Neoplastic Disorders Of The Spleen
Section 7 -
Mesenchymal Tumors, Metastases and Non-Neoplastic Disorders That Mimic
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
Capillary and cavernous hemangiomas occurring in the spleen are solitary or less commonly multiple
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
Littoral cell angioma (LCA)
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
. 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 . 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 ; they are characterized by distinctly
malignant features including necrosis, severe cytologic atypia and more than rare mitoses .
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.
Angiosarcomas of the spleen are rare, usually multifocal proliferations, heterogeneous in morphology
and clinical behavior
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 .
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
Lymphangiomas are thin-walled cysts of various sized lined by a flat endothelial cells, and they
contain watery, pink proteinaceous materials but not blood
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 
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
It consists of ectatic sinusoids and blood-filled cysts that are present throughout the
organ . 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 . 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 . 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 . 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  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.
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'
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)
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
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 .
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 are most commonly single and unilocular. The majority of these are so-called false
cysts that lack epithelial linings
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
Similarly, splenic hamartomas occasionally may result in hypersplenism
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 . 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 . 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 . 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 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
Most cause tumor masses, but some may infiltrate the organ
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+|
| ||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
Table 7-2 Differential Diagnosis of Inflammatory Pseudotumor of
| ||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.|
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