Sclerosing Angiomatoid Nodular Transformation (SANT) of the Splenic Red Pulp
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).
Recent data show some possible relationship with infectious diseases, particularly EBV infection of myofibroblasts or with IgG4-related diseases.
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).
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).
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).
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).
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).
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.
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.
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.
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.
To our knowledge, no molecular features have been reported.
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
- 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.
- 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
- 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