Primary vascular tumors of the lung are rare and represent a small percentage of primary lung neoplasms. They may be benign or malignant; however, no association with any specific factors has been found. Vascular tumors can be classified as follows:
Benign Vascular Tumors
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Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma)
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Capillary hemangiomatosis
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Hemangioma
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Lymphangioma
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Malignant Vascular Tumors
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Angiosarcoma
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Epithelioid hemangioendothelioma
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Kaposi sarcoma
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The most important clinical and immunohistochemical features are summarized in Table 8-1 .
| Tumor | Presentation | Histopathologic Features | Positive Immunohistochemical Staining |
|---|---|---|---|
| Angiolymphoid hyperplasia with eosinophilia | Tumor nodule | Eosinophils, lymphoid hyperplasia, endothelial hyperplasia | CD31, CD34, factor VIII |
| Hemangioma | Tumor nodule | Capillary, cavernous Lack of atypia or mitosis | CD31, CD34, factor VIII |
| Capillary hemangiomatosis | Diffuse | Widespread presence of small interstitial capillaries containing red cells | CD31, CD34, factor VIII |
| Lymphangioma | Tumor nodule, diffuse | Abnormal proliferation and dilatation of pulmonary lymphatics | CD31, CD34 (weak), D2-40 in lymphatics |
| Angiosarcoma | Multiple nodules | Cellular atypia, mitosis, necrosis/hemorrhage | CD31, CD34, factor VIII |
| Epithelioid hemangioendothelioma | Multiple nodules | Nodules in different stages of development—sclerotic, myxoid Calcified Rarely, mitotic figures | CD31, CD34, factor VIII |
| Kaposi sarcoma | Multiple nodules | Spindle cells with vascular slits; hyaline droplets, mitotic figures | CD31, CD34 |
ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA
Angiolymphoid hyperplasia with eosinophilia (ALHE), or epithelioid hemangioma, is an unusual lesion that has only recently been described as a primary pulmonary tumor. Before this designation, considerable controversy had existed regarding the classification of similar lesions described by other names—for example, Kimura’s disease, epithelioid hemangioma, angioreticuloma of the heart, atypical vascular proliferation of large vessels, and hemangioendothelioma of bone. Some researchers have attempted to unify these terms under a single clinicopathologic entity ; for the most part, however, such attempts have failed, and currently it is accepted that Kimura’s disease and ALHE represent two different conditions. Nevertheless, an important point is that regardless of their specific name, both of these conditions primarily affect anatomic sites other than the lung, including subcutaneous tissue, salivary glands, the orbit, and lymph nodes. Both conditions also have an unknown etiology, and thus far, not a single case of aggressive behavior has been reported for either lesion. Thus, ALHE in the lung is likely to follow a clinical course similar to that observed for benign lesions reported outside of the thoracic cavity.
Clinical Features
The only two reported cases of pulmonary ALHE were in a man and a woman 27 and 60 years of age, respectively. A history of asthma and a pulmonary mass was recorded for one patient; the second patient presented with a history of cough and dyspnea and radiographic evidence of a pulmonary mass. Neither patient had any evidence of nodal or soft tissue disease.
Macroscopic Features
Both patients underwent resection of the pulmonary mass. The tumors were well circumscribed but not encapsulated, of soft consistency, grayish, and the cut surface is partly cystic. Tumor size ranged from 2 to 3 cm in greatest dimension. Hemorrhage and necrosis were not described in either lesion.
Histopathologic Features
At low magnification, the ALHE process was seen as a well-circumscribed tumor replacing normal lung parenchyma with extensive areas of eosinophilic infiltrate, medium-sized vessel proliferation, and aggregates of lymphoid nodules ( Figs. 8-1 to 8-3 ). Higher magnification revealed a proliferation of small-caliber vessels with hyperplastic endothelial lining and extensive deposition of eosinophils ( Figs. 8-4 and 8-5 ). In some areas the process involved larger-caliber vessels ( Fig. 8-6 ), and more discrete involvement of the airway was seen ( Fig. 8-7 ). The epithelioid component showed medium-sized cells with large nuclei and eosinophilic cytoplasm. Some cells displayed prominent cytoplasmic vacuoles. In focal areas, the alveoli were filled with eosinophils, mimicking the histologic picture in an eosinophilic pneumonia ( Fig. 8-8 ).
