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Volume 30 |
June 2008 |
Number 3 |
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Sclerosing Angiomatoid Nodular Transformation of the Spleen
Xiaodong Teng, M.D., Xinru Yu, M.D., Guihua Wang, M.D., Linjie Xu, M.D., and Maode Lai, M.D.
OBJECTIVE: To study clinical and pathologic features of sclerosing angiomatoid nodular transformation (SANT) and differential diagnosis, we reviewed splenectomy specimens from the Department of Pathology, First Affiliated Hospital, School of Medicine, Zhejiang University (January 1990 to December 2006) and another case from consultation at Second Jiaxing Municipal Hospital, Zhejiang Province, finding 7 cases of this lesion.
STUDY DESIGN: Clinicopathologic characteristics and immunophenotype of 7 cases of SANT were studied.
RESULTS: Five cases were incidentally found during routine examination. One had concurrent hepatic angioma. Microscopically, all cases were characterized by multiple angiomatoid nodules of various sizes embedded in fibrosclerotic stroma. Each nodule was composed of slit-like, round or irregularly shaped vascular spaces lined by plump endothelial cells and interspersed by a population of spindle or ovoid cells. In one case, an angiomatoid nodular lesion and a hamartoma-like lesion appeared together. Heterogeneous immunohistochemical features of the lining cells were revealed. CD34 was expressed in the narrow, well-formed capillaries and CD8 in some sinusoid-like structures, but without CD34 expression. CD31 staining highlighted numerous lining cells and interspersed cells. Some lining cells were focally CD68 positive.
CONCLUSION: SANT is a rare lesion. Based on morphologic and immunohistochemical features, it may be a variant of splenic hamartoma. (Anal Quant Cytol Histol 2008;30:125–132)
Keywords: hamartoma, immunohistochemistry, multinodular hemangioma, sclerosing angiomatoid nodular transformation, spleen.
Vascular neoplasms, such as hemangioma, lymphangioma, hamartoma, littoral cell angioma, hemangioendothelioma and angiosarcoma, are the most common nonhemopoietic proliferating lesions of the spleen. Sclerosing angiomatoid nodular transformation (SANT) is a new and rare member of unknown histologic nature.1 No more than 30 cases of SANT have been reported worldwide to date.2-5 We found 7 cases of SANT when we reviewed all splenic tumors during the past 17 years in the Department of Pathology at the First Affiliated Hospital, School of Medicine, Zhejiang University. We believe that SANT may be a variant of splenic hamartoma.
Materials and Methods Clinical Findings
Six splenectomy specimens were collected in the Department of Pathology, First Affiliated Hospital, School of Medicine, Zhejiang University from January 1990 to December 2006, and another case was obtained from consultation (from the Second Jiaxing Municipal Hospital, Zhejiang Province). They were from 4 female and 3 male patients. The mean patient age was 40.1 years (range, 31–58).
Five patients showed a splenic mass on routine health examination, of which 1 had calculus of the bile duct and another had concurrent hepatic angioma. The remaining 2 patients presented with upper abdominal discomfort and waist-back pain. The clinical details are given in Table I. Abdominal sonography demonstrated decreased echogenicity in the spleen. Plain computerized tomograms (CTs) showed a solitary, well-demarcated hypodense splenic mass with increased signal intensity after the intravenous administration of gadopentetate-dimeglumine. Magnetic resonance imaging (MRI) showed low signal intensity on T1-weighting and high intensity on T2-weighting (Figure 1). All patients underwent splenectomy.
Review of Histology and Immunostaining
Archival hematoxylin-eosin (H-E)–stained slides were all reviewed by senior pathologists (X.T., X.Y. and M.L.). Immunohistochemical staining was carried out using a standard EnVision 2-step method (Dako, Glostrup, Denmark) according to the manufacturer’s instructions. Briefly, after antigen retrieval by pressure cooking for 3 minutes in EDTA buffer (pH 8.0) and digestion by trypsin for 10 minutes at room temperature when appropriate, the slides were incubated with diluted primary antibody for 60 minutes, then incubated with the secondary antibody for 30 minutes at room temperature and developed with DAB. Antibodies used in this study were CD8 (c8/144B, 1:50), CD21 (1F8, 1:80), CD31 (JC/70A, 1:80), CD34 (QBEnd10, 1:100), CD35 (Ber-MAC-DRC, 1:80), CD68 (KP1,1:80), ALK (ALK1, 1:80), SMA (smooth muscle actin, 1A4, 1:80), actin (HHF-35, 1:80) and desmin (DER-11, 1:80) (all antibodies were from Dako).
