Case 1 -
Lester J. Layfield, University of Utah, Salt Lake City, UT
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The patient is a 43 year old Iraqi American with a history of hypertension and hemophilia with Factor VIII deficiency. He has received numerous blood transfusions to help control his hemophilia. The patient is HIV positive secondary to multiple blood transfusions and also is known to be Hepatitis C positive. In May of 2009, the patient presented to Orthopedic Oncology Clinic with a large (20 cm) right thigh and hip mass. The mass was initially believed to be a massive hematoma based on his known history of hemophilia. Imaging studies including CT and MRI were equivocal for a neoplasm and a fine-needle aspiration was obtained. The FNA revealed rare atypical cells admixed with a large amount of blood. The patient underwent drainage and debulking of the suspected hematoma. Histologic evaluation of the specimen resulted in a diagnosis of malignancy. Following this diagnosis, the mass was resected. The patient was placed on chemotherapy and followed with CT examinations of the leg to detect possible recurrence as well as chest x-rays every three months. In October of 2011, multiple pulmonary nodules were detected as was an adrenal mass. Fine-needle aspiration of the adrenal mass was performed which yielded the material submitted for review.
Case 1 - Figure 1
Smear preparation showing a hypercellular area with many single cells and occasional small cell clusters. (Diff-Quik, x 200)
Case 1 - Figure 2
Single non-cohesive tumor cells with a polygonal shape. The nuclei are large and irregular. A single non-symmetrical mitotic figure is present. (Diff-Quik, x 200)
Case 1 - Figure 3
The individual neoplastic cells have moderate to abundant amounts of cytoplasm. The nuclei are eccentrically located and hyperchromatic often with large nucleoli. (Diff-Quik, x 400)
Case 1 - Figure 4
Cell block with tissue fragment composed of fibrous tissue surrounding groups of large epithelioid cells with abundant cytoplasm. (H&E, x 200)
Case 1 - Figure 5
Smear preparation containing a small cluster of tumor cells surrounding a clear lumen. (Diff-Quik, x 400)
Case 1 - Figure 6
Cell clusters composed of epithelioid and spindle-shaped cells. Many cells have a vacuolated cytoplasm. (Diff-Quik, x 600)
Case 1 - Figure 7
Oval to polygonal cells with large nuclei containing prominent nucleoli. Nuclei often have nuclear membrane irregularities. (Diff-Quik, x 1000)
Case 1 - Figure 8
Smear preparation containing occasional cells with atypical mitotic figures. (Diff-Quik, x 400)
Case 1 - Figure 9
Large tumor cells with multilobulated nuclear and large intracytoplasmic vacuoles. (Diff-Quik, x 1000)
Case 1 - Figure 10
Large mononuclear and binucleate tumor cells with abundant cytoplasm. (Diff-Quik, x 1000)
Case 1 - Figure 11
Large epithelioid cells some of which have vacuoles. The nuclei are often eccentrically located and have prominent nucleoli. (Diff-Quik, x 1000)
Case 1 - Figure 12
Multinucleated tumor giant cell. (Diff-Quik, x 1000)
Diff-Quik stained smears are of variable cellularity with areas of hypercellularity varying with
paucicellular areas dominated by red blood cells. The dominate cell type is a large polygonal or
epithelioid cell. These cells have moderate to abundant amounts of finely granular or vacuolated
cytoplasm. The nuclei are large and hyperchromatic with generally oval nuclei which may lie
eccentrically within the cell cytoplasm. Variability in nuclear size and shape is prominent with a
minority of cells having a "spindle" shape. The majority of cells are non-cohesive and lie individually
within the background. The nuclei contain prominent nucleoli or chromocenters. Nuclear membranes are
often slightly irregular but folds and grooves are not a prominent feature. Nuclear cytoplasmic
pseudoinclusions are not present. Occasional cells demonstrate erythrophagocytosis while others contain
a golden-brown pigment. Mitotic figures including atypical forms are present. Occasional cell clusters
are seen which may contain a central lumen. In most cases, the lumen is empty but occasionally contains
one or two red blood cells. The background is dominated by red blood cells but in some areas contains
necrotic cellular debris, fragments of disrupted cytoplasm and granules of golden-brown pigment.
- Malignant melanoma
- Clear cell sarcoma of tendon sheath (melanoma of soft parts)
- Epