Case of the Month: Spleen

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2016, case 18, and is a sclerosing angiomatoid nodular transformation.

The H&E sections consist of splenic architecture effaced by large bands of fibrosis which are surrounding nodules of cells. The nodules contain slit-like blood vessels lined by plump endothelial cells. The endothelial cells do not show marked pleomorphism and no increase in the number of mitotic figures is identified. There is little to no normal white pulp or red pulp in the sections examined, except on slides where focal white pulp with germinal centers is found at the periphery near the capsule.

This case demonstrates sclerosing angiomatoid nodular transformation (SANT) which is a rare, benign vascular lesion of unknown etiology. SANT is composed of multiple confluent vascular nodules with a unique composition of three variant vessels, including capillaries, venules, and sinusoids, as well as intervening fibrosis. Although the etiology is still undetermined, SANT may represent a peculiar reaction to inflammation, to tumor, or to hemorrhage or other trauma. Some have considered SANT a fibrosing variant of a splenic hamartoma or hemangioma. Others have postulated that it may be part of the IgG4 related systemic disease, since some cases have shown increased IgG4 by immunohistochemistry.

SANTs are generally seen in middle age adults (median of 50 years), with a wide age range (22-82 years) and slightly more common in females (F:M 1.3-2:1). The majority of patients are asymptomatic, and the lesion may be found incidentally after splenectomy for some other reason, such as trauma. Abdominal pain and splenomegaly are the most common presenting symptoms. Laboratory tests are generally unremarkable, with a small percentage of patients having anemia, thrombocytopenia, or leukocytosis. Prognosis is excellent with a splenectomy being curative.

Grossly, SANT is generally a single, well-circumscribed, non-encapsulated, bosselated mass with unusual cases being multifocal. The lesions range in size from 3.0 to 17.0 cm with unremarkable surrounding splenic tissue. In approximately half of cases, the spleens have normal weight (<200 gram). The lesion consists of multiple red-brown nodules representing the angiomatoid nodules surrounded by white fibrous tissue.

Microscopically, SANT has a multinodular appearance on low power with coalescing angiomatoid nodules of variable sizes containing vessels of capillary or small venule size, as well as sinusoids. The vessels are usually small veins or capillaries that appear slit-like, round, or regular with plump endothelial cells. Extravasation of red blood cells is a common feature. Individual angiomatoid nodules may be surrounded by sclerosis, fibrinoid material, or concentric layers of collagen. The nodules may be surrounded by unremarkable splenic white pulp and red pulp. No significant cellular atypia or necrosis is present. Mitotic figures are rare (less than 1 per 10 high power fields). Variable amounts of inflammatory cells are present, which may be reminiscent of an inflammatory pseudotumor. The splenic capsule typically remains intact.

Immunohistochemically, the capillaries are CD34, CD31, ERG and WT-1 positive, but are CD8 negative. Sinusoids are CD31+ and CD8+ and CD34 negative. The small veins are CD31 positive, but negative for CD8 and CD34. Myofibroblasts in the fibrous tissue are positive for smooth muscle actin. SANT is negative for EBER and HHV8.

Included in the differential diagnosis are other benign vascular lesions (littoral cell hemangioma, hemangiomas, and hamartomas), angiosarcoma, and inflammatory pseudotumor. Both histology and immunohistochemical staining can be helpful in making the diagnosis. 

Angiosarcoma is a malignant vascular tumor composed of hemorrhagic nodules with multiple anastomosing vessels lined by atypical cells and containing frequent mitoses. Angiosarcoma is immunoreactive with CD34 and CD31, but negative for CD8. The pleomorphic cells and necrosis seen in angiosarcoma are not found in SANT.

Littoral cell hemangioma is a rare vascular neoplasm of the spleen commonly found in association with other neoplasms, and commonly presents with anemia and thrombocytopenia. These tumors are often multiple, nodular, spongy lesions with cystic spaces and vessels lined by distinctive plump cells (littoral cells). The littoral cells may form papillary structures, and they may “fall off” of the cyst and be seen sitting within the vascular lumens. The lining cells are tall endothelial cells, protruding into the lumen, with little atypia, which express both vascular and histiocytic markers. Factor VIII, CD21, CD31, and CD68 are all immunoreactive in littoral cell angioma. They do not typically express CD8 or CD34. A recent paper by O’Malley, et al. found that littoral cell angioma is negative for WT-1 staining, in contrast to most other vascular lesions including SANT. Littoral cell angiomas do not show the three variant vessels or the fibrosis of SANT. Likewise, SANT would not contain littoral cell-lined cysts of a littoral cell angioma.