Immunohistochemical Features
Although the identification of the two reported cases of ALHE was accomplished using hematoxylin-eosin–stained sections, immunohistochemical studies may help in distinguishing ALHE from other, more common pulmonary conditions that may behave more aggressively. CD31, CD34, and factor VIII will help in identifying vessels; lymphoid markers, including leukocyte common antigen (LCA) and B and T cell markers such as L-26 and UCHL-1, may show the dual lymphoid population of these lesions. Keratin antibodies also may stain entrapped alveolar tissue.
Differential Diagnosis
Several conditions should be considered in the differential diagnosis for ALHE, ranging from benign inflammatory and infectious diseases to malignant lymphoproliferative disorders. Eosinophilic pneumonia may be confused with ALHE in small biopsy specimens, owing to the extensive presence of eosinophils; however, the clinical finding of a pulmonary nodule or mass would be unusual for eosinophilic pneumonia, which is a more diffuse process. Infectious conditions caused by parasites or fungal organisms may be associated with similar findings of a pulmonary mass with eosinophilia; in such cases, however, the identification of the causative organisms by light microscopy or tissue cultures will lead to the correct interpretation. Because of the presence of the lymphocytic component, ALHE also may be confused with a low-grade lymphoma, which can manifest as a pulmonary mass. In cases of pulmonary lymphoma, however, the lymphocytic proliferation will show clonality on immunohistochemical studies, rather than the polymorphous component of ALHE.
Treatment and Prognosis
Surgical resection is the treatment of choice and is curative in these lesions. The behavior of similar lesions outside of the thoracic cavity has been described as benign.
CAPILLARY HEMANGIOMATOSIS
Capillary hemangiomatosis is a rare vascular lesion characterized by proliferation of capillary channels. The lesion appears to occur at any age, without any gender predilection, and in many instances it is diagnosed at autopsy after the patient has died from the disease.
Historical Aspects
The first description of this lesion was made by “Wagenvoort” and colleagues, who in 1978 described a 71-year-old woman who presented with a 3-week history of respiratory infection and dyspnea. Over a period of 5 months, the patient’s clinical condition deteriorated, eventuating in death. Autopsy findings included the presence of heavy and firm lungs with a nodular cut surface. On histologic examination, atypical capillary-like channels were seen to be distributed in the fibrous septa and interstitium, around the bronchi, and in the pulmonary blood vessels, particularly the veins. The patient also had a cavernous-type hemangioma in the spleen that did not resemble the lesion in the lungs. Almost simultaneously, Rowen and associates described three children between the ages of 4 and 7 years in whom autopsy revealed the presence of what was described as “pulmonary hemangiomatosis.” These investigators concluded that the presence of a combination of diffuse interstitial infiltration and bloody pleural effusion in a child is pathognomonic for capillary hemangiomatosis. Histologic features include cavernous-type and capillary changes. Although in most cases the diagnosis of capillary hemangiomatosis has been made at autopsy, Wagenaar and coworkers described the case of a 12-year-old girl in whom recurrent severe hemoptysis required a left pneumonectomy. The histopathologic findings indicated capillary hemangiomatosis. Of interest, the clinical picture was favorable at the 36-month follow-up evaluation, suggesting that if the diagnosis of pulmonary capillary hemangiomatosis is made early, aggressive treatment may prevent a fatal outcome.
Clinical Features
Capillary hemangiomatosis can affect children and adults of all ages, without predilection for either gender. Most cases, however, are diagnosed during the third and fourth decades of life. Langleben and colleagues described capillary hemangiomatosis in three siblings who had died of pulmonary hypertension. The investigators concluded that capillary hemangiomatosis may have an autosomal recessive inheritance pattern. Similarly, Oviedo and coworkers described two cases of congenital pulmonary capillary hemangiomatosis in which the affected neonates had other anomalies, including renal and bladder agenesis and hypertrophic cardiomyopathy. Although pulmonary hypertension is a common clinical finding in pulmonary capillary hemangiomatosis regardless of the age of the patient, other findings may suggest different entities, such as interstitial lung disease.
Clinical signs and symptoms of capillary hemangiomatosis may include cough, hemoptysis, respiratory distress, and chest pain. More recently, Havlik and associates retrospectively studied autopsy findings in a series of 140 patients and noted the presence of pulmonary capillary hemangiomatosis–like foci in approximately 5.7% of the cases. These workers concluded that these findings were incidental, and because none of the patients had a known history of pulmonary hypertension, the hemangiomatosis-like foci were not thought to contribute to the clinical outcome. In some unusual cases, capillary hemangiomatosis may arise in patients with hereditary hemorrhagic telangiectasia.
