| | Splenic vascular tumorsAbstract Splenic vascular tumors are uncommon and are more typically encountered as benign incidental findings. By contrast, splenic angiosarcoma may present acutely and dramatically and typically pursues a very aggressive clinical course. Vascular tumors in the spleen may show conventional endothelial, specialized endothelial (sinusoidal/littoral cell) or lymphatic differentiation and there is morphologic overlap between some of the currently defined diagnostic categories, within which benign, intermediate, and malignant subsets are recognized. The greatest problem in trying to better define and analyze these tumors is the availability of only relatively small case numbers. This overview describes the diagnosis and differential diagnosis of splenic vascular tumors as presently understood.
PRIMARY SPLENIC vascular neoplasms are uncommonly encountered in the practice of general surgical pathology. Pathophysiologic vascular changes secondary to systemic disorders are far more frequently observed in splenectomy specimens than true neoplasms. The benign or malignant vascular tumors of the spleen appear to be derived from lining cells of the specialized components of the splenic vasculature, ie, the arterial and venous system, the lymphatics or, most commonly, the sinuses. The combined morphologic and immunohistochemical analysis of these lesions has identified the features that distinguish the majority of these lesions and has provided some insight into their histogenesis. However, little understanding of the mechanisms through which these rare tumors arise is currently available. This overview discusses the major benign and malignant vascular tumors of the spleen and emphasizes recent studies that have aided in their classification and distinction from non-neoplastic cystic lesions of the spleen.
Benign vascular tumors  Hemangioma Splenic hemangioma remains the most common benign neoplasm of the spleen, although these are infrequent lesions, with larger autopsy series reporting the incidence at 0.02% to 0.16%.1 Hemangiomas of the spleen are incidental surgical, radiologic, or autopsy findings in the vast majority of cases.1, 2, 3, 4 Arber et al3 reported that 7 of 7 localized splenic hemangiomas were discovered incidentally in surgical patients, and Willcox et al2 found 80% of the splenic hemangiomas in their series were present in asymptomatic patients and identified during evaluation for other disorders (11 discovered radiologically and the remaining 21 during surgical procedures). Much less commonly, symptoms or physical signs directly related to the presence of a splenic hemangioma are present. In the larger series, of 32 total patients only 6 presented with abdominal symptoms and of these patients only 4 had a palpable spleen.2 Because of the general absence of presenting symptoms and the typically incidental nature of these hemangiomas, it is not surprising that significant variability in the age of presentation exists in the literature. Several nonautopsy, surgical series reveal an average age of detection/presentation of between 51 to 63 years.2, 3 However, examination of autopsy data reveals a much younger average patient age (42 years, including a 4-month-old infant) (reviewed in ref 1) indicating that these benign lesions are likely to be present but undetected for long periods of time. A gender or race predilection has not been reported for this entity. Although benign, splenic hemangiomas are not entirely without complications as larger lesions may rupture with resulting intra-abdominal hemorrhage.1, 5, 6, 7, 8 Splenic hemangiomas are typically solitary lesions; however, careful inspection can reveal multiple lesions in a significant percentage of cases.1, 2 As may be expected, the size of these lesions varies greatly between those removed because of symptoms and those found incidentally at surgery or autopsy. Pines and Rabinovitch1 reported that, in their autopsy group, the spleen was of relatively normal size and the hemangiomas varied in size from 1 mm to 4.5 cm. In contrast, in the surgical group, spleen weights were often greatly increased (415–7240g) and the hemangiomas typically presented as a single large growth involving the entire or the major portion of the organ (up to 36 cm in some cases). Willcox et al2 found that in 11 patients with hemangiomas detected incidentally by computed tomography