Results Pathologic Examination
Grossly, the lesion was located in the splenic parenchyma, measuring 3
 3 to 8.58.5 cm. The tumors were round or lobulated with a demarcated border but without encapsulation. The cut surface of the
lesion had a solid, gray-red or red-brown appearance (Figure 2). The lesion was interspersed with gray-white scar-like strips showing a nodular appearance. Microscopically, round or ovoid nodules showing angiomatoid features were surrounded by proliferative fibrous tissue with varying amounts of collagen. Crevice-like, irregular or slightly dilated blood vessels were lined with plump endothelial cells and located in the center of the nodule. Erythrocytes were present in the lumen of some blood vessels. The stroma separating blood vessels was dense fibrous or fibromyxoid tissue that had proliferative spindle or oval cells with unclear cell borders. Lymphocytes, plasma cells and histiocytes were not uncommon in the nodules. Some nodules showed granuloma-like changes. Some cases had a foreign-body granulomatous reaction around the nodules, including dense collagenous fibrous tissue, hemosiderin pigment, giant cell reaction and foci of calcification (Figure 3), mimicking an organized thrombus at low magnification. However, at high magnification, the surroundings of the nodule were found to be proliferative fibrous tissue rather than vessel walls. Case 6 showed predominantly larger hamartoma-like nodules with a scarce peripheral fibrous strip. A few typical sclerosing angiomatoid nodules and nodules with transitional features could be found in other areas (Figure 4). We supposed that these patterns were probably the early pathologic features of this lesion.
Histochemical and Immunohistochemical Findings
Histochemical staining for reticulin highlighted the intricate vascular network within the nodules as well as the sinusoid-like structures. Immunohistochemical staining for CD31 displayed numerous cells within the angiomatoid nodules, including sporadic cells, recognizable vascular channels and extremely complex meshworks. CD34 staining indicated endothelial cells lining the small, narrow capillaries, but positive cells varied in different nodules. CD34-positive capillaries and endothelial cells were markedly fewer than CD31-positive ones. Few CD8-positive cells were found in the lining cells of narrow capillaries without CD34 expression. Some of the sinusoid lining cells showed focal CD68-positivity. SMA-positive cell clusters were seen between vessels and around the nodules (Figure 5). Some spindle cells between these nodules expressed actin. There were no desmin-, CD21-, CD35- or ALK-positive cells in the SANT samples.
Discussion
Vascular tumors are the second most common tumor of the spleen, including hamartoma, hemangioma, littoral cell tumor and hemangioendothelioma. SANT is a newly defined tumor, first described by Krishnan et al6 in 1993. It was initially named cord capillary hemangioma and reinterpreted as a variant of hamartoma in 2003.6,7 Kraus and Dehner8 and Karim et al9 described it as a benign vascular neoplasm of the spleen with myoid and angioendotheliomatous features. It is referred to as multinodular hemangioma in Rosai and Ackerman’s Surgical Pathology, emphasizing the characteristic histologic changes of its multiple nodules.10 Some cases of previously reported splenic hemangioendothelioma and hamartoma might also belong to this category.11,12 Martel et al1 reviewed 25 cases (14 from Italy, 9 from Hong Kong and 2 from consultation) and designated the lesion SANT of the spleen, according to the histologic characteristics and immunophenotype.
Most patients with SANT have no obvious clinical symptoms and only a splenic mass as an incidental finding at routine examination. About 20% of cases are accompanied by other diseases, most of which are malignant. In this report, 5 cases were
incidental findings at health examination, among which 1 had concurrent hepatic angioma. The coexistence of SANT and hepatic angioma in a patient has never been reported. CT showed a solitary, well-demarcated, hypodense splenic mass, and
the intravenous administration of gadopentetate-dimeglumine increased the signal intensity. Here, we provide the first MRIs showing low signal intensity on T1-weighting, and high intensity on T2-weighting, thus differentiating them from hypostatic tumor.
The SANT cases had characteristic pathologic morphology. Grossly, the lesion presented as a single, well-circumscribed, round or oval mass. Microscopically, it showed multiple nodular angiomatoid changes. In a few cases, granulomatous change was evident. Each nodule was surrounded by dense or relatively dense collagenous fibrous tissue. Narrow sinusoid vascular spaces lined by plump endothelial cells accumulated in the nodules. These vascular spaces showed 3 distinct immunophenotypes, recapitulating the normal composition of the red pulp: cord capillaries (CD34+/CD8-/CD31+), sinusoids (CD34-/CD8+/CD31+) and small veins (CD34-/CD8-/CD31+) (Table II). Focal staining of the lining cells with CD68 was identified, and SMA staining revealed conglomerates of spindle cells around and between the vascular channels. The type IV collagen staining showed abundant deposition of basement membrane material, displaying the intricate vascular network within the nodules. Some spindle cells between the nodules were focally actin-positive, while desmin, CD21, CD35 and ALK were negative.
