cytoplams in 25 PSH patients. However, in the polygonal cell membranes, the expression levels of these molecules were decreased, and mainly cytoplamic. Specifically, E-cadherin, beta-catenin and p120(ctn) were expressed in both the cytoplasm and on the cell membranes in the intracavitary lining cells of the hemorrhagic regions. The expression phenotype in proliferating type II pneumocytes in the eight pulmonary inflammatory pseudotumors was similar to that in the cuboidal cells in PSH patients. CONCLUSION: The cuboidal cells, resembling inflammatory proliferative type II pneumocytes, display several characteristics of epithelial cells, including normal expression of E-cadherin and catenin. Comparatively, polygonal cells are not as mature as cuboidal cells and lack of expression of E-cadherin and catenin.

Proteomic analysis of pulmonary sclerosing hemangioma.

Sclerosing hemangioma (SH) is a rare benign pulmonary tumor derived from the primitive respiratory epithelium. However, the pathogenesis of SH has not yet been clear. Surfactant protein, thyroid transcription factor-1, epithelial membrane antigen, cytokeratin, and vimentin have been identified in SH by immunohistochemistry and electron microscopy. To identify proteins specifically regulated in SH, 2-D PAGE was performed using SH and paired normal tissues. Ten selected differentially expressed protein spots were identified by PMF, MALDI-TOF-MS, and database searching. Apolipoprotein A-1, antizyme inhibitor, heat shock 27-kDa protein 1, and antioxidant proteins, such as peroxiredoxin II (Prx II) and GST, were identified among the down-regulated proteins in SH. Western blot and immunohistochemistry confirmed reduced expressions of Prx II and GST in SH versus normal lung tissue. This study is the first report on the reduced expressions of Prx II and GST in SH.

Expression of the estrogen receptor beta in 37 surgically treated pulmonary sclerosing hemangiomas in comparison with non-small cell lung carcinomas.

Sclerosing hemangioma (SH) of the lung is an uncommon tumor with a predilection for middle-aged women. This special phenomenon prompted us to examine SH for the expression of ERalpha (human estrogen receptor) and ERbeta (a second isoform of estrogen receptor). To investigate the staining pattern of these tumors, we also stained lung tissues from patients with non-small cell lung carcinomas and nonneoplastic type II pneumocytes for comparison. Thirty-seven pulmonary SHs and 301 non-small cell lung cancers specimens were explored. Expression of ERalpha and ERbeta was immunohistochemically measured. The overall frequency of overexpression for ERbeta was 91.9%. It was detected in both female (in 91.4% of 35 cases) and male (in 100.0% of 2 tumors from men) patients. There was ERbeta overexpression in all 9 tumors of solid pattern, 6 of 7 tumors of papillary pattern, all 4 tumors of sclerotic pattern, 12 of 13 tumors of hemorrhagic pattern, and 3 of 4 tumors of mixed pattern. The staining pattern of the neoplastic cells of the SH was similar to that of type II pneumocytes adjacent to the tumor rather than that of non-small cell lung cancers, in which the frequency of ERbeta overexpression was 45.8%. However, there was no ERalpha detectable in these neoplasms. Estrogen receptor beta overexpression is very frequent in pulmonary SHs, which is similar to that of alveolar cells but quite different from non-small cell carcinoma.