or ultrasound, all lesions were ≤4 cm. In addition, a report of 7 incidental hemangiomas found lesions that ranged in size from 1.0 to 3.5 cm with spleen weights from between 125 to 435 g.3 Hemangiomas typically appear as circumscribed nonencapsulated, honeycomb-like, red-purple masses that frequently blend imperceptibly into the surrounding splenic parenchyma. The spaces are composed of sponge-like tissue filled with dark red-blood and are often separated by fibrous septa. Thrombosis and infarction occur in many cases, presumably because of abnormalities in the vascular supply of the tumor. When completely organized, infarcted hemangiomas may resemble a “fibroma” or a healed, simple infarct of the spleen. Occasional calcification may be seen, often in association with an organized infarct.9, 10 In addition, cystic changes can occur secondary to either 1) liquefaction of a hemorrhagic or infarcted area, 2) isolation of a dilated sinus from the vasculature, or 3) the formation of a cyst in the surrounding splenic parenchyma with subsequent involvement of the hemangioma.1 Microscopically, the majority of hemangiomas are cavernous in nature, consisting of large interconnected, dilated, blood-filled spaces lined by a monolayer of cytologically bland endothelial cells separated by thin fibrous septa or splenic pulp tissue (Fig 1). Pure capillary architecture is less common, with, instead, many lesions containing varying proportions of both cavernous and capillary components. The cells of normal red pulp sinusoids are unique to the spleen, showing biphenotypic immunoreactivity for vascular and histiocytic markers. These cells express endothelial cell markers CD31 and von Willebrand factor, monocytic markers CD68 and lysozyme, but do not express the vascular marker CD34.11 In contrast to sinusoidal lining cells, endothelial cells of small vessels in the spleen are consistently positive for CD34. In addition, staining for CD8 provides evidence for the presence of normal subsets of splenic red pulp lining cells.12 These subsets include cells that express lysozyme and CD8, with a separate population that are positive for CD68 and lysozyme, but negative for CD8. Immunophenotypically, splenic hemangiomas show reactivity of the endothelial lining cells for the vascular markers CD31, von Willebrand factor, Ulex europeaus lectin I, and CD34.3, 11 These cells variably express the histiocytic marker CD68, are negative for CD21, and only very rarely CD8 positive. This immunophenotypic pattern, which includes CD34 immunoreactivity, raises the possibility that splenic hemangiomas may derive from (or differentiate towards) a combination of splenic venous structures, as well as, splenic sinusoidal cells. The use of CD8 and CD21 antibodies may help to differentiate the lining cells in hemangiomas (CD8−, CD21−) from the endothelial cells present in littoral cell angiomas (CD21+, CD8−)and splenic hamartomas (CD21−, CD8+).3, 11, 13 Hamartomas are also distinguished from hemangiomas by their usually more poorly defined margins. Diffuse hemangiomatosis of the spleen is a very rare variant of splenic hemangioma in which the spleen is diffusely replaced by blood vessels of varying caliber.1, 3, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 Typically, these lesions are associated with generalized angiomatosis of other hematopoietic organs including the bone marrow and liver, and less commonly the skin. In addition, hematologic abnormalities including anemia, thrombocytopenia, and severe coagulopathies, such as microangiopathic hemolytic anemia, frequently accompany these lesions.3, 14, 16, 19, 20 An immunophenotypic study of 3 diffuse hemangiomas of the spleen showed somewhat stronger CD68 positivity than localized hemangiomas3 and revealed a phenotype somewhat similar to that seen in littoral cell angiomas. However, in contrast to littoral cell angiomas, the diffuse hemangiomas were CD21 negative. In addition, none of these cases had the morphologic or cytologic features of littoral cell angiomas. In contrast, Ruck et al18 described 1 case of diffuse hemangioma with a unique immunophenotype, in which the vascular lining cells focally expressed CD8 and were negative for CD68, a pattern more reminiscent of splenic hamartoma. Lymphangioma Lymphangioma of the spleen is even less common than hemangioma of the spleen, with clinical manifestations ranging from