Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Sclerosing Angiomatoid Nodular Transformation (SANT) of the Splenic Red Pulp

  • Jacques Diebold
  • Josée Audouin
  • Agnès Le Tourneau
  • Thierry Jo MolinaEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_5014-1

Synonyms

Definition

In 2004, Martel et al. reported 25 cases of a unique distinctive lesion of the spleen, constituted by multiple nodules realizing a single mass in the center of the organ. These well-circumscribed lesions show a peculiar vascular pattern, with a distinctive immunophenotype profile and a benign evolution. They propose the term sclerosing angiomatoid nodular transformation (SANT) of the spleen red pulp. A few years later, we published another series of 16 cases of patients (Diebold et al. 2008), presenting the same lesions in the spleen, which have been often diagnosed before as inflammatory pseudotumor (IPT).

It can be postulated (Martel et al. 2004) that this peculiar transformation of the red pulp of the spleen may represent an exaggerated response of stromal proliferation to a disruption of the small vascular outflow tracts leading to hyperplasia of the proximal vascular bed, with nodular changes and fibrosis.

The lesions of the centers of angiomatoid nodules resemble more or less the pattern of granulation tissue developing during wound healing or various hyperplasic reactions including botryomycoma and epulis in other tissues than spleen or during the organization of vascular thrombosis, particularly in veins (e.g., what has been called initially “vegetating intra vascular hemangio-endothelioma” by Pierre Masson) or what happens after chronic lymph stasis leading to vascular transformation of lymph nodes sinuses (Martel et al. 2004; Diebold et al. 2008).

Another hypothesis has been discussed: the possible evolution and transformation of a previous hamartoma also called splenoma (Martel et al. 2004; Falk et al. 2012).

Recent data show some possible relationship with infectious diseases, particularly EBV infection of myofibroblasts or with IgG4-related diseases.

Clinical Features

Many cases are silent, and the incidental discovery of a splenomegaly or of a mass in the spleen by imaging techniques is often the first step to the diagnosis.

Other patients complain of abdominal pain (Diebold et al. 2008; Falk et al. 2012; Wang et al. 2012) or discomfort. Sometimes an anemia, a pancytopenia, or a von Willebrand disease is disclosed. Fever, hyperleukocytosis with polynucleosis, and raised erythrocyte sedimentation rate lead to the search of an infection (e.g., cases associated with pyelonephritis or paramyxovirus 19 infection have been reported).

Some cases associated with various malignancies such as myeloproliferative neoplasms, B-CLL, and carcinomas (colic, stomach, kidney, lung) have been observed.
  • Incidence

    The incidence seems to be very low. For example, the 16 cases we reported (Diebold et al. 2008) have been collected in our department and specialized in spleen diseases between 1972 and 2007. But, data are not available today for a precise appreciation of the real incidence, 42 cases published at the time of our report, more than 100 cases today (Bagul and Sten 2015; Gaeta et al. 2017).

  • Age

    All the patients reported in the two main series are adults, and as far as we know, no cases in children have been published today. The age of the patients in Martel’s series is ranging from 22 to 74 years (median age: 56 years) and, in ours, from 22 to 82 years (median age: 44.4 years). The majority of the cases belong to the 30–60 years age group (Falk et al. 2012; Pradhan and Mohanti 2013).

  • Sex

    A slight prevalence of women is observed in Martel et al. series (17 female, 8 male) and in our series (9 female, 7 male) and confirmed by other (Pradhan and Mohanti 2013).

  • Imaging

    Such studies are useful for the positive and differential diagnosis despite the absence of specific features (Subhawong et al. 2010; Pradhan and Mohanti 2013).

    Ultrasonography reveals a hypoechogenic mass (Cao et al. 2010). With computed tomography scan, the splenic lesions appear as heterogeneous, low-attenuation of unenhanced images (Pradhan and Mohanti 2013).

  • Treatment and Outcome

    The majority of the published cases have been splenectomized with a favorable evolution for all the patients. Recently partial splenectomy has been performed in some patients with success (Gaeta et al. 2017).

