—  SHORT COURSE #39  —

Neoplastic Disorders Of The Spleen

Section 7 - Mesenchymal Tumors, Metastases and Non-Neoplastic Disorders That Mimic Neoplasms

Attilio Orazi
Dennis P. O'Malley


Splenic Vascular Tumors

Because of its vasculature-rich architecture, the spleen presents with a variety of vascular neoplasms, both benign and malignant [Table 7-1]. The features of several of these are covered below [1, 2, 3].

Hemangiomas
Capillary and cavernous hemangiomas occurring in the spleen are solitary or less commonly multiple [1, 2, 3]. Their gross appearance is of a non-encapsulated mass with irregular borders that is hemorrhagic and spongy. Prominent cystic changes may occur, as can thrombosis and infarction. Their morphologic features are similar to those observed elsewhere. Immunohistochemically, they are positive for vascular markers (CD31, vWF, Ulex) and for CD34 and negative for CD8. Problems in differential diagnosis are occasionally encountered in cases of diffuse angiomatosis and littoral cell angiomas (LCA). Diffuse hemangiomatosis is a congenital condition with multiple organ involvement by hemangiomas. Besides spleen, involvement often includes the liver, bone marrow, and less commonly, the skin. These "diffuse" benign conditions need to be distinguished from the highly malignant angiosarcoma of the spleen. Occasionally, capillary hemangiomas can have large amounts of sclerosis. When this occurs, they can closely resemble inflammatory pseudotumor (discussed below).

Littoral Cell Angioma
(Slide #9)

Littoral cell angioma (LCA) [1, 2, 3, 4] is a vascular neoplasm unique to the spleen, with no counterpart in soft tissue. LCA is most often found as an incidental finding in a radiologic evaluation. There is a well-documented but poorly understood association between LCA and second malignancies including lymphomas, carcinomas, etc.

The histogenesis may be related to that of cell that lines the red pulp sinuses (littoral cell). Grossly, LCA most often appear as multiple spongy, cystic nodules. The endothelial cells are usually plump and cuboidal. A distinctive feature is focal aggregates of intracytoplasmic eosinophilic globules [3]. Papillary projections of LCA cells may protrude into the vascular spaces. Vascular lumens also contain abundant desquamated littoral cells and macrophages (sometimes exhibiting erythrophagocytosis). Mild cytological atypia may be present.

A recent study suggests that intermediate between LCA and angiosarcoma is a neoplasm termed littoral cell hemangioendothelioma [5]. This tumor is purported to have a more aggressive clinical behavior than its benign counterpart. It is reasonable to assume that there is a spectrum of clinical behavior in these neoplasms, but that LCA is by far the most common, and is benign. The malignant features that distinguish a more aggressive neoplasm from LCA include cellular atypia and higher mitotic activity and an arborizing, highly-anastomotic or solid pattern of growth. Rare cases of malignant littoral cell tumors (termed littoral cell angiosarcoma) have been reported [6]; they are characterized by distinctly malignant features including necrosis, severe cytologic atypia and more than rare mitoses [6].

The most useful vascular markers in LCA are CD31, vWF, and Ulex, which stain the majority of cases. CD34 is uniformly negative. They are also variably positive for CD68 and CD21. LCA may rarely express CD8, typical of splenic sinusoidal endothelium, although more recent publications suggest that they are more often negative.

Angiosarcoma
Angiosarcomas of the spleen are rare, usually multifocal proliferations, heterogeneous in morphology and clinical behavior [1, 2, 3, 7]. They are usually symptomatic, as compared to the benign splenic vascular lesions. They often present with splenomegaly, and rarely with spontaneous rupture. In low grade lesions, they may resemble littoral cell angiomas, but they contain areas of unequivocal malignancy [7].

High-grade angiosarcomas in the spleen usually contain solid areas with spindle-cell morphology and little evidence of vascular differentiation. In these cases the differential diagnosis includes other spindle cell sarcomas; most of these have been regarded as examples of malignant fibrous histiocytoma in older publications. The most useful marker for confirmation of the vascular nature of a poorly differentiated sarcoma is CD31.

The presence of CD8 and/or CD68 positivity in some of these tumors supports the concept that a subset of angiosarcomas may arise from sinusoidal endothelium.

Kaposi sarcoma is a vascular tumor of intermediate malignancy (1-3). It has locally aggressive behavior and can recur and metastasize. The spleen is not commonly involved. As anticipated, the tumor, which is often multifocal, is localized to the trabeculae and/or the red pulp. The histologic findings are similar to that of other body sites: slit-like vascular space formed by spindle shaped endothelial cells. The majority of these tumors are seen in patients with HIV/AIDS, and there is often evidence of HHV-8 infection.