insignificant incidental findings24, 25 to large, symptomatic multicystic splenic masses requiring surgical intervention.25, 26, 27, 28, 29, 30, 31, 32 Most often, the latter examples are seen in conjunction with an associated childhood syndrome, disseminated lymphangiomatosis, in which the lymphangiomatous process diffusely involves other sites or organs, such as the bone, soft tissue, or viscera.24, 33, 34, 35, 36, 37, 38, 39 Splenic lymphangiomas are usually small multicystic, subcapsular proliferations that are difficult to grossly distinguish from either hemangiomas40 or mesothelial cysts.41 In fact, many mesothelial cysts in the past were mistakenly diagnosed as lymphangioma.41 Careful immunophenotypic analysis of these lesions showed evidence of mesothelial (keratin and the mesothelial cell marker, HBME-1 positive) rather than lymphatic (uniformly negative for the vascular markers Factor VIII-related antigen, CD31, and CD34) origin of the cystic lining cells.41 True lymphangioma of the spleen can be microcystic or solid and may show central fibrous scarring.36 Unlike splenic hemangiomas, which typically show random localization in the spleen, splenic lymphangiomas are frequently subcapsular or trabecular in location, regions where splenic lymphatics are normally situated.42 Histologically, the spaces are thin-walled cystic structures of varying size lined by predominantly flat, bland appearing endothelium and filled with a pink, watery proteinaceous material devoid of red blood cells (Fig 2A). Foamy macrophages and occasionally cholesterol clefts can be seen within the cyst contents lines the cavities. However, with careful inspection, foci of plump lining cells, often forming striking papillary projections, are typically seen32, 33, 42 (Fig 2B). Caution should be exercised in distinguishing these papillary areas from angiosarcoma. Their frequent occurrence in lymphangioma and the bland cytologic features of the lining cells indicate that these regions represent a morphologic variant of the benign endothelial lining. Extensive splenic involvement by fatal, frankly malignant vascular neoplasms with features often associated with lymphangioma can rarely be seen.11 These features include eosinophilic protein—rich fluid filled spaces lined by malignant cells, numerous papillary structures, and focal lymphoid infiltrate. Definitive distinction between lymphangiosarcoma and angiosarcoma is currently not possible; therefore cases such as these are best classified as angiosarcoma. Immunophenotypically, the lining cells of splenic lymphangiomas express markers typical of lymphatic endothelium including CD31, CD34, Ulex europeaus Lectin I and von Willebrand Factor (Factor VIII-related antigen)11, 33, 43 (Figs 2C and D). These cells are negative for CD8, occasionally faintly positive for CD68 and rarely reactive for lysozyme.11 Littoral cell angioma Littoral cell angioma (LCA) of the spleen is a vascular tumor that represents a lesion unique to the spleen, without a soft tissue counterpart.44 Unlike splenic hemangiomas, which probably, in part, recapitulate splenic blood vessels such as veins, LCAs are believed to derive from (or differentiate towards) the lining cells of the splenic red pulp sinuses, which normally demonstrate both endothelial and histiocyte/macrophage appearances and properties.45 These combined features may be caused by an altered functional state of the sinus endothelium, which under certain physiologic or pathologic conditions may show phagocytosis, particularly those requiring increased phagocytic function (eg, hemolytic anemias).46 Clinically, these lesions can occur in all age groups without sex predilection, but most commonly present in middle age.3, 44 LCAs are typically identified in patients undergoing splenectomy for splenomegaly of unknown origin44 or radiographically during workup for other abdominal processes.47, 48, 49 Like splenic hemangiomas, LCAs may also be associated with splenomegaly leading to thrombocytopenia or anemia.3, 44, 50 Some patients with LCA may have fevers, which resolve after splenectomy.44 Interestingly, 9 of 29 well-documented cases of LCA reported in the literature are described as being associated with other cancers including non-Hodgkin’s lymphoma in 2 cases, 2 colorectal carcinomas, 2 renal cell carcinomas, a nonsmall cell lung carcinoma, gastric leiomyosarcoma and a pancreatic carcinoma.3, 