pulmonary sclerosing hemangioma ( sh ) was first described by liebow and hubbell in 1956 ( 1 ) .
sh is thought to be a rare benign neoplasm , but it has uncertain histogenesis and biologic behavior .
sh comprises a mixture of four histologic patterns , such as papillary , sclerotic , solid and hemorrhagic .
sh consists of two cell types ; eosinophilic cuboidal epithelial lining cells and round cells with either eosinophilic or clear cytoplasm forming sheets .
the lining epithelial cells are termed as surface or cuboidal cells , while the other as round , stromal , or lesional cells .
although sh originally termed a variant of hemangioma ( 1 ) , subsequent authors have suggested the origin of sh as mesenchymal ( 2 ) , mesothelial ( 3 ) and neuroendocrine ( 4 ) derivation .
now there is a consensus that they are epithelial tumors ( 5 , 6 ) .
the finding that sh has features of a neoplasm was the reason for its being moved from the category of tumor - like lesions in the 1981 world health organization ( who ) classification of lung tumors ( 7 ) to the category of miscellaneous tumors in the new 1999 who / international association for the study of lung cancer classification ( iaslc ) ( 8) .
we reviewed the clinicopathologic features of sixteen cases diagnosed as sh including five cases with unusual presentations .
all sixteen cases of pulmonary sh diagnosed in the department of pathology , samsung medical center , seoul , korea , from 1996 to september , 2003 were retrieved ( table 1 ) .
hematoxylin and eosin - stained slides were reviewed to reconfirm the diagnosis and to find the multiple histologic features by two experienced pathologists .
immunohistochemical stainings were performed on paraffin - embedded tissue of all 16 cases using labeled streptavidin - biotin peroxidase technique .
the panel of antibodies included anti - thyroid transcription factor-1 ( ttf-1 ) ( 1:50 , dako , glostrup , denmark ) , anti - pancytokeratin ( ae1/3 , 1:80 , zymed , san francisco , ca , u.s.a . ) , anti - epithelial membrane antigen ( ema ) ( 1:50 , dako ) , antisynaptophysin ( 1:40 , dako ) , chromogranin ( 1:2,000 , dako ) , cd34 ( 1:100 , dako ) , cd56 ( 1:20 , monosan , uden , netherlands ) , smooth muscle actin ( sma ) ( 1:100 , dako ) , p53 protein ( bp 53.12 , 1:400 , zymed ) and ki-67 ( 1:100 , dako ) .
a case was regarded as positive for ttf-1 if more than 10% of the specific cell population showed nuclear staining .
the mean age of the patients ranged from 37 to 73 yr ( mean 50.6 yr ) . among the 16 cases , there was marked female predominance , with a female to male ratio of 15:1 .
one case of sh was located at the interlobar fissure of the lung , one was a visceral pleural - based pedunculated lesion and the rest were intraparenchymal lesion .
six tumors were located at the left lower lobe , four at the right middle lobe , three at right lower lobe , two at the left upper lobe , and one at the right upper lobe .
the size of sh ranged from 0.3 cm to 8 cm ( mean 2.6 cm ) in 17 masses out of 16 cases .
macroscopically , the tumors were rather well circumscribed and mostly pale yellowish and dark red in color if they were of hemangiomatous variety .
the major histologic patterns composed of a variable proportion of all four patterns in 9 out of 17 masses .
hemorrhagic pattern was observed in all except for the smallest one ( 0.3 cm ) .
all tumors composed of more than two histologic patterns and none demonstrated a single pattern ( table 1 ) .
the tumors were composed of varying proportions of two cell types , namely surface ' lining cells ' or ' cuboidal ' , and pale polygonal ' lesional cells ' or ' round cells ' .
these lining cells resembling type ii alveolar cells were most prominent in the areas with papillary pattern ( fig .
the round lesional cells were pale round cells showed uniform , medium - size polygonal nuclei with moderate amounts of pale , eosinophilic or clear cytoplasm .
mitotic figures were rarely seen in the cell population of the two cases . there were scattered alveolar macrophages , multinucleated giant cells , clumps of hemosiderin pigments , mast cells and eosinophils . occasionally psammoma bodies were seen in five cases , cholesterol clefts in three cases and intralesional adipose tissue in one case .
immunohistochemical study showed that both surface cells and round cells of sh were diffuse positive for ttf-1 in nucleus ( fig .