Lymphangioma
Lymphangiomas are thin-walled cysts of various sized lined by a flat endothelial cells, and they contain watery, pink proteinaceous materials but not blood [1, 2, 3]. Not uncommonly, lymphangiomas of the spleen are part of congenital syndromes of diffuse lymphangiomatosis. More rarely they are found as incidental isolated masses in the spleen. They are typically multicystic in appearance and are most often found in subcapsular or paratrabecular locations. Cytologically, the lining cells are quite bland. Papillary projections of these cells may project into the lumen of the cyst. Foamy macrophages and cholesterol clefts are commonly seen. They are positive for CD31, Ulex, vWF and negative for CD34 and CD8. Arber et al [24] found that many of their cases, originally thought to be lymphangiomas, were in fact mesothelial cysts. Although lymphangiomas undoubtedly exist, any cystic space filled with watery, proteinaceous fluid should be evaluated by a keratin stain. If the lining is keratin positive, then it is more likely a mesothelial cyst rather than a lymphangioma.

Peliosis is a rare condition, of unknown etiology, that may mimic true neoplastic vascular lesions [2, 8]. It consists of ectatic sinusoids and blood-filled cysts that are present throughout the organ [9]. Smaller cysts are lined by sinusoidal endothelium but in larger lesions this is often absent. The cysts are often located adjacent to the PALS and in the perifollicular zones. Its clinical importance lies in its association with spontaneous splenic rupture, due to a combination of spleen enlargement and fragility of the dilated, cystic sinusoids.

Nonvascular Stromal Tumors

Follicular dendritic cell tumor (FDCT) or follicular dendritic cell sarcoma is a rare neoplasm derived from the follicular dendritic cell of the germinal center, which has been observed to occur rarely in the spleen [9]. FDCT are characterized grossly by fleshy or solid nodules and, histologically, by oval or spindle cells usually growing in bundles and whorls. Nuclei are bland in appearance, and have a low mitotic rate. The neoplastic cells are typically CD21 and CD35 positive. The clinical behavior of these tumors appears to be more aggressive than the relatively bland cytology would suggest. Unfavorable prognostic factors include coagulative necrosis, > 5 mitoses per 10 hpf, size >6 cm and significant cellular atypia or pleomorphism [9]. A variant, which simulates inflammatory pseudotumor, can also be seen (see discussion below under Inflammatory pseudotumor).

The etiology of dendritic cell tumors is unknown, although a minority of cases has been associated with the plasma cell variant of Castleman Disease. There may be an association with low-grade B-cell lymphomas as well.

Interdigitating dendritic cell tumor (IDCT) is a rare tumor that is thought to arise from interdigitating dendritic cells [10]. The disease usually involves lymph nodes, but splenic involvement may occur in disseminated cases. The gross and histologic features of IDCT are similar to those described above for FDCS. In paraffin sections, the cells are positive for S-100 and variably positive for CD68; lack CD1a, B-cell, T-cell, and specific follicular dendritic cell antigen expression.

Angiomyolipoma can rarely be identified in the spleen, as part of involvement by multifocal disease. There has been a single case report [11] of primary splenic angiomyolipoma. As in renal and other sites, the typical histologic picture is that of mature fat, smooth muscle and vascular components. Immunohistochemical staining is typical, including at least focal positivity for HMB-45.

Other Nonvascular Sarcomas of the Spleen
Rare sarcomas may present with secondary involvement of the spleen. It is extremely unlikely that the spleen would serve as a primary site for a sarcoma. The most common subtype of sarcoma reported is malignant fibrous histiocytoma (MFH). However, with current revisions of soft tissue classification, and the extreme rarity of this tumor, subclassification of these tumors is unlikely to be adequately addressed anytime soon. A single case showing rhabdomyosarcomatous differentiation has been reported.

Inflammatory Pseudotumor
(Slide #10)

Historically, inflammatory pseudotumor (IPT) has been used as a catch-all term for identifying distinct entities that can occur in the spleen, some of which are clonal rather than 'pseudotumor' [2, 12, 13, 14, 15]. These entities are biologically distinct but have considerable morphologic overlap. There are three main categories: clonal neoplasms of myofibroblastic cells (inflammatory myofibroblastic tumor); clonal neoplasms of follicular dendritic cells that are associated with EBV infection (inflammatory pseudotumor-like follicular dendritic cell tumor); and polyclonal entities that are truly 'inflammatory' and probably not uncommonly infection-related [Table 7-2]. Any of these lesions can mimic a malignant process of the spleen clinically, and often radiologically and grossly. IPT is often asymptomatic; occasional patients have abdominal pain or sense of fullness.