44, 51, 52, 53 Although no specific genetic or molecular abnormalities to suggest a reason for this apparent association with malignancy elsewhere have been found, some authors recommend close follow-up and careful investigation in search of a second visceral neoplasm when an LCA is identified.51 However, it may be that these LCAs were simply identified by chance in this subset of patients undergoing extensive radiologic investigation for other disease. Macroscopically, splenic involvement by LCA is typically characterized by multiple, spongy, cystic blood filled, circumscribed nodules ranging in size from 0.2 to 9.0 cm.42, 44 Less commonly, the lesions can be solitary or completely replace the splenic parenchyma.3, 44 Microscopically, these cystic regions correspond to a complex anastomosing network of vascular spaces of varying size, some with narrow compressed lumens; others are composed predominantly of large dilated blood-filled spaces (Figs 3A and B). In nearly all cases, a single layer of endothelial cells with two distinct morphologies lines the vascular channels.44 The majority of lining cells demonstrates features of tall endothelium with large vesicular nuclei and small but distinct nucleoli (Figs 3C and D). Occasionally, the nuclei are indented or kidney shaped. Mitotic figures and nuclear pleomorphism or atypia are not seen. In addition, some of the cells possess small basal nuclei with nuclear irregularities, dense chromatin, and scant cytoplasm that are virtually indistinguishable from the sinus-lining cells found in the adjacent uninvolved splenic parenchyma. In nearly all cases, papillary projections or fronds with a central core of fibrous stroma are seen. Numerous exfoliated lining cells are also commonly observed within the vascular spaces and, on occasion, extensive intraluminal sheet-like proliferation of cells can be seen. In contrast to the tall endothelial-like morphology of the cyst lining cells, the exfoliated cells possess a distinctly macrophage/histiocyte-like morphology, often showing hemophagocytosis, prominent hemosiderin deposition, and foamy cytoplasm (Figs 3C and D). In addition to these findings, a very characteristic feature of the littoral cells are focal aggregates of eosinophilic globules 0.5 to 2 μ in size, which often entirely fill the tumor cell cytoplasm.54 Ultrastructurally, the globules were composed of abundant cytoplasmic aggregates of lysosomes and residual bodies. The globules most probably originate from the phagocytized red blood cells, lymphocytes, and plasma cells. Immunohistochemical analysis of LCA clearly shows the vascular nature of the lining cells with positive staining for the vascular markers CD31 (Fig 4A), Factor VIII-related antigen and Ulex europeaus Lectin I. Interestingly, the vascular marker CD34 is not expressed in the plump, tall, histiocyte-like LCA lining cells3, 11, 44; however, more basal, CD34-positive flattened endothelial-like cells are occasionally identified3, 11 (Fig 4B). Additional features support a combined endothelial/histiocytic cell of origin for LCAs, with reactivity of most lesions for the histiocytic markers CD68 (Fig 4C), alpha1-antichymotrypsin, cathepsin-D and lysozyme.3, 11, 44, 53, 54, 55 Interestingly, although the majority of normal splenic sinus lining cells shows immunoreactivity for CD8,45 studies in paraffin embedded tissue reveals absent CD8 staining in LCA lining cells.3, 11 In addition, the C3d (CR2) complement receptor, CD21, is also expressed in LCA lining cells, a finding that appears unique to LCA among splenic vascular tumors and can be diagnostically useful in tumor classification (Fig 4D).3, 11 Whereas the absence of CD8 reactivity may indicate origin from a CD8 negative-subset of sinus lining cells,12 the unique phenotype of the LCA could imply origin from an unidentified cell distinct from the sinus lining (littoral) cell. Alternatively, this immunophenotype may result from the neoplastic transformation of a more typical sinus-lining cell. Several morphologic features of LCA, including the papillary projections and occasional solid areas, can make differentiation from angiosarcoma sometimes challenging. Morphologic features that favor LCA over angiosarcoma are architectural features of typical splenic sinuses; absence of irregular, anastomosing, complex vascular channels; and the absence of cellular atypia or mitoses.42 In