Macroscopy

In the majority of the cases, the spleen presented a single mass, rounded or bosselated, well-circumscribed but not encapsulated (Fig. 1). In the series of Martel et al., the weight of the spleens ranged from 68 to 1425 g and the diameter of the mass ranged from 3 to 17 cm. In our series (Diebold et al. 2008), seven spleens had a normal weight (between 160 and 220 g) with a mass measuring between 1 and 5.5cm in diameter, and five spleens had an increased weight (between 430 and 840 g) with a mass measuring between 5.5 and 10 cm in diameter. The two last patients in our series had very enlarged spleen. For one, the spleen weighted 1760 g, with a single mass measuring 15 cm, and for the other, the weight was 2400 g due to the association with primary myelofibrosis and the presence of three masses, measuring, respectively, 1, 2, and 3 cm.
Fig. 1

SANT realizes a round nonencapsulated mass constituted by multiple nodules separated by irregular bands of fibrosis, white or ochre brown due to siderosis

All the masses presented a multinodular pattern of the cut surface, with white areas of fibrosis alternating with ochre brown areas and some hemorrhagic zones, without any necrosis.

Microscopy

In all the reported cases, the single mass is constituted by multiple roundish nodules replacing and compressing the surrounding normal red pulp (Fig. 2). These nodules are separated or coalescent, often surrounded by an incomplete ring of collagen fibrosis. Their periphery is occupied by eosinophilic PAS-positive deposits suggestive of fibrin (Fig. 3). Their center is made of loose connective tissue either edematous or containing a variable amount of collagen fibers with fusiform cells and dispersed reactive cells (lymphocytes, plasma cells, granulocytes mostly neutrophils) (Fig. 4). The most characteristic feature is represented by a dense vascular network constituted by arterioles, capillaries, and small veins, realizing a pattern suggestive of a granulation tissue growing in the cords. Between the branches of this network, other segments of vessels represent remnants of sinus. Due to this vascular component, the term “angiomatoid nodules” has been proposed (Martel et al. 2004). During the evolution, the amount of collagen fibers increases in the center of some nodules, with progressive obliteration of these centers.
Fig. 2

Multiple small nodules with a peripheral ring of fibrin representing the angiomatoid nodules are grouped in a large nonencapsulated mass in direct contact with the spleen parenchyma

Fig. 3

Same case (PAS). Notice the peripheral rim of PAS-positive fibrin deposits

Fig. 4

The center of this angiomatoid nodule is rich in inflammatory cells and remnant of red pulp sinuses

The angiomatoid nodules are surrounded by bands of tissue either densely fibrous or fibromyxoid or hyaline with even in few cases calcifications. Sometimes around the angiomatoid nodules, the tissues are histologically indistinguishable from IPT associated with EBV infection (Martel et al. 2004). Some of these fibrotic bands surrounded arteries with hyalinization of the wall, as well as large veins (probably trabecular veins), showing compression or dilatation of the lumen, or thrombosis at different phases of organization. Remnants of follicles, clusters of lymphoid cells and/or plasma cells, and numerous macrophages some containing hemosiderin pigment are observed in the fibrosis and sometimes in a giant cell foreign body reaction (Fig. 5).
Fig. 5

The centers of the lesions between the nodules were occupied by loose connective tissue comprising varying amount of collagen and inflammatory cells

At distance from the angiomatoid nodules, the compressed red pulp shows areas of blood stasis occurring in both cords and sinuses. In other places, areas of fibromyxoid tissue could be interspersed with angiomatoid tissue composed of compressed red pulp, realizing a “reverse pattern” as described by Martel et al. (2004).

The importance of fibrosis explains that the diagnosis of “inflammatory pseudo tumor” has been proposed for some cases.

Immunophenotype

The segments of red pulp sinuses remaining between the capillary network could be revealed by their positivity for CD8 (sometimes only faintly), Factor VIII, and CD31, but not for CD34.

CD34 and CD31 have been detected but not CD8 in the endothelial cells boarding the narrow lumen of the dense capillary network present in the angiomatoid nodules (Fig. 6). Factor VIII antigens are also expressed by these cells, as well as in the fibrin deposits at the periphery of the nodules.
Fig. 6

Angiomatoid nodule (immunohistochemistry, CD34). This staining underlines a dense network of blood vessels resembling the vascularization observed in granulation tissue

The coexistence in nodular masses, of these three types of vessels corresponding to spleen sinuses, to capillaries, and to venules well demonstrated by Martel et al. (2004) and also observed in all the published cases, seems to be very characteristic of the diagnosis of SANT.

Alpha smooth muscle actin is detected in sheets of fusiform cells in the loose connective tissue of the angiomatoid nodules and between the nodules (Martel et al. 2004; Diebold et al. 2008), reflecting probably the presence of myofibroblasts always present in granulation tissue. These cells were negative for follicular dendritic cells (CD 21, CD23, CD35, and CNA42) and for histiocytic markers (CD68).

