Charuhas G. Deshpande , M.B., B.S. and Kar-Ming Fung, M.D., Ph.D. Last update: September 30, 2003.

Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK

Clinical information: 

    The patient was a 55 year-old woman. A well-defined round lesion in the lung that was discovered on routine chest X-ray. The resection yielded the following specimen.

Pathology of the case: 

A.	B.	C.	D.	E.

    Panel A shows features of the periphery of the tumor that interfaces with the non-neoplastic lung parenchyma. Many choloesterol clefts are present and probably due to resolved hemorrhage. Panel B shows the periphery of the tumor which gives a papillary type of architecture although a real fibrovascular core is absent. Panel C shows the details of these areas. The lesional tissue appear to be composed of solid sheets of mononuclear cells with amphophilic cytoplasm. The cell border is quite clear in some areas but no intercellular bridges or keratinization is present. The surface of the solidly packed cells are lined by a single layer of cuboidal mononuclear cells. The papillary-like structures that are typically seen in the periphery transform into solidly packed tumor cells at the center of the lesion as illustrated in Panel D. Sclerotic changes is also present at the center of the lesion as illustrated in Panel E.

Discussion: General Information    Pathology    Differential diagnosis    Pathogenesis

General Information    

    Sclerosing hemangioma was first described by Liebow and Hubell ¹. They represent about 22.2% - 32.8% of all benign pulmonary tumors ². There is a definitive female preponderance with a male to female ratio in the range of 1:4 to 1:15. The age range is also wide and spans from 13-78 years ^{3, 4, 5}. The majority of sclerosing hemangiomas are incidental findings on routine chest x-ray examination. When sclerosing hemangioma manifests, the symptoms include recurrent chest pain, cough, hemoptysis and rarely as exertional dyspnea ^{3, 6, 7}.  Although sclerosing hemangioma often occurs as a solitary mass, there are cases with multiple nodules, mediastinal mass and lymph node metastases with no effect on prognosis  ^{8, 9, 10, 11, 12}. Extracapsular enucleation is the treatment of choice for sclerosing hemangiomas ¹³.

    On plain film, sclerosing hemangioma occurs as solitary central, intraparenchymal or peripherally located, pleural-based lesion with as well-defined homogeneous, round to oval shadow on chest roentgenograms ³. Sclerosing hemangioma appears as homogeneous mass on CT scan. A hypodense portion would be seen if cystic changes are present. On MRI scan, they appear as lesions with mixed areas of high- and low-signal intensity on both T1- and T2-weighted images that demonstrate postcontrast ^{2, 14}.

Pathology

    Macroscopically, sclerosing hemangiomas are usually small, solitary nodules with a mean diameter of about 2.5 cm and the range is 0.3 to 7.0 cm ^{3, 5, 6, 15}. The margin is well defined and the cut surface is variegated gray to tan-yellow. Cystic changes, focal hemorrhage, and calcifications may be present.

    Microscopically, sclerosing hemangiomas have two salient histologic features: marked proliferation of sclerotic, small blood vessels and dual population of mononuclear cells with pale or eosinophilic cytoplasm and pnemocyte-like cuboidal cells. The interplay of these two components generates four recognizable patterns, namely, papillary, solid, hemorrhagic, and sclerotic.  The sclerotic pattern does not usually occur as a pure pattern but accompanies the three patterns. The center of the tumors tends to be more sclerotic. In the sclerotic areas, the collagen is dense and the tumor cells are sparse. In the papillary tumor, the periphery of the tumor has papillary structures lined by eosinophilic cuboidal cells that resemble the alveolar pneumocytes. These cells may continue with the surrounding non-neoplastic alveolar lining cells. There is often a transition of papillary pattern to broad areas of medium-sized, round or polygonal cells with pale eosinophilic or clear cytoplasm. The nuclei are usually oval, with fine chromatin and occasional nucleoli. The solid pattern is composed predominantly of solidly packed tumor cells without significant papillary component. The hemorrhagic pattern appears hemangioma-like and is associated with hemorrhage. A mixed pattern is seen in most sclerosing hemangiomas. Histologic changes secondary to the hemorrhage including hemosiderin-laden histiocytes, cholesterol clefts, and calcifications are common. Presence of tumorlets, areas with neuroendocrine features and foci of mucin production have been described as accompanying findings. The histological features are usually specific enough to allow rapid diagnosis. 