Macroscopic Features
Two patterns are recognized by which capillary hemangiomatosis may compromise the lung parenchyma. The diffuse pattern is characterized by a congested lung parenchyma with areas of consolidation and multicystic sponge-like areas, which may be more conspicuous in the lower lobes ( Fig. 8-9 ). In other cases, the cut surface of the lung parenchyma has been described as liver-like. The multifocal pattern is characterized by multiple, patchy, reddish-brown and white areas of consolidation. The lung parenchyma can be affected in differing proportions; reported cases have ranged from 10% involvement to extensive diffuse involvement with the entire lung parenchyma described as deeply congested ( Figs. 8-10 to 8-12 ).
Microscopic Features
The histopathologic features of capillary hemangiomatosis echo the gross appearance in terms of pulmonary involvement, which can be diffuse or patchy and may be characterized by expansion of the pulmonary congestion into the interstitium. Higher magnification reveals a proliferation of small capillaries distributed along the interstitium and infiltrating into the bronchovascular bundle. The capillary proliferation does not display cytologic atypia, although mitotic figures may be seen occasionally. It may extend transmurally into larger vessels and bronchi, resulting in the narrowing of their lumens. Adjacent pulmonary vasculature also may show features of hypertrophy. One of the most reliable histologic features of capillary hemangiomatosis is the presence of double capillaries (or more) along both sides of the alveolar wall. In advanced cases, however, extensive sheets or nodules of capillaries may be seen.
Differential Diagnosis
In small transbronchial biopsy specimens, an accurate diagnosis of capillary hemangiomatosis may prove difficult to obtain, because the lung parenchyma may not be represented. An open lung biopsy may be necessary; however, the benefits of this procedure must be weighed against the possible complications, including hemorrhage. When the histologic findings include pools of blood and areas of fibrosis, capillary hemangiomatosis may be mistaken for conventional cavernous hemangioma. Pulmonary interstitial disease should be considered in cases in which the lung parenchyma shows an inflammatory infiltrate without the capillary proliferation. Pulmonary veno-occlusive disease also may be considered in the differential diagnosis. Both capillary hemangiomatosis and veno-occlusive disease display extensive vascular obstruction; in capillary hemangiomatosis, however, the process originates from the capillaries, whereas in veno-occlusive disease the process originates from pulmonary venules and small veins. Some researchers have suggested that capillary hemangiomatosis may be an angioproliferative process secondary to postcapillary obstruction, rather than a separate disease.
Treatment and Prognosis
The treatment of capillary hemangiomatosis is surgical resection of affected lung tissue; however, this may prove to be a radical procedure owing to the extensive nature of the process in the lung parenchyma. Because patients often present with pulmonary hypertension and severe hemoptysis, the outcome may be fatal if the condition is not diagnosed and treated promptly. Successful treatment with pneumonectomy has been reported. In addition, some success with treatment with recombinant interferon alfa-2a has been documented.
HEMANGIOMA
Primary pulmonary hemangiomas are exceedingly rare benign vascular tumors. They have been described in both pediatric and adult patients, without any predilection for either gender or for any specific anatomic area.
Patients may present with a variety of nonspecific clinical signs and symptoms, including fever and pneumonia. More specific manifestations related to the location of the tumor have included hemoptysis, dyspnea, and hemopneumothorax. A case of pulmonary hemangioma in a child with partial trisomy D has been reported. The initial radiologic evaluation may reveal a solitary pulmonary mass or multiple pulmonary nodules. A case of giant cell hemangioma and a case of concurrent hemangiomas of the liver and lung have been described.
Macroscopic Features
As noted, hemangiomas may manifest either as a single intrapulmonary mass or as multiple pulmonary nodules. The tumor may range in size from 1 cm to greater than 3 cm in greatest dimension and often appears as a cystic mass with a glistening surface. On examination of the cut surface, thin-walled cysts of different sizes, which are filled with blood, may be observed ( Fig. 8-13 ). In some cases the tumor may appear to be encapsulated, and less frequently, it has been reported to manifest as a pseudocyst. Hemangioma also may manifest as a bronchial tumor, and in unusual cases it may grow in a polypoid fashion.
Microscopic Features
Pulmonary hemangiomas are histologically similar to those arising in more common locations, such as the skin or superficial soft tissues, and like other hemangiomas, they occur in two histologic patterns, cavernous and capillary. Cavernous hemangiomas are characterized by dilated, cyst-like structures filled with blood, thin walls, and adjacent inflammatory reaction in a background of fibroconnective tissue, which can display thickened, dilated vasculature ( Figs. 8-14 and 8-15 ). The cellular proliferation does not show cytologic atypia, although mitotic figures rarely may be present. Capillary hemangiomas ( Figs. 8-16 and 8-17 ) are characterized by the proliferation of small-caliber vessels with little intervening stromal reaction. The vessels may show hyperplastic changes, and occasionally, mitotic figures may be observed. When the tumor grows in a polypoid fashion in the bronchial wall, the surface may show inflammatory changes similar to those described in pyogenic granulomas of the skin. In both histologic patterns, the tumor replaces normal lung parenchyma.