addition to these morphologic features, LCA’s unique reactivity for CD21 and absence of staining for CD34, a vascular antigen normally present in angiosarcoma, may be of diagnostic utility in distinguishing these entities3, 11, 56 (also see below under littoral cell angiosarcoma). Maligant vascular lesions Angiosarcoma Primary splenic angiosarcomas are rare, clinically aggressive lesions that are associated with an extremely poor prognosis. Since their first description by Langhans in 1879,57 much of the literature regarding these tumors has come in the form of small series and case reports3, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92; however, more recently, 2 large series of cases have been described.11, 93 These tumors most commonly arise in adults in their 6–7th decades (majority >40 years old) with a median age between 55–65.11, 93 While there is no apparent gender predilection, 1 study has found that women present at a statistically significant older age than men (68 years old v 53).11 Unlike angiosarcoma of the liver, the etiology of splenic angiosarcoma remains mysterious, with no evident association with a history of exposure to arsenic, vinyl chloride, or thorium oxide (Thorotrast) that has been found. Some small series have noted histories of exposure to ionizing radiation prior to the development of splenic angiosarcoma,82, 89 a finding not seen in subsequent larger series.11, 94 Concomitant malignant tumors have been described to occur at low frequency and have included carcinoma of the breast, kidney, colon, and non-Hodgkin’s lymphoma.89, 92, 93, 95 No clear relationship between prior chemotherapy has been established to date. In contrast to other splenic vascular tumors, angiosarcoma is typically associated with significant symptomatology. The majority of patients experience abdominal pain, typically localized to the left upper quadrant, with some reporting weakness or fatigue, weight loss, and/or fever. The duration of symptoms is short, ranging from 1–7 months, and does not correlate with patient outcome.11 The vast majority of patients have splenomegaly and spontaneous splenic rupture with hemoperitoneum is commonly seen. Interestingly, splenic rupture does not appear to be associated with outcome11 or patient’s age, laboratory values, or tumor size.61, 83 Abnormal laboratory findings are seen in nearly all patients, with a normochromic, normocytic anemia being most common, followed by thrombocytopenia. The mechanism for the anemia is likely to be multifactorial but may include chronic disease, bleeding, hemolysis, sequestration of erythrocytes, or marrow replacement by tumor.11 White blood cell counts are generally depressed and patients present with pancytopenia; however, examples of elevated white cell counts or even thrombocytosis have been reported.11, 40, 58, 61, 63, 65, 81, 88, 93 An elevated erythrocyte sedimentation rate is also occasionally seen, and less commonly a coagulopathy (elevated PT/PTT) or microangiopathic hemolytic anemia is noted.61, 65, 82 Prognosis for angiosarcoma of the spleen is dismal with the majority of patients rapidly dying of disseminated disease. Most studies with follow-up information reveal that the majority of patients have median survivals of around 5 to 6 months with nearly all patients dying within 3 years.11, 93 This bleak outlook holds true regardless of treatment, which in most cases involves splenectomy followed by adjuvant radiation and/or chemotherapy.11, 81, 93 Metastasis is an early and frequently widespread feature in angiosarcoma of the spleen, with rates of metastatic spread reported to be from 70% to 85% in a single and compiled series.11, 93 Most patients demonstrate multifocal metastatic deposits in many organs. Common sites of metastatic disease are liver, lung, lymph node, and bone, with less frequent sites of involvement including brain, soft tissue, and adrenal gland. Perhaps surprisingly, metastatic disease at diagnosis does not appear to be associated with a higher death rate or accelerated demise.93 This may in part be due to the presence of occult metastases in cases originally felt to have disease confined to the spleen. Alternatively, the profound hematological abnormalities accompanying the isolated tumors may play a significant role in the patient’s ultimate demise. Gross examination of spleens involved by angiosarcoma reveal 85% to 90% of cases