In the angiomatoid nodules and between them, numerous CD68-positive macrophages could be detected as well as sheets of polytypic plasma cells.

Detection of HHV8 antigens remains negative as well as the search for EBER expression by in situ hybridization.

At distance from the SANT mass, in all our cases, the spleen parenchyma showed a normal architecture with cell populations showing a normal immunophenotype.

Molecular Features

To our knowledge, no molecular features have been reported.

Differential Diagnosis

The hallmark criteria for the diagnosis of SANT are constituted by the angiomatoid nodules first recognized and named by Martel et al. The presence of such nodules allows eliminating the different following entities.

Different types of hemangiomas (capillary, cavernous, multinodular, or mostly littoral cell type) can be discussed as well as hemangioendothelioma of the spleen. But all these lesions present more as a vascular proliferation with a different morphology and immunophenotype than that of angiomatoid nodules which are lacking. Difficult problems can be raised by the development of fibrosis during organization of hemorrhages and thrombosis occurring in the evolution of these hemangiomas.

Angiosarcoma is the most frequent nonlymphoid malignant primary tumor of the spleen. The architecture is destroyed by invasion of abnormal cells with numerous mitosis and atypia.

Splenic hamartoma also called splenoma realizes a mass mostly constituted of red pulp with distension of both cords and sinuses, a variable amount of fibrosis but no angiomatoid nodules.

In a very few number of cases of carcinoma metastasis in the spleen, a pattern similar to SANT, with typical angiomatoid nodules, may develop (Chapel et al. 1999; Diebold et al. 2008; Fakan and Michal 1994). Such association is leading the pathologist in each case of SANT, to search carefully carcinoma cells either dispersed or in column or in nests or rarely in large sheets between the angiomatoid nodules or in their center and also in the lumen of lymphatic vessel beneath the endothelial cells of trabecular veins or in the lymphatic vessels present in the adventitia of trabecular arteries. Immunohistochemical demonstration of cytokeratins is useful. So in such an association, the question is not really a differential diagnosis but the recognition of carcinoma metastasis within a SANT.

Finally, today the most difficult differential diagnosis is with some inflammatory diseases, complicated by the fact that some of these diseases seem to have some connections with SANT of the spleen.

In few cases of SANT (Nagai et al. 2008; Gaeta et al. 2017), among the plasma cells infiltrating the sheets of fibrosis, a high number of IgG4 + plasma cells resembling what has been regarded as specific for various chronic autoimmune diseases collected under the term IgG4 related disease (autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, breast lesions, prostatitis, lung lesions, Mikulicz disease, Kuttner tumor) has been reported raising the differential diagnosis between those two diseases (Gaeta et al. 2017).

In one of these cases, with true SANT, EBER-positive nuclei have also been demonstrated particularly in cells with the morphology and the immunophenotype of myofibroblasts (Kashiwagi et al. 2008) leading to the discussion of an infection by EBV and to correlation with the next entities.

Inflammatory pseudotumor (IPT) of the spleen is a rare, not well-defined entity (Krishnan and Frizzera 2003) characterized by the development of a mass in the red pulp constituted by mutilating fibrosis associated with sheets of polytypic plasma cells and a diffuse infiltrate of CD8-positive cytotoxic T lymphocytes. But the diagnosis of SANT cannot be made due to the lack of angiomatoid nodules.

Follicular dendritic cell tumors and myofibroblastic tumors of the spleen are constituted by sheets of fusiform cells with a peculiar immunophenotype and absence of angiomatoid nodules, the hallmark for the diagnosis of SANT.

So SANT presented with some characteristics of an inflammatory disease and perhaps some correlations with autoimmune disorders and with proliferations of myofibroblasts and follicular dendritic cells, opening new fields for research in the future.

