Sclerosing hemangioma of the lung.
Abstract: * We present a brief review of sclerosing hemangioma, an uncommon but histologically distinctive neoplasm of the lung. Based on immunohistochemical and molecular findings, sclerosing hemangioma is thought to be derived from incompletely differentiated respiratory epithelium. Sclerosing hemangiomas typically present as asymptomatic, peripheral, solitary, well-circumscribed lesions in women with a mean age at diagnosis in the fifth decade. Rare cases are reported to have regional lymph node metastases; however, metastases do not appear to affect long-term survival. Histologically, sclerosing hemangioma is characterized by a distinct constellation of findings including 2 epithelial cell types, surface cells and round cells, which form 4 architectural patterns, papillary, sclerotic, solid, and hemorrhagic. Sclerosing hemangioma of the lung is generally considered to be a benign lesion, and surgical excision is curative without the need for additional treatment.
Article Type: Report
Subject: Immunohistochemistry (Usage)
Immunohistochemistry (Analysis)
Radiography (Usage)
Hemangioma (Diagnosis)
Lung tumors (Diagnosis)
Authors: Keylock, Joren B.
Galvin, Jeffrey R.
Franks, Teri J.
Pub Date: 05/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: May, 2009 Source Volume: 133 Source Issue: 5
Topic: Event Code: 350 Product standards, safety, & recalls Canadian Subject Form: Lung tumours
Organization: Organization: World Health Organization
Accession Number: 230152008
Full Text: Sclerosing hemangioma, first described by Liebow and Hubbell (1) in 1956, is an uncommon lung tumor initially thought to be of vascular origin. Since the original description, multiple theories have been proposed for its histogenesis including mesothelial, mesenchymal, epithelial, and neuroendocrine origin. (2-4) However, immunohistochemical results in the largest series reported to date strongly suggest that sclerosing hemangioma originates from primitive respiratory epithelium. (5) This conclusion has recently been supported with molecular studies as we describe in the Ancillary Studies section. Thus, the name sclerosing hemangioma is a misnomer. Other terms such as pneumocytoma, sclerosing pneumocytoma, and papillary pneumocytoma have been suggested for this lesion; however, the term sclerosing hemangioma is still preferred by the World Health Organization for historic reasons. (6)

CLINICAL FEATURES

Sclerosing hemangioma typically occurs in middle-aged adults, with a female to male ratio of 5:1. (5) However, lesions in younger patients have been reported including 10-year-old and 19-year-old patients with lymph node me tastases. (7,8) There is no racial bias. Most patients are asymptomatic with tumors identified incidentally on screening chest radiograph. Symptomatic patients most commonly present with hemoptysis, chronic cough, or chest pain. (5)

RADIOLOGIC FEATURES

On chest radiographs, sclerosing hemangioma typically presents as a peripheral, solitary, well-defined, homogeneous nodule or mass without predilection for a particular lobe. (9) Calcification is seldom seen and cavitation does not occur. (8) Computed tomography of the chest demonstrates a round to oval nodule or mass with smooth margins that enhances following injection of intravenous contrast agents. (10,11) Although not typical on radiographs, calcification may be evident on computed tomography (Figure 1, A and B). (8) These imaging characteristics are not specific for sclerosing hemangioma but suggest a benign process. Positron emission tomography using 18F-fluorodeoxyglucose is often used to evaluate pulmonary nodules and masses, particularly indeterminate lesions. Malignant lesions and some inflammatory conditions tend to have relatively high standardized uptake values of 18F-fluorodeoxyglucose. While a single case report of histopathologically-diagnosed sclerosing hemangioma describes an intermediate level standardized uptake value similar to that seen in carcinoids, there are no large series defining the positron emission tomography characteristics of sclerosing hemangioma. (12)

GROSS PATHOLOGY

On gross examination, sclerosing hemangiomas are well-circumscribed, yellow-tan masses located in the peripheral lung (Figure 2, A and B). Although the majority of tumors occur within the lung parenchyma, endobronchial and polypoid pleural-based tumors have been reported. (5,13,14) Most sclerosing hemangiomas are solitary and range from 0.3 to 7 cm in greatest dimension. (5,8) Rare examples of multiple unilateral and bilateral lesions have been described. (5,15) Lesions are typically solid and firm, and areas of hemorrhage are not uncommon.