with splenic weights well over 250 g, with mean weights in 2 large series of 1,073 g and 1,116 g, respectively.11, 93 Spleens that rupture are on average much larger than those that do not, showing nearly twice the mean weight on average in the largest series (1,986 g v 1,041 g).93 The appearance of the tumor’s cut surface is highly variable. Most frequently the lesions are multinodular and hemorrhagic, with nodules ranging in size from 1.0 cm to as large as 18 cm. These nodules may be discrete and well circumscribed or poorly delimited. Cystic, hemorrhage filled spaces and necrosis are common. A dominant mass may be present. Tumor size did not correlate with clinical outcome in one series.11 Histologically, splenic angiosarcoma has an extremely varied appearance, often making diagnosis based on light microscopy alone difficult. This heterogeneity in microscopic appearance is seen not only from case to case, but within a given tumor, making complete sampling of lesions imperative. While low power views typically demonstrate a nodular appearance, higher power examination invariably reveals the tumor’s infiltrative nature. The most frequent and extensively seen pattern is a vasoformative one (Fig 5). To some degree, nearly all cases demonstrate a spongiform or honeycomb-like proliferation comprised of an irregularly anastomosing network of slit- or capillary-like spaces. Frequently, spongiform areas can blend with more cavernous cystic spaces that closely resemble cavernous hemangioma. Occasionally, papillary fronds may be seen protruding into these cystic spaces. While these architectural patterns are similar to those seen in other benign splenic vascular neoplasms, what distinguishes these cases as angiosarcoma is the cytologic atypia of the lining cells. Focally, the degree of atypia may be subtle (Fig 5B), but in general the degree of nuclear atypia is striking and provides clear evidence of malignancy. In contrast to other benign vascular tumors of the spleen, mitotic figures and multinucleated, bizarre, tumor giant cells are frequently seen. Extracellular or intracellular periodic acid-Schiff-positive hyaline globules of varying sizes and hemophagocytosis can sometimes be seen. Sheet-like or solid proliferations, occasionally simulating carcinoma, are also frequently observed (Fig 6). These cells can be spindled, polygonal, epithelioid, or round and primitive in appearance. While these regions are easily recognizable as malignant, the lack of a vasoformative pattern may make identification as angiosarcoma difficult. Immunohistochemical studies are often invaluable in this regard, confirming the vascular nature of such tumors. Most cases are positive for 2 or more markers of vascular differentiation including CD31, CD34, Ulex europeaus lectin 1, VEGFR3, or von Willebrand factor.3, 11, 93 CD31 is often the most sensitive and specific marker, usually demonstrating reactivity in even the most poorly differentiated tumors (Fig 6C). Some variability exists in immunohistochemical studies for markers of sinus derivation such as CD68 or CD8, but recent studies clearly reveal that a significant subset of tumors are positive for these markers.3, 11 One report has also identified enzymatic evidence for sinus endothelial cell derivation of splenic angiosarcoma.96 Occasional focal reactivity for keratin3 and S-100 protein3, 93 has been reported as well. Although long-term survivors are rare, no distinguishing histologic feature seems to predict more favorable outcome among these patients. Littoral cell angiosarcoma Rarely malignant splenic vascular tumors are encountered with the morphologic features of littoral cell angioma, yet which display malignant nuclear cytology and an infiltrative or solid growth pattern.44, 56, 96, 97 Macroscopically, these lesions show an ill-defined, nonlobulated pattern with alternating dark red-spongy nodules and interspersed solid white areas. Light microscopic examination reveals a diffuse growth pattern, with vascular spaces of varying shape and size lined by bland, grooved lining cells resembling those of typical littoral cell angioma. Focally, however, sinusoidal spaces show a haphazardly anastomosing arrangement with admixed solid, sheet-like cellular areas, both comprised of malignant-appearing cells with large, irregular hyperchromatic nuclei and small to medium-sized distinct nucleoli. Similar to LCA, frond-like