The correct diagnosis can be made without the use of immunohistochemical stains. However, hemangiomas demonstrate positive staining for vascular markers such as factor VIII, CD34, and CD31 in the vascular proliferation.
Differential Diagnosis
The diagnosis of pulmonary hemangioma is rather straightforward. However, in areas in which a cavernous hemangioma shows dilated vascular spaces filled with blood, the tumor may resemble the so-called sclerosing hemangioma (pneumocytoma). In this setting, the positive staining for vascular markers will lead to the correct interpretation, because negative staining for those markers is characteristic of sclerosing hemangiomas. One possible consideration in the differential diagnosis for capillary hemangioma is angiolymphoid hyperplasia with eosinophilia. However, this clinical entity is characterized by the presence of lymphoid hyperplasia and eosinophilia, which generally are absent in capillary hemangioma.
Prognosis and Treatment
Hemangiomas are benign tumors that are cured by complete surgical resection, which can be accomplished by lobectomy, wedge resection, or sleeve resection. When the tumors are multiple, the procedure may be more extensive.
LYMPHANGIOMA
By definition, pulmonary lymphangioma is the abnormal proliferation of lymphatics within pulmonary parenchyma. This process may be the result of congenital errors of lymphatic development, which can lead to several conditions that have been described by various names in the literature. Thus, it is important to distinguish among the many conditions that may be related to lymphatic abnormalities, including lymphangiomas, lymphangiectasis, lymphangiomatosis, lymphatic dysplasia syndrome, lymphangioleiomyomatosis, hemangiolymphangioma, generalized lymphangiomatosis, and diffuse pulmonary lymphangiomatosis. Because of the diverse nature of these conditions, proper correlation of clinical findings and histopathologic findings is imperative. For this reason, Faul and associates have argued that the classification of lymphatic disorders should be based on both clinical and histopathologic criteria. Some of these conditions, although of lymphatic origin, may follow a clinical course that ranges from very benign to more aggressive. Some conditions, such as lymphangiectasis, may affect primarily neonates, wherease others, including lymphangioleiomyomatosis, are more common in young female patients. Still other conditions, such as lymphatic dysplasia syndrome, may constitute entirely different clinicopathologic entities. Some of these conditions may affect other extrathoracic areas, in addition to the lung parenchyma. The focus here is on the benign tumoral condition referred to as lymphangioma , although this particular tumor also has been referred to as “lymphangiomyoma” in the literature. Also, some of the previously reported cases of lymphangiomyoma or lymphangioma may represent different conditions, such as lymphangioleiomyomatosis or alveolar adenoma.
Two different patterns of lung parenchyma involvement have been described: solitary pulmonary mass and diffuse pulmonary involvement. Lymphangiomas may involve other mediastinal structures, including the pericardium, in addition to the lung and pleura. Tazeelar and colleagues coined the term diffuse pulmonary lymphangiomatosis in their description of nine cases, including those in children and young adults. Clinical signs and symptoms reported in these patients varied and included cough, shortness of breath, asthma, chylous effusions, and evidence of restriction on pulmonary function tests. The investigators determined that this condition was a separate entity from previously described lymphatic lesions. In seven of the patients, however, the process was not limited to the lung but also involved the mediastinum. Therefore, when the process is more diffuse in the lung parenchyma, it also is highly likely to extend outside the lung, or even outside the thoracic cavity. Nevertheless, these workers clearly defined lymphangiomatosis as a process in which the number of complex anastomosing lymphatic channels is increased, in contrast with lymphangiectasis , in which the existing lymphatic channels are dilated.
When the process involves a solitary lung mass, some patients may be asymptomatic, whereas others experience symptoms of lung obstruction. Both presentations have been described in both male and female patients and in children as well as in adults.
Macroscopic Features
The solitary lesion is characterized by a tumor mass that destroys lung parenchyma and may be as large as 10 cm in greatest dimension. The gross tumor has a glistening surface, but the cut surface reveals a cystic configuration. The cystic structures may contain yellowish or serosanguineous fluid. When the process is diffuse, the lung parenchyma may have a honeycomb appearance.