Splenic IPT usually presents as a solitary, circumscribed pale whitish nodule. The borders can be well-circumscribed or vague and indefinite.

Histologically, the common findings observed in the majority of IPT include a proliferation of bland looking spindle-shaped cells within a polymorphic background, which contains a variable number of monocytes, lymphocytes, granulocytes, and polyclonal plasma cells.

Inflammatory myofibroblastic tumor (IMT) is a true neoplasm of spindle cells of myofibroblastic lineage. The clinical findings show a female predominance and a wide age range of presentation. The behavior is variable with splenectomy being curative in most cases, but rarely there are recurrences and even metastatic spread. IMT may be associated with other malignancies including various carcinomas and Hodgkin lymphoma. Immunohistochemical staining smooth muscle actin is positive in the spindle-cell population. Occasional cases of IMT may show positivity with ALK and p80 staining, a result which confirms their neoplastic nature.

A relatively recently described clonal entity which may be observed in the spleen is the inflammatory pseudotumor-like follicular dendritic cell tumor (IPTLFDC) [2, 16]. Unlike conventional follicular dendritic cell tumor (see previous section), IPTLFDC has a marked female predominance. The clinical behavior is typically indolent. As the name implies, IPTLFDC shows IPT-like background which contains bland spindle cells positive for dendritic cell markers (see section on FDCT. Essentially all cases are positive for EBV.

Most of the splenic IPT belong, however, to the category of true reactive inflammatory lesions. These are predominantly composed of histiocytes, neutrophils, polyclonal plasma cells and fibroblasts. Extensive sclerotic changes are commonly observed in these cases. Review of the clinical history may rarely reveal an infectious etiology, but typically studies for specific organisms are negative in the splenic tissues.

Distinction from cases of diffuse large-cell lymphoma with prominent sclerosis can be greatly facilitated in these cases by IHC and/or molecular techniques. In addition to splenic lymphoma, the differential diagnosis of splenic IPT also includes splenic hamartoma and hemangioma. Splenic hamartomas are typically surrounded by a rim of compressed red pulp usually without associated fibrosis. In addition, the sinus or cordlike spaces characteristically observed in the splenic harmartoma are not observed in IPT.

Splenic capillary hemangiomas with sclerosis may occasionally resemble IPT. These will tend to have a predominant component of small vessels with increased numbers of histiocytes. Their histologic pattern is often lobular in appearance. They can be differentiated by immunohistochemistry, highlighting the vascular nature of lesion. This entity may correspond to the "cord capillary hemangioma" described by Krishnan and Frizzera [12].

Tumor-like Lesions
Several benign lesions involving the spleen can grossly mimic malignant lymphoma by virtue of the production of mass lesions that may be associated with hypersplenism, although their benign nature usually is readily apparent microscopically.

Splenic Cysts
Splenic cysts are most commonly single and unilocular. The majority of these are so-called false cysts that lack epithelial linings [17, 18, 19]. These are often the result of previous trauma to the spleen, with hematoma formation and subsequent resolution. Approximately 20% of splenic cysts have an epithelial lining, which usually is of stratified squamous type. These are termed true cysts or epidermoid cysts. Rarely, true cysts can result in hypersplenism. As mentioned previously, lymphangiomas can easily be confused with mesothelial-derived cysts. A keratin stain will be positive in the lining of a mesothelial cyst [24].

Splenic Hamartoma
Similarly, splenic hamartomas occasionally may result in hypersplenism [2, 12, 20], although they are more commonly found as incidental findings at autopsy or in spleens removed for unrelated causes. Splenic hamartomas are usually well-circumscribed nodules that resemble normal red pulp histologically with slit-like vascular spaces lined by plump endothelial cells of littoral cell derivation (i.e. CD8 positive). Splenic trabecular architecture and white pulp structures are only rarely seen in hamartomas, although scattered lymphocytes often are found. They can be easily distinguished from capillary hemangioma by virtue of their immunohistochemical reactivity with CD8 and CD68 and lack of CD34 expression [21]. Unlike LCA, they are negative for CD21.