Hemangiomas are the most common primary tumors of the spleen. Grossly, they are usually bloody and cystic. They resemble hemangiomas at other sites and are often cavernous. They express Factor VIII and CD31 but lack CD8 expression. Hemangiomas do not show the three types of variant vessels that are identified in SANT. Except for sclerosing hemangiomas, fibrosis is also not a typical component in these lesions.

Hamartomas are rare, well-circumscribed lesions, which are made up of red pulp elements. They are composed of a proliferation of sinuses, similar to that of the surrounding red pulp. White pulp elements are distinctly not present in these lesions. Unlike the dense fibrous stroma of SANT, the stroma in a hamartoma is loose with inflammatory cells, spindle cells, and less fibrosis. The lining cells are positive for CD8, similar to normal red pulp sinuses, which can help to differentiate it from other vascular lesions. CD31 and Factor VIII are also positive.

Inflammatory pseudotumors are well-circumscribed and usually singular. The cut surface is white or yellow. They consist of a mixture of lymphocytes, plasma cells, and possibly neutrophils and eosinophils, with areas of fibrosis containing benign-appearing spindle cells. They do not consist of the angiomatoid nodules seen in SANT.

1. Which of the following is true regarding sclerosing angiomatoid nodular transformation of the spleen?
   1. Contains significant focal atypia
   2. Diffusely infiltrates the spleen
   3. High tendency to recur after excision
   4. Majority of patients present asymptomatically
   5. Tendency to spontaneously involute
2. Which of the following favors a diagnosis of sclerosing angiomatoid nodular transformation of the spleen, as compared to littoral cell angioma?
   1. Cystic spaces
   2. Endothelial cells expressing CD68
   3. Presence of anemia and/or thrombocytopenia
   4. Unifocal lesion
   5. Vascular papillary projections
3. Of the following vascular neoplasms, which of the following is most likely to have lining cells expressing Factor VIII, CD31, CD68, and are negative for CD34 and WT-1 on immunohistochemical staining?
   1. Angiosarcoma
   2. Hamartoma
   3. Inflammatory pseudotumor
   4. Littoral cell angioma
   5. Sclerosing angiomatoid nodular transformation

1. Auerbach A. Diagnostic Pathology: Spleen. 1st ed. Salt Lake City, UT: Amirsys Inc; 2014:2:86-91.
2. Falk GA, Nooli NP, Morris-Stiff, et al: Sclerosing angiomatoid nodular transformation (SANT) of the spleen: case report and review of the literature. Int J Surg Case. 2012;3(10):492-500.
3. Giorlandino A, Caltabiano R, Lanzafame S. A case of sclerosing angiomatoid nodular transformation of the spleen. Pathologica. 2013;105:3:94-97.
4. Lewis, RB, Lattin GEJr, Nandedkar N, Aguilera NS. Sclerosing angiomatoid nodular transformation of the spleen: CAT and MRI features with pathologic correlation. AJR Am J Roentgenol. 2013;200:4:W353-360.
5. Metin MR, Evrimler S, Cay N, Cetin H: An unusual case of Sclerosing angiomatoid nodular transformation: radiological and histopathological analyses. Turk J Med Sci. 2014;44(3):530-533.
6. O’Malley DP, Kim YS, Weiss LM: Distinctive immunohistochemical staining in littoral cell angioma using ERG and WT-1. Ann Diagn Pathol. 2015;19(3):143-145.
7. Pradhan D, Mohanty SK. Sclerosing angiomatoid nodular transformation of the spleen. Arch Pathol Lab Med. 2013;137(9):1309-1312.

2016
Emily Heckendorn, DO
Pathology Resident
Walter Reed National Military Medical Center
Bethesda, Maryland

Aaron Auerbach, MD, MPH
Surgical Pathology Committee
The Joint Pathology Center
Silver Spring, MD

1. Majority of patients present asymptomatically (d)
2. Unifocal lesion (d)
3. Littoral cell angioma (d)