    Cytologic diagnosis of sclerosing hemangioma on fine needle aspiration requires the identification of the dual cell population, specifically the cuboidal pneumocyte-like cells and the solid sheets of cells ¹⁶. A diagnosis of pulmonary sclerosing hemangioma can be made at intra-operative frozen sections in most cases. When only a single histological pattern is identified or when there is significant cytological atypia, distinction from other tumors can be problematic, and the diagnosis is best deferred ¹⁷.

     The immunohistochemical profile of sclerosing hemangioma has been extensively studied.  The consistent positive immunoreactivity for epithelial membrane antigen (EMA) in both the epithelial cells and solid sheets of cells,  favors the notion that the tumor cells of sclerosing hemangioma are epithelial, and the strong thyroid transcription factor-1 (TTF-1) immunoreactivity suggests differentiation toward pulmonary epithelium ^{3, 4, 15, 18, 19, 20, 21, 22, 23, 24}. The papillary lining cells expressing EMA as well as PE10 or CAM 5.2 likely represent entrapped metaplastic alveolar epithelium, whereas the papillary lining cells expressing only EMA more likely constitute true neoplastic cells similar to those in the solid areas ²⁴.  Neuroendocrine differentiation of sclerosing hemangioma has been suggested recently by Xu et al ⁵.

Differential diagnosis

    Inspite of the disagreement about its histogenesis, the histological appearance is sufficiently specific to make the diagnosis apparent.  In the past it was confused with the inflammatory pseudotumor, a lesion comprised of plasma cells, histiocytes and fibroblasts, with an inconspicuous vascularity and no papillary proliferation.  The focal areas of sclerosis may produce a disturbing appearance, but the mixture of elements present is not seen in metastatic papillary carcinomas or in other pulmonary tumors.

Pathogenesis

    Sclerosing hemangioma has been called historically as histiocytoma, xanthoma, pneumocytoma, benign sclerosing pneumocytoma or papillary pneumocytoma ^{1, 25, 26}. Although it has morphological features of a sclerosing tumor of vascular origin, hence the name sclerosing hemangioma, the histogenic origin remains uncertain.  Epithelial, neuroendocrine, endothelial, mesothelial, histiocytic, bronchioloalveolar, and nonendothelial mesenchymal origins have been implicated by various studies to date. In fact, current evidence heavily favors an epithelial origin over an endothelial or mesothelial origin ^{1, 2, 3, 4, 5, 10, 27, 28}.  Confusion arises as of whether the surface epithelial cells lining the papillary cores or the cells within the core, so-called stromal or lesional cells, are the neoplastic cells.  Presence of entrapped normal alveolar lining cells and presence of tumorlets or carcinoid-like features adds up to the pre-existing debate.  Using the human androgen receptor (HUMARA) gene or the phosphoglycerate kinase (PGK) gene as X-chromosome-linked polymorphic markers, Niho et al. (1998) have shown monoclonal origin of both the pale cells as well as the cuboidal cells after micro-dissecting them, proving that both cellular components are neoplastic ²⁹.

    Ultrastructural studies revealed unequivocal epithelial cells in both the irregular spaces and the solid areas of the tumor; some of these cells were identical to granular pneumonocytes. The true vascular component was sparsely distributed, suggesting that the term, "sclerosing hemangioma" was a misnomer, rather being an essentially epithelial lesion  ^{26, 30}.  Satoh et al. using immunohistochemistry and immunoelectron microscopy techniques demonstrated that the cytoplasm of some of the sclerosing hemangioma tumor cells was positive for the anti-lung surfactant apoprotein monoclonal antibody (PE-10). These cells were the pale cells of the solid areas, the cells covering the papillary projections, and the cells lining the cleft-like spaces. These cells also were positive for conventional epithelial cell markers. Some cells also were positive for vimentin. Electron microscopic study showed that the predominant cell was a poorly differentiated pneumocyte. Immunoelectron microscopic study also demonstrated that PE-10 existed in the rough endoplasmic reticulum of some of the cells in the solid areas, in the same way as normal type II pneumocytes. These authors concluded that the sclerosing hemangioma is an epithelial tumor with differentiation towards type II pneumocytes ¹⁸.

Reference: 

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