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HISTOPATHOLOGY

The name sclerosing hemangioma reflects 2 common histologic features of these lesions, sclerosis and ectatic vascular spaces. Currently, these features are considered secondary changes in what is regarded to be an epithelial neoplasm. (5) Sclerosing hemangiomas are morphologically distinct, consisting of 2 epithelial cell types, surface cells and round cells, and 4 architectural patterns, papillary, sclerotic, solid, and hemorrhagic (Figure 3, A through D). Surface cells are cuboidal and resemble reactive type II pneumocytes. Round cells are small with well-defined borders, fine chromatin, and inconspicuous nucleoli. Although typically bland with a low mitotic rate, either cell type can display moderate to marked nuclear atypia (Figure 4). Ninety-five percent of sclerosing hemangiomas display 3 architectural patterns, most commonly papillary, sclerotic, and solid, and all contain at least 2 patterns. (5) In the papillary pattern, complex papillae are comprised of surface cells covering a stroma of round cells. The sclerotic pattern shows hyalinized collagen in papillae, in solid areas, or at the periphery of hemorrhagic areas. Sheets of round cells bordered by surface cells form the solid pattern. Finally, the hemorrhagic pattern is composed of large blood-filled spaces. Ciliated bronchiolar epithelium is often trapped within the tumor. Other common microscopic findings include chronic inflammation, mast cells, xanthomatous histiocytes, hemosiderin, cystic spaces, calcifications, cholesterol clefts, and large lamellar structures that represent extracellular accumulation of surfactant (Figure 5). (5) In combination, these features give sclerosing hemangioma its hallmark histologic heterogeneity.

The cytology of sclerosing hemangioma has not been defined in large numbers of cases. However, one of the most helpful features is the presence of a dual cell population. (16) Bronchial washings from endobronchial lesions are reported to have sheets and clusters of round cells with well-defined cell borders, central nuclei, even chromatin pattern, scant cytoplasm, and no atypia. Papillary clusters and epithelial cells with more abundant cytoplasm, resembling pneumocytes, may be seen. (13) Fine-needle aspiration with cell block preparation and immunohistochemical evaluation can be diagnostic. (16,17) Aspiration often shows sheets of bland, polygonal cells with a background of red blood cells and foamy macrophages. Papillary groups may be seen, but the sclerotic pattern is not frequently present in aspiration samples. However, many fine-needle aspiration cases are not conclusive for sclerosing hemangioma. The cytologic differential diagnosis includes well-differentiated adenocarcinoma, particularly bronchioloalveolar carcinoma, and the similarities between the two have led to misdiagnosis of malignancy. (18,19) Proposed features that strongly favor adenocarcinoma over sclerosing hemangioma include the presence of necrosis and multiple nuclei (3 or more) within single cells. (20)

[FIGURES 3-5 OMITTED]

ANCILLARY STUDIES

Several immunohistochemical studies have demonstrated that both the surface cells and the round cells exhibit nuclear expression of thyroid transcription factor 1 (TTF-1) and membranous/cytoplasmic expression of epithelial membrane antigen (EMA) in nearly all cases (Figure 6, A through D). (5,21,22) The surface cells also exhibit strong cytoplasmic positivity for both pancytokeratin (AE1/AE3) and surfactant proteins A and B. However, the round cells frequently lack surfactant expression and have a more variable keratin profile. Round cells are often negative with pancytokeratin antibodies (AE1/AE3) but can have variable, focal expression of cytokeratin 7 and low molecular weight cytokeratin (CAM 5.2). This immunophenotype is consistent with a primitive respiratory epithelial cell origin, with the surface cells being more differentiated (pancytokeratin-positive and surfactant-positive) than the round cells (surfactant-negative). Neuroendocrine markers, chromogranin and synaptophysin, may stain scattered cells, especially among the surface cells. Calretinin, a mesothelial marker, is uniformly negative for staining. (5) Given the female predominance of these tumors, sex hormone receptor expression has been studied. Few cases exhibited progesterone receptor expression, and only rare examples were estrogen receptor-positive. (5)

By electron microscopy, the surface lining cells have abundant lamellar bodies similar to type II pneumocytes. Round cells lack well-defined lamellar bodies, but instead display variably-sized electron-dense bodies that have been interpreted to represent different stages of lamellar body maturation. (5)

Recently, various molecular pathology techniques have been utilized to further elucidate the molecular pathogenesis of sclerosing hemangioma. One study used laser capture microdissection and reverse transcriptase-polymerase chain reaction (RT-PCR) to study mRNA expression. (23) Consistent with the immunohistochemistry results, the cuboidal cells were shown to express cytokeratin, epithelial membrane antigen, surfactant, and TTF-1. Similar molecular analysis of the polygonal cells showed TTF-1 expression but significantly less epithelial membrane antigen expression, consistent with more primitive respiratory epithelium. Supporting the neoplastic nature of sclerosing hemangiomas, clonal analysis has demonstrated monoclonality of both epithelial populations. (23) To our knowledge, to date proteomic analysis has been reported in only a single case of sclerosing hemangioma. When compared to normal lung tissue, downregulation of peroxiredoxin II and glutathione-S-transferase, both involved in the numerous antioxidant mechanisms that are necessarily expressed within normal lung parenchyma, was seen within the tumor. (24) The significance of this is unclear. Interestingly, loss of heterozygosity analysis, studying microsatellite markers adjacent to known tumor suppressor genes, showed similar patterns of allelic loss for both sclerosing hemangioma and bronchioloalveolar carcinoma, suggesting a possible related pathogenesis for these 2 pulmonary tumors. In particular, sclerosing hemangiomas had frequent loss of heterozygosity at 5q and 10q, markers adjacent to APC and PTEN tumor suppressor genes, respectively. (25) Furthermore, another microsatellite study found allelic losses at the p16 locus, a tumor suppressor gene, in both the surface cells and round cells in 4 out of 9 cases. This same study, using fluorescent in situ hybridization and mutational analysis, did not support a pathogenesis pathway involving EGFR, HER-2,or K-RAS genes. (26) Similarly, p53 gene mutation is not a common finding in sclerosing hemangioma. (27) Despite recent immunohistochemical and molecular research, the diagnosis of sclerosing hemangioma remains grounded in routine histology, based on recognition of the 4 architectural patterns and 2 epithelial cell types.