Microscopic Features
Under low magnification, the solitary mass does not appear to be a well-defined process replacing the lung parenchyma but rather is seen as a proliferation of ectatic lymphatic channels, of differing sizes, that merge with the normal alveolar parenchyma. Higher-power examination of these lymphatic channels reveals an endothelial lining that does not exhibit cellular atypia or mitotic activity ( Figs. 8-18 to 8-21 ). Acellular fluid, without blood, is present within the lumens of the lymphatic channels. However, when the tumor also displays a component of hemangioma (hemangiolymphangioma), some of the lumens may contain hemorrhagic fluid. When the process is more diffuse, it replaces extensive areas of normal alveolar lung parenchyma, displaying many cystically dilated spaces and taking on a honeycomb- or sponge-like appearance. In both presentations, it is possible to identify a smooth muscle component of variable proportion relative to overall composition. Adjacent lung parenchyma may show iron-filled or foamy macrophages, with little inflammatory reaction of the interstitium ( Figs. 8-22 to 8-24 ). Areas of frank hemorrhage and necrosis are not common in lymphangiomas.
Immunohistochemical Features
Immunohistochemical studies may be useful in cases in which the diagnosis is not readily apparent. Staining for CD34, CD31, and factor VIII may give a weakly positive reaction in the endothelial lining. More recently, some investigators have claimed that D2-40 is a reliable marker for lymphoendothelium. Lymphangiomas also may show positive staining for smooth muscle actin and desmin in the smooth muscle component. A majority of cases show negative staining for HMB-45 and estrogen and progesterone receptors, with only a single reported case documenting progesterone receptor positivity.
Differential Diagnosis
Although the diagnosis of lymphangioma does not usually pose a problem, some conditions warrant specific consideration in the differential diagnosis. For a solitary lung mass, the so-called alveolar adenoma and hemangioma may be considered. Alveolar adenomas should not demonstrate positive staining with vascular markers, whereas hemangioma should display abundant blood in the vascular lumens. When the process is diffuse, the most important differential diagnostic consideration is lymphangioleiomyomatosis. In this setting, clinical information (occurrence in a young female patient), findings on immunohistochemical studies (HMB-45 positivity), and the histologic distribution (diffuse) of the process are important clues to an accurate diagnosis.
Prognosis and Treatment
The treatment of choice for lymphangioma is surgical resection of the tumor. This procedure may range in extent from a wedge resection to a pneumonectomy, according to the particular circumstances. Although the prognosis with localized lymphangioma is good, a diffuse process involving mediastinal areas may be more difficult to manage.
ANGIOSARCOMA
Primary angiosarcomas of the lung are exceedingly rare. In a study of rare pulmonary tumors of the lung at a major institution in the years 1980 to 1990, Miller and Allen encountered only 2 cases in a series of more than 10,000 pulmonary tumors and estimated the occurrence of this malignancy to be approximately 0.02%. Differentiation of primary from metastatic angiosarcoma in the lung can be quite difficult, however, because the clinical, radiologic, and histopathologic features of each are similar. In a study by Pate and Ryu of 15 patients with angiosarcoma of the lung, all of the patients were diagnosed with metastatic disease to the lung, and in 12 of these cases the diagnosis was made ante mortem. The most common radiographic feature was presence of multiple pulmonary nodules; the most common clinical manifestation was hemoptysis. The designation of some cases as primary pulmonary tumors has been debated, either because they did not display all of the histopathologic features of angiosarcoma or because available clinical information was inadequate to rule out a possible extrapulmonary origin. Nevertheless, some well-documented cases of primary angiosarcomas of the lung have been reported, and in other instances the diagnosis has been made with confidence because no other site of malignancy was encountered.
In cases reported as primary angiosarcoma of the lung, clinical presentation has varied, with tumors occurring in both young and older adults. In many instances, multiple bilateral pulmonary nodules are evident on radiographic examination, making the distinction from metastatic disease an impossible task. A history of environmental exposure, irradiation, or farming has been reported in some patients; presenting clinical signs and symptoms may include shortness of breath, hemoptysis, or frank pulmonary hemorrhage. In some unusual cases, the pulmonary angiosarcoma has been associated with other malignancies of different histologic type. Complete physical and radiologic evaluation will be required to determine the primary site, owing to the difficulty in distinguishing primary from metastatic angiosarcoma.
Macroscopic Features
Although a majority of cases will manifest with multiple pulmonary nodules of various sizes distributed haphazardly throughout the lung parenchyma, presentation as a single pulmonary mass has been reported ( Fig. 8-25 ). The tumors appear hemorrhagic and ill-defined, and can reach more than 5 cm in greatest dimension.