arrangements of these cells may also be seen lining or filling the vascular spaces. In addition, these cells can show hemophagocytosis of erythrocytes and nuclear debris and/or increased mitotic activity. In at least one case, clinical behavior intermediate to that of LCA or angiosarcoma was identified.56 This lesion was not rapidly fatal and recurred 8 years after splenectomy, with an abdominal mass and multiple liver metastases, resulting in the patient’s death. These tumors have largely been regarded as malignant counterparts of littoral cell angioma or littoral cell angiosarcomas, based on immunohistochemical and ultrastructural studies suggesting features of splenic sinus lining cells.97, 98 However, studies showing a splenic sinus lining cell origin of many primary angiosarcomas make reliable or meaningful distinction between these entities difficult. Staining for CD21 has been reported to be positive in only one case to date,56 with the entire immunohistochemical profile being consistent with that of a classic littoral cell angioma (positive for factor VIII, CD31, CD68, cathepsin D, and CD21 and negative for CD34 and CD8). Lesions such as these may truly represent a biologically distinct entity from angiosarcoma. Overall, because of difficulties in predicting biological behavior based on histological features of splenic littoral cell tumors, long-term follow-up for these patients, especially for those with atypical histology, is recommended. Miscellaneous lesions including hemangioendothelioma So-called “hemangioendothelioma” of the spleen is a controversial entity that may represent a vascular lesion with morphologic and clinical properties that are intermediate between those of the hemangioma and angiosarcoma. The lesions typically demonstrate a range of microscopic features with ill-defined vascular spaces, epithelioid morphology with mild cellular atypia, a low mitotic rate, and absence of necrosis. The tumors may also show variable prominent areas with solid spindle cell features. Importantly, their malignant potential is best described as borderline or intermediate.99 Although some authors feel that the majority of such lesions most likely represent examples of angiosarcoma,99 other so-called variants of hemangioendothelioma, particularly those with spindle and epithelioid morphology or an endovascular papillary angioendothelioma pattern probably do represent distinct entities that warrant separation from angiosarcoma, as with comparable lesions in soft tissue.100 With this in mind, only rare reports of such splenic lesions exist in the literature.101, 102, 103, 104, 105, 106, 107 Several well-circumscribed hemangioendotheliomas with spindle and/or epithelioid morphology and no evidence of metastatic spread have been described.101, 102, 106, 107 Suster et al101 reported a distinctive 4.5-cm vascular neoplasm of the spleen in a 3-year-old boy. This lesion was characterized histologically by a biphasic growth pattern, with discrete nodular areas composed of atypical, epithelioid cells with large nuclei and prominent nucleoli, and intermixed areas showing an intricate proliferation of vascular channels lined by elongated spindle cells. Immunohistochemical studies showed the tumor cells were positive for factor VIII-related antigen, Ulex europeaus lectin 1, and negative for keratin, actin, desmin, lysozyme, and S-100 protein. Electron microscopy revealed features consistent with vascular endothelial cells. The absence of mitoses, infiltration of adjacent splenic tissue and lack of necrosis were not in keeping with angiosarcoma and it was felt this lesion was best considered an “epithelioid and spindle cell hemangioendothelioma.” Kaw et al102 described a similar tumor in an adult patient who presented with chronic anemia but was otherwise asymptomatic. The 7.0-cm solitary tumor involved half the organ and was unencapsulated. Microscopically, it demonstrated a lobular growth pattern with vascular spaces lined by spindle-shaped cells with hyperchromatic nuclei. The stroma surrounding the vascular spaces also demonstrated a proliferation of plump eosinophilic spindle cells. Only moderate atypia and rare mitoses were observed. The lining cells stained positively for factor VIII-related antigen and Ulex europeaus lectin 1. One year after splenectomy, all hematologic parameters slowly improved and normalized and no evidence of