DIFFERENTIAL DIAGNOSIS

The histologic differential diagnosis includes benign and malignant lung tumors and metastatic carcinoma. The distinction between benign and malignant can be difficult, particularly at the time of intraoperative consultation. With frozen section artifact, the architectural variation and 2 epithelial cell types may not be readily appreciated, leading to misdiagnosis as malignancy. However, the typical radiologic and macroscopic findings of a well-circumscribed tumor strongly favor a benign neoplasm and should lead the pathologist to exercise caution before diagnosing a lesion as malignant. Identifying 3 of the 4 major architectural patterns within the tumor can be extremely helpful in suggesting sclerosing hemangioma during intraoperative consultation. (28) Additionally, sclerosing hemangiomas rarely have significant cytologic atypia. On permanent sections, the main malignant neoplasms in the differential diagnosis include bronchioloalveolar carcinoma, metastatic papillary thyroid carcinoma, metastatic renal cell carcinoma, and carcinoid. The presence of the 2 distinct epithelial cell populations and the mixture of architectural patterns are helpful in differentiating sclerosing hemangioma from bronchioloalveolar carcinoma with a papillary architecture. The typical nuclear features of papillary thyroid carcinoma are not seen in sclerosing hemangioma. Immunohistochemistry for TTF -1 is not helpful in distinguishing sclerosing hemangioma from the rare occurrence of metastatic papillary thyroid carcinoma to the lung; however, immunohistochemistry for thyroglobulin is useful in this setting. Like metastatic renal cell carcinoma, sclerosing hemangioma may have cells with clear cytoplasm, but the nuclear atypia and striking vascularity typical of renal cell carcinoma are not identified in sclerosing hemangioma. The usual organoid and ribbonlike growth patterns of carcinoid are not seen in sclerosing hemangioma. Immunohistochemistry for neuroendocrine markers is negative in sclerosing hemangioma except for areas with entrapped respiratory epithelium containing neuroendocrine cells. Benign lung tumors in the differential diagnosis include clear cell tumor, pulmonary hamartoma, and hemangioma. In contrast to sclerosing hemangiomas, clear cell tumors (so-called sugar tumors) have abundant clear cells with scant stroma, thin-walled vessels, and strong HMB-45 expression. Pulmonary hamartomas can have a wide variety of microscopic appearances, but they are usually readily identifiable by their combination of cartilage, myxoid stroma, adipose tissue, and trapped respiratory epithelium. True hemangiomas of the lung are very rare, have either a cavernous or capillary morphology, and lack epithelial cells.

[FIGURE 6 OMITTED]

CURRENT TREATMENT AND PROGNOSIS

Sclerosing hemangiomas of the lung are generally considered benign lesions, and surgical excision is curative without the need for additional treatment. Rare lesions demonstrate regional lymph node metastasis, including involvement of multiple nodes, which apparently does not affect prognosis. (7,8,29) While these findings suggest that sclerosing hemangioma may have low malignant potential, thus far mortality has not been attributed to this lesion.

Accepted for publication August 15, 2008.

References

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CPT Joren B. Keylock, MC, USA; Jeffrey R. Galvin, MD; Teri J. Franks, MD

From the Department of Pathology, Madigan Army Medical Center, Tacoma, Wash (Dr Keylock); the Department of Radiologic Pathology, Armed Forces Institute of Pathology and the Department of Diagnostic Radiology, University of Maryland School of Medicine, Baltimore, Md (Dr Galvin); and the Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, DC (Dr Franks).

The authors have no relevant financial interest in the products or companies described in this article.

The opinions and assertions contained herein are the expressed views of the authors and are not to be construed as official or reflecting the views of the Departments of the Army or Defense. This is a US Government work, and as such, is in the public domain in the United States of America.

Reprints: Teri J. Franks, MD, Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Bldg 54, Room 2071, 6825 16th Street NW, Washington, DC 20306-6000 (e-mail: frankst@afip.osd.mil).
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