Recently, Krishnan and Frizzera have proposed four subtypes of splenic hamartoma; the classical type, cord capillary hemangioma, myoid angioendothelioma, and histiocyte-rich type [12]. They propose that each subtype presents with a dominant expression of one or more component of the splenic red pulp. The cord capillary type differs from classical hamartoma because of: striking lobularity, bands of fibrosis, abundant plasma cells and a CD34+, /CD8- phenotype of the vascular lining cells. In our opinion, this lesion may overlap with splenic capillary hemangioma with sclerosis (see above). The myoid angioendothelioma (originally described as "benign vascular neoplasms of the spleen with myoid and angioendotheliomatous features" by Kraus and Dehner), is a vascular lesion lined by CD34+ cells, with prominent stromal cells positive for smooth muscle actin and muscle specific actin [22]. The histiocyte-rich type has a predominance of histiocytes, including pseudosinuses lined by CD68+ histiocytes, not endothelial cells. The latter two lesions are exceptionally rare. It is unclear if the division into these subgroups has any clinical significance.

Metastatic Tumors
Metastatic tumors are uncommon in the spleen, perhaps because of the absence of splenic afferent lymphatics. A large variety of types of carcinomas, as well as melanoma, and more rarely sarcomas, have been reported in the spleen [2, 23]. Most cause tumor masses, but some may infiltrate the organ diffusely.

Table 7-1 Summary of Findings of Vascular Neoplasms of the Spleen
Diagnosis Features Immunos/Special Studies
Non-neoplastic Peliosis Rare. Unknown etiology. Ectatic sinusoids and blood-filled spaces. Endothelial lining positive for CD31/FVIII/Ulex
Hamartoma Red pulp, very little or no white pulp seen. CD31+, FVIII+, CD8+
Benign neoplasms Angiomyolipoma Very rare. Combination of adipose tissue, abnormal blood vessels and smooth muscle. HMB-45 positive
Hemangioma Most common vascular neoplasm of spleen. Cavernous or capillary. Single or multiple. Similar features to other body sites. CD31+, FVIII+
CD34+
Lymphangioma* Flattened lining cells. Filled with proteinaceous fluid. Rarely single, more often part of multisystem lymphangiomatosis Must rule out mesothelial cyst which are keratin +. Lined by CD31+ FVIII+ CD34- cells.
Littoral cell angioma (LCA) Neoplasm of sinus lining cells. Larger, plump cells. May have papillary features and form cystic spaces. Focal hemophagocytosis CD31+, FVIII+, CD34-, CD68+, CD21+
CD8 usually -
Neoplasms with potentially aggressive behavior Littoral cell Hemangioendothelioma Intermediate-grade malignancy with features similar to LCA. Often increased cellularity or atypia or increased mitoses or focal necrosis Similar to LCA
Kaposi Sarcoma Vascular neoplasm. Typically seen in HIV/AIDS patients. Small slit-like vascular spaces, with spindled endothelial cells. CD31+, FVIII+, CD34+, most HHV8+
Malignancy LC angiosarcoma Very rare. Malignant vascular tumor with similar histologic or immuno features of LCA CD31/FVIII/Ulex variably positive. CD68+
Angiosarcoma Vascular malignancy. May have solid areas. Anaplasia, mitoses, necrosis not uncommon. CD31/FVIII/Ulex variably positive. CD34 + in 50%. CD8 variable.

*Many 'lymphangiomas' are actually thin-walled mesothelial-derived cysts, which stain positive for cytokeratin.

Table 7-2 Differential Diagnosis of Inflammatory Pseudotumor of Spleen
Etiology Distinguishing Features
Inflammatory pseudotumor Reactive, most probably secondary to infectious causes. Prominence of inflammatory and/or sclerotic changes. Clinical history
Inflammatory pseudotumor-like follicular dendritic cell tumor Neoplasm of follicular dendritic cells; EBV-associated. Spindle cells are CD21/CD35 positive; EBV positive.
Inflammatory myofibroblastic tumor Neoplasm of myofibroblastic cells. Increased smooth muscle actin/HHF-35 positive spindle cells; Occasionally ALK positive; cytogenetic abnormalities.
Capillary hemangioma with prominent sclerosis Benign neoplasm of vascular components. Simulates IPT but with prominent vasculature. Lobular nature of involvement is a diagnostic clue. Vascular markers highlight prominent capillaries.
Hamartoma Non-neoplastic proliferation of stromal components, simulating red pulp. Red pulp appearance with slit-like vascular sinuses. Little or no white pulp.



References
  1. Arber DA, Strickler JG, Chen YY, Weiss LM. Splenic vascular tumors: a histologic, immunophenotypic and virologic study. Am J Surg Pathol, 1997;21(17):827-835.

  2. O razi A, O'Malley DP. Pathology of the Spleen. In: Disorders of Lymph Nodes and Spleen. Jaffe ES, Vardiman J, Harris NL Eds. In press.