metastasis was found. Ferrozzi et al107 reported a 58-year-old woman with a palpable, well-circumscribed 9-cm lesion histologically consistent with hemangioendothelioma that had no evidence of metastatic spread. Finally, Cerda et al106 report on a new born child presenting with splenic rupture and hypovolemic shock who underwent segmental resection of the spleen. The spleen revealed a tumor mass with histologic findings consistent with hemangioendothelioma. No other evidence of disease was noted and splenic function was normal after 1 year. Other cases with histologic features reportedly similar to those mentioned above have shown more aggressive behavior typified by extra-splenic spread. These cases have showed involvement of the liver,103, 104 regional lymph nodes,104 and brain.105 Because of the rarity of these lesions, the clinical consequences of the presence of extra-splenic involvement are uncertain. At least 1 patient who received no therapy, described by Budke et al,104 with 4 years of follow-up remains alive and disease free.99 Additionally, Katz et al108 reported an endovascular papillary angioendothelioma (papillary intralymphatic angioendothelioma or Dabska-like tumor) in the spleen of a 5-year-old boy presenting with splenomegaly. Endovascular papillary angioendothelioma is a rare vascular neoplasm principally involving the skin and subcutaneous tissues in children.109, 110 This splenic lesion showed a histologic pattern similar to comparable skin and soft tissue lesions characterized by anastomosing vascular channels with intravascular papillary, tuft-like outpouchings lined by atypical plump, columnar endothelial cells. Immunohistochemical studies supported endothelial cell differentiation with immunoreactivity for factor VIII-related antigen and Ulex europeaus lectin 1. While the concept of borderline malignancy in vascular tumors is evolving and is still poorly defined,111 examples of these so-called variants of hemangioendothelioma that possess potential for multifocal organ involvement yet generally benign clinical behavior (in contrast to angiosarcoma) warrant separation from other splenic vascular lesions. Finally, Kraus and Dehner112 reported an unusual benign neoplasm with apparent myoid and angioendotheliomatous features in a total of four patients. These usually small lesions were comprised of sheets of spindled-to-epithelioid cells with irregular nuclear features and a sieve-like array of erythrocyte-filled spaces with bland, flat lining cells. Immunophenotypic studies revealed the epithelioid elements to be reactive for smooth muscle actin, muscle specific actin, and vimentin, but negative for CD31, CD34, CD21, CD8, and CD68. The attenuated lining cells, however, were CD34+, vimentin+, SMA-, with variable expression of CD31 and von Willebrand factor. One case demonstrated elongated SMA and MSA positive cell processes similar to myoid elements present in the normal spleen, suggesting that these lesions represent benign neoplasms of myoid elements of the spleen. Conclusions Splenic vascular tumors are such uncommonly encountered specimens in the practice of surgical pathology that they may often pose a diagnostic challenge. Immunohistochemical studies have been helpful in distinguishing the vascular nature of poorly differentiated lesions and in distinguishing between various benign entities, including hemangioma, lymphangioma or littoral cell angioma. However, aside from conventional morphologic assessment, reliable indicators for a malignant phenotype or aggressive biological potential do not exist. Careful attention to morphologic features and correlation with clinical findings is necessary for most cases. Until better markers to predict clinical behavior exist, the presence of atypical cytologic features justifies, at the least, close monitoring of such patients. Unfortunately, until better therapies exist for angiosarcoma of the spleen, accurate detection of its presence is of little clinical consequence. References 1.
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a Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA  Address reprint requests to Christopher D.M. Fletcher, MD, FRCPath, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115, USA
PII: S0740-2570(03)00011-X doi:10.1016/S0740-2570(03)00011-X © 2003 Elsevier Inc. All rights reserved. | 
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