References and Further Reading

  1. Bagul KA, Sen A. (2015). Sclerosing angiomatoid nodular transformation of spleen masquerading as a splenic abscess. Indian J Pathol Microbiol, 58(3), 359–61.CrossRefGoogle Scholar
  2. Cao, J. Y., Zhang, H., & Wang, W. P. (2010). Ultrasonography of sclerosing angiomatoid nodular transformation in the spleen. World Journal of Gastroenterology, 16(29), 3727–3730.CrossRefGoogle Scholar
  3. Chang, K. C., Lee, J.-C., Wang, Y.-C., et al. (2016). Polyclonality in Sclerosing Angiomatoid nodular transformation of the spleen. The American Journal of Surgical Pathology, 40, 1343–1351.CrossRefGoogle Scholar
  4. Chapel, F., Baume, B., & Bereder, J. M. (1999). Unusual vascular changes in the red pulp of the spleen accompanying breast carcinoma metastasis. Pathology, Research and Practice, 195, 53–56. With critical commentary from: Diebold J, same journal p.58.CrossRefGoogle Scholar
  5. Diebold, J., Le Tourneau, A., Marmey, B., et al. (2008). Is sclerosing angiomatoid nodular transformation (SANT) of the splenic red pulp identical to inflammatory pseudo-tumor? Report of 16 cases. Histopathology, 53, 299–310.CrossRefGoogle Scholar
  6. Fakan, F., & Michal, M. (1994). Nodular transformation of splenic red pulp due to carcinomatous infiltration. A diagnostic pitfall. Histopathology, 25, 175–178.CrossRefGoogle Scholar
  7. Falk, G. A., Nooli, N. P., Morris-Stiff, G., et al. (2012). Sclerosing angiomatoid nodular transformation (SANT) of the spleen: Case report and review of the literature. International Journal of Surgery Case Reports, 3(10), 492–500.CrossRefGoogle Scholar
  8. Gaeta, R., Donati, F., Kauffman, E. F., & Campani, D. (2017). A splenic IgG4+ sclerosing angiomatoid nodular transformation (SANT) treated by hemisplenectomy: A radiologic, histochemical and immunohistochemical study. Applied Immunohistochemistry & Molecular Morphology.  https://doi.org/10.1097/PAI.0000000000000560.
  9. Kashiwagi, S., Kumasaka, T., Bunsei, N., et al. (2008). Detection of Epstein-Barr virus-encoded small RNA-expressed myofibroblasts and IgG4-producing plasma cells in sclerosing angiomatoid nodular trans-formation of the spleen. Virchows Archiv, 453, 275–282.CrossRefGoogle Scholar
  10. Krishnan, J., & Frizzera, G. (2003). Two splenic lesions in need of clarification: Hamartoma and inflammatory pseudo-tumour. Seminars in Diagnostic Pathology, 20, 94–104.CrossRefGoogle Scholar
  11. Kuo, T. T., Chen, T. C., & Lee, L. Y. (2009). Sclerosing angiomatoid nodular transformation of the spleen (SANT). Clinicopathological study of 10 cases with or without abdominal disseminated calcifying fibrous tumour and the presence of a significant number of IgGA4 + plasma cells. Pathology International, 59, 844–850.CrossRefGoogle Scholar
  12. Martel, M., Cheuk, W., Lombardi, L., et al. (2004). Sclerosing angiomatoid nodular transformation (SANT): Report of 25 cases of a distinctive benign splenic lesion. The American Journal of Surgical Pathology, 28(10), 1268–1279.CrossRefGoogle Scholar
  13. Nagai, Y., Hayama, N., Kishimoto, T., et al. (2008). Predominance of IgG4+plasma cells and CD68 positivity in Sclerosing Angiomatoid nodular transformation (SANT). Histopathology, 53, 495–498.CrossRefGoogle Scholar
  14. Pradhan D, Mohanty SK. (2013). Sclerosing angiomatoid nodular transformation of the spleen. Arch Pathol Lab Med, 137(9), 1309–12.CrossRefGoogle Scholar
  15. Subhawong, T. K., Subhawong, A. P., & Kamel, I. (2010). Sclerosing Angiomatoid nodular Transformation of the spleen: Multimodality imaging findings and pathologic correlate. Journal of Computer Assisted Tomography, 34(2), 206–209.CrossRefGoogle Scholar
  16. Wang HL, Li KW, Wang J. (2012). Sclerosing angiomatoid nodular transformation of the spleen: report of five cases and review of literature. Chin Med J (Engl), 125(13), 2386–9.Google Scholar
  17. Weinreb, I., Bailey, D., Battaglia, D., et al. (2007). CD30 and Epstein-Barr virus RNA expression in sclerosing angiomatoid nodular transformation of the spleen. Virchows Archiv, 451, 73–79.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Jacques Diebold
    • 1
  • Josée Audouin
    • 2
  • Agnès Le Tourneau
    • 2
  • Thierry Jo Molina
    • 3
    Email author
  1. 1.Pathology, EA7324, Sorbonne Paris Cité, AP-HP, Necker Enfants MaladesUniversité Paris DescartesParisFrance
  2. 2.Department of PathologyHotel-Dieu HospitalParis Cedex 04France
  3. 3.Department of PathologyNecker-Enfants-Malades HospitalParis Cedex 15France