  3. Kutok JL, Fletcher CD. Splenic Vascular Tumors. Semin Diagn Pathol. 2003 May;20(2):128-39.

  4. Falk S, Stutte HJ, Frizzera G. Littoral cell angioma. A novel splenic vascular lesion demonstrating histiocytic differentiation. Am J Surg Pathol 1991;15:1023-1033.

  5. Ben-Izhak, O, Ben-Eliezer S, Vlodavsky E. Splenic littoral cell haemangioendothelioma: a new low-grade variant of malignant litorral cell tumour. Histopathology, 39:469-475, 2001.

  6. Rosso R, Paulli M, Gianelli U, Boveri E, Stella G, Magrini U. Littoral cell angiosarcoma of the spleen. Case report with immunohistochemical and ultrastructural analysis. Am J Surg Pathol 1995;19:1203-1208.

  7. Falk S, Krishnan J, Meis JM. Primary angiosarcoma of the spleen. A clinicopathologic study of 40 cases. Am J Surg Pathol 1993;17:959-970.

  8. Kohr RM, Haendiges M, Taube RR. Peliosis of the spleen: a rare cause of spontaneous splenic rupture with surgical implications. Am Surg 1993;59:197-199.

  9. Chan JKC, Fletcher CDM, Nayler SJ, et al: Follicular Dendritic Cell Sarcoma: Clinicopathologic Analysis of 17 Cases Suggesting a Malignant Potential Higher than Currently Recognized. Cancer 1997;79:294.

  10. Kawachi K, Nakatani Y, Inayama Y, et al. Interdigitating dendritic cell sarcoma of the spleen: report of a case with a review of the literature. Am J Surg Pathol 2002;26:530-537.

  11. Tang P, Alhindawi R, Farmer P. Case report: primary isolated angiomyolipoma of the spleen. Ann Clin Lab Sci 2001 Oct;31(4):405-410.

  12. Krishnan J, Frizzera G. Two Splenic Lesions in Need of Clarification: Hamartoma and Inflammatory Pseudotumor. Semin Diagn Pathol. 2003 May;20(2):94-104.

  13. Kutok JL, Pinkus GS, Dorfman DM, Fletcher CD. Inflammatory pseudotumor of lymph node and spleen: an entity biologically distinct from inflammatory myofibroblastic tumor. Hum Pathol 2001;32:1382-1387.

  14. Neuhauser TS, Derringer GA, Thompson LD, et al. Splenic inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and immunophenotypic study of 12 cases. Arch Pathol Lab Med 2001;125:379-385.

  15. Sarker A, An C, Davis M, Praprotnik D, McCarthy LJ, Orazi A. Inflammatory Pseudotumor of the spleen in a 6-year-old child: A clinicopathologic study. Arch Pathol Lab Med, 2003 Mar;127(3):e127-30.

  16. Cheuk W, Chan JK, Shek TW, et al. Inflammatory pseudotumor-like follicular dendritic cell tumor: distinctive low-grade malignant intra-abdominal neoplasm with consistent Epstein-Barr virus association. Am J Surg Pathol 2001;6:721-731.

  17. Burrig K-F: Epithelial (true) splenic cysts. Pathogenesis of the mesothelial and so-called epidermoid cyst of the spleen. Am J Surg Pathol 1988;12:275-281.

  18. Talerman A, Hart S: Epithelial cysts of the spleen. Br J Surg 1972;57:201-204.

  19. Tsakraklides V, Hadley TW: Epidermoid cysts of the spleen. A report of five cases. Arch Pathol 1973;96:251- 254.

  20. Rosati S, Frizzera G. Pseudoneoplastic lesions of the hematolymphoid system. In: Pathology of Pseudoneoplastic Lesions. Eds: Wick MR, Humphrey PA, Ritter JH. Lippincott-Raven, 1997: 449-543.

  21. Zukerberg LR, Kaynor BL, Silverman ML, Harris NL. Splenic hamartoma and capillary hemangioma are distinct entities: immunohistochemical analysis of CD8 expression by endothelial cells. Hum Pathol 1991:22:1258-1261.

  22. Kraus MD, Dehner LP. Benign vascular neoplasms of the spleen with myoid and angioendotheliomatous features. Histopathology. 1999 Oct;35(4):328-36.

  23. Wick MR, Scheitauer BW, Smith SL, Beart RW Jr. Primary nonlymphoreticular malignant neoplasms of the spleen. Am J Surg Pathol 1982;6:229-242.

  24. Arber DA, Strickler JG, Weiss LM. Splenic mesothelial cysts mimicking lymphagiomas. Am J Surg Pathol. 1997;21(3):334-338.