 The nature of SANT remains uncertain, and it is regarded as an undefined descriptive designation in the splenic tumors. It remained to be determined whether this is a de novo lesion or the final common pathway of a variety of benign splenic conditions, including inflammatory myofibroblastic tumor, hamartoma, hemangioma and hematoma. This study showed combined immunophenotypes and morphologic features of angiomatoid nodules and hamartoma lesions in SANT. These phenomena suggest the possibility of histogenous homogeneity of SANT and hamartoma. We suggest that SANT is probably a form of endothelium-related benign lesion and may be a variant of splenic hamartoma.
Differential Diagnosis SANT of the spleen shows a characteristic nodular structure and can be recognized easily, but it is often mistaken for other lesions. In this report, 3 cases were previously misdiagnosed as hemangioma with extensive organization and hamartoma with infarction nodular organization. SANT should be differentiated from the following lesions, and the differential diagnosis may be based on the immunohistochemical features listed in Table II.1
Classic Hamartoma of the Spleen. This lesion is composed of red pulp and has an overlapping immunophenotype with SANT. But SANT has a clear boundary and proliferative fibrous tissues showing multiple nodular features, whereas splenic hamartoma usually appears as a rather uniformly diffuse lesion.2 Hemangioma and lymphangioma of the spleen are composed of a single type of vessel structure. Splenic hemangioma often belongs to the cavernous and occasionally the capillary type and consists of blood vessels; the endothelial cells of blood vessels often express both CD31 and CD34, but not CD8. Although regressive changes such as infarction, thrombosis with organization and fibrosis may occur, they do not display the distinctive angiomatoid nodular changes of SANT.3 Bacillary angiomatosis of the spleen is a very rare, reactive tumor-like lesion of blood vessel hyperplasia. It is composed of lobules of small blood vessels and capillaries. The plump endothelial cells are similar to those in epithelioid hemangioma. Granuloma can be seen between the blood vessels. Warthin-Starry staining shows bacterial bacilli. Multiple nodules are uncommon in this lesion.4 Littoral cell tumor of the spleen is composed of vascular sinus-like channels, sometimes with papilla formation. The endothelial cells lining the channel and papilla express CD31, CD68 and CD21, but not CD34. The multiple nodular pattern and fibrosis are also absent.5 Hemangioendothelioma of the spleen is a vascular tumor intermediate between hemangioma and angiosarcoma, characterized by proliferative endothelial cells, myxoid stroma and proliferative fibrous tissue. The endothelial cells appeared spindle-shaped, plump or epithelioid, with mild to moderate atypia, clustering as cords, nests or capillary structures. These cells express CD31 and CD34, but not CD8.6 Lesions with granuloma-like changes of the spleen. SANT is similar to granuloma-like nodules at low magnification. However, under high magnification, SANT does not show classical granulomatous features, including few scattered histiocytes, no multinuclear giant cells, no classical epithelioid cells and necrosis.7
Inflammatory Myofibroblastic Tumor of the Spleen. Grossly, this appears as a gray-white mass with a clear boundary. Histologically, this lesion is composed of proliferative myofibroblasts and inflammatory cells, including plasma cells, lymphocytes, neutrophils and many histiocytes without angiomatoid nodule formation. SMA and CD68 are invariably positive in this lesion. ALK is possibly positive, but endothelial markers are typically negative.8 Other nodular lesions of the spleen. Rarely, metastatic cancer of the spleen may induce prominent fibrosis with a nodular appearance, but the tumor cells show significant atypia.
Prognosis and Treatment Although its histogenesis and denomination remain to be further studied, SANT has an excellent prognosis and is cured by splenectomy. Martel et al1 reported that clinical follow-up of 21 of 25 cases for 2 to 9 years showed no evidence of recurrence, which suggests that SANT of the spleen is a completely benign lesion.
References
From the Department of Pathology, First Affiliated Hospital, and Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou; and Department of Pathology, Second Jiaxing Municipal Hospital, Zhejiang Province, China.
Dr. Teng is Associate Chief Physician, Department of Pathology, First Affiliated Hospital, School of Medicine, Zhejiang University. Dr. Yu is Professor, Department of Pathology, First Affiliated Hospital, School of Medicine, Zhejiang University.
Dr. Wang is Chief Physician, Department of Pathology, Second Jiaxing Municipal Hospita. Dr. Xu is Technician, Department of Pathology, First Affiliated Hospital, School of Medicine, Zhejiang University.
Dr. Lai is Professor, Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University. Address correspondence to: Maode Lai, M.D., Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, 388 Yuhang Tang Road, Hangzhou 310058, Zhejiang Province, China (lmd@zju.edu.cn).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.
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