1f ) , and negative for synaptophysin , chromogranin , cd34 and sma in all cases . cd56
however , round cells rarely reacted with cytokeratin except one case that showed focal positivity for cytokeratin ( fig .
the index of positivity of p53 protein ranged from negative to 20% ( mean 6% ) and the ki-67 labeled proliferating index ranged from negative to 10% ( mean 4.5% ) .
we experienced five unusual presentations of sh including one case with two nodules ( 1.2 cm and 0.3 cm ) and multiple small atypical alveolar hyperplasia ( aah)-like nodules in background of the lung parenchyma .
one case showed papillary adenocarcinoma - like area , and one case with one sh having regional lymph node metastasis .
one case showed an alveolar adenoma - like area , and one case revealed a visceral pleural - based pedunculated mass that presented as a mediastinal mass clinically .
the first case is a 42-yr - old female patient who was found to have a right lower lobe mass on chest radiograph without subjective symptoms .
the size of the two tumors were 1.2 cm and 0.3 cm , respectively ( fig .
the first case of 1.2 cm sized nodule showed four histologic patterns of papillary , solid , sclerotic and hemorrhagic , and focal mild atypia .
the second case of the smaller nodule showed two histologic patterns of papillary and sclerotic .
we could also find twelve small - sized aah - like nodules with some papillae and micropapillae in background lung parenchyma of same lobe ( fig .
the histology was similar to that of alveolar adenoma or aah , but these had papillary or micropapillary structure and variably distributed irregular pattern .
the size of the small nodules ranged from 0.1 cm to 0.7 cm ( mean 0.35 cm ) .
immunohistochemically , the lining cells of the small nodular lesion reacted with ttf-1 and ema , and the interstitial stromal cells were focally positive for ttf-1 ( fig .
2d ) and ema . the second was a 37-yr - old female patient who presented with a 2 cm sized sh with one peribronchial regional lymph node metastasis ( nodal stage , n1 ) .
the metastatic tumor cells showed predominantly papillary structure lined by cuboidal cells and round cells ( fig .
the third case was a 36-yr - old female patient with a 3 cm sized tumor with alveolar adenoma - like area peripherally to the main mass .
the alveolar adenoma - like area continued to the main mass and had thin - walled multiple cystic spaces lined by low cuboidal cells , measuring 1 cm in length ( fig .
the fourth case was a 59-yr - old female patient who presented with a mediastinal mass .
chest computed tomography showed a large pleural based mass that was located adjacent to the right cardiac border . on gross examination , the mass measured 8 cm in the greatest diameter , and was in continuity with the right middle lobe of the lung .
the tumor displayed three major histologic patterns of sh ; predominantly hemorrhagic , solid and papillary .
the areas showing hemorrhagic pattern were composed of large blood - filled spaces lined by epithelial cells and were reminiscent of a cavernous hemangioma ( fig .
this case was proven as sh by gross examination , operative record , histologic features and immunohistochemical study .
the last case was a 43-yr - old female patient with one 1.3 cm sized tumor with an adenocarcinoma - like area , measuring 0.4 cm in the longest diameter ( fig .
the ki-67 labeled proliferating index and the index of p53 protein were 5% and 20% , respectively .
all 16 patients were alive and well without recurrence or metastasis during a follow - up period of 1 month to 6.8 yr ( mean 2.3 yr ) .
although sh originally termed a variant of hemangioma ( 1 ) , subsequent authors have suggested the origin of sh as mesenchymal ( 2 ) , mesothelial ( 3 ) and neuroendocrine ( 4 ) derivation .
now , there is a consensus that they originated from primitive epithelial cells ( 5 , 6 ) .
the epithelial origin of the tumor was also supported by ttf-1 and ema positivity in both the surface cells and round cells in the majority of the cases ( 6 , 9 ) .
ttf-1 is expressed in the thyroid , lung , and the diencephalons of the brain . in the lung
, it binds to the surfactant a , b , c and clara cell secretory protein genes .
it is expressed in the non - ciliated columnar cells of the fetal lung as early as 11 weeks of gestation , and in type ii pneumocytes and clara cells of the adult lung ( 10 , 11 ) .
the ttf-1 expression of both cells supported that both cells were derived from a primitive respiratory cell or may represent incompletely differentiated pneumocytes or clara cells ( 5 , 6 , 12 ) .
pancytokeratin ( ae1/3 ) usually reacts with surface cells , and not with round cells .
however , round cells rarely reacted with cytokeratin except one case that showed focal positivity for cytokeratin .
the immunohistochemical findings of the round cells were positive for ttf-1 and cytokeratin , suggesting that intermediate differentiation between differentiated epithelial cuboidal cells and undifferentiated round pale cells ( 5 , 6 ) .
although it is thought to be benign , rare cases apparently showed metastatic potential . in 1986 , tanaka and colleagues reported the first case of sh with lymph node metastasis ( 13 ) .
we found thirteen cases in nine previously reported literatures with metastasizing pulmonary sh ( table 3 ) ( 5 , 6 , 13 - 20 ) . including the current case
, there were seven cases of single lymph node metastasis and six cases of multiple ( > 2 ) lymph nodes metastases .
two cases of mediastinal ( nodal stage , n2 ) lymph node metastases were found ( 17 , 18 ) .
the primary tumor size ranged from 1.5 to 10 cm ( mean 4.7 cm ) .
we assumed that the primary tumor size and male ratio in the metastasizing pulmonary sh had increased as compared to the population with no lymph node metastasis , however we do not have statistical data . in the 9 cases ,
the mean time was 3.4 yr ( ranging from 1 to 10 yr ) ( table 3 ) .
the metastatic lymph node of the current case also showed both surface and round cells like that of previously described cases .
the prognosis did not appear to be affected by the presence of regional lymph node metastases .
a study using microdissection technique demonstrated that both surface cells and round cells of sh showed similar clonality and represented a variable differentiation from a common progenitor cell ( 21 ) .
a few series have described multiple sh ( 6 , 14 , 22 - 29 ) and the incidence was 4 - 5% ( 6 , 24 , 26 , 28 ) .
to our knowledge , two cases of bilateral multiple sh were described in the english - language literature ( 27 , 29 ) .
the cases of aah in continuity with multiple sh ( 25 ) , alveolar adenoma with sh ( 17 ) , and transition from atypical hyperplasia of type ii pneumocyte to sh ( 29 ) have been described .
the reports suggested that aah of type ii pneumocytes could be a focus of atypical growth of lining epithelial cells of sh . in our series
, there was one case of alveolar adenoma - like area in the peripheral portion of the sh .
another case with two sh had a background of multiple aah with papillae in the right lower lobe .
we could not verify whether this case indicated multicentric origin of the sh or intrapulmonary metastasis , or incidental findings .
even if the aah - like lesion with papillae is presumptive precursor lesion of sh , there are limitations for the postulation so far .
a longer follow - up data , ample cases , and further studies are needed to support that .
the sh could be presented clinically with mediastinal mass , and be located at the interlobar fissure ( 6 , 30 ) .
sakamoto et al . ( 31 ) reported a case of sh isolated in the mediastinum , and suggested the hypothesis of three mechanism that may account for the development of mediastinal sh .
the second mechanism was that the tumor could have originated from ectopic lung tissues , such as bronchogenic cysts .
the final mechanism was that the sh developed from the lung as a pedunculated pleural mass that slowly pulled away from the lung surface .
all three of these potential mechanisms are plausible ; however , the first mechanism was against findings that all previously reported cases of lymph node metastasis from sh had evidence of primary tumor . a case report of sh arising in the extrapulmonary sequestration was described in the english literature and may support the second mechanism ( 32 ) . in the cases that presented as a pleural based or mediastinal mass ,
however , after careful review of the operative findings , chest radiographs , and histologic findings , it was apparent that these lesions arose from the periphery of the lung and protruded from the visceral pleural surface , giving the initial impression of an extrapulmonary origin ( 6 , 33 ) .
our current case which presented mediastinal mass also revealed a pulmonary origin after check of additional gross examination , operative findings , and compatible immunohistochemical studies .
( 28 ) and aihara and nakajima ( 34 ) studied both estrogen receptors ( er ) and progesterone receptors ( pr ) immunohistochemically .
they reported that most patients were positive for both er and pr , suggesting a relationship between this tumor and female sex hormones .
one case showed a focus of papillary adenocarcinoma - like area within the sh , measuring 0.4 cm in the longest diameter , and mitotic figure was not absent .
the diagnoses included insufficient specimen in four , malignancy versus sh in two and suspicion of adenocarcinoma in four .
the severe cytologic atypia made it difficult to make a diagnosis of sh in aspiration cytology .
the above findings ; lymph node metastasis , severe atypia , and multifocal distribution , may suggest that sh is a low grade malignancy . however , sh is a clinically benign tumor and has a good prognosis .
all our current cases showed no recurrent or metastasis after excision , and the patients all are alive and well at present . in conclusion , sh may show hilar or mediastinal lymph nodes metastases , cytologically severe atypia , and multicentricity .
complete excision of lesion is a curable treatment method and leads to an excellent prognosis .
further studies on many cases of sh are necessary to elucidate the mechanism of metastasis , multiplicity , and extrapulmonary manifestation .
 sclerosing hemangiomas ( sh ) of the lung are uncommon tumors and are thought to be benign . 
 however , the biologic behavior of this tumor has not yet been characterized adequately . 
 the clinicopathologic features were reviewed and analyzed for 16 cases of sh . 
 the age of the patients ranged from 37 to 73 yr ( mean 50.6 yr ) . 
 there were fifteen female and one male patient . 
 the sh located at the intraparenchyme in 14 cases , the interlobar fissure in one case and the visceral pleura in one case . 
 the size of sh ranged from 0.3 cm to 8 cm ( mean 2.6 cm ) . 
 there were five unusual presentations of sh including a case having two sh with multiple nodules of atypical adenomatous hyperplasia in the same lobe , a case showing adenocarcinoma - like area within the sh , a case showing one peribronchial lymph node metastasis ( n1 nodal stage ) with location of interlobar major fissure , a case showing alveolar adenoma - like area within the sh , and one case with a large visceral pleural - based pedunculated mass presenting as mediastinal mass . 
 all patients were alive and well without recurrence at the last follow up . here , 
 we reviewed previously published literatures and discussed the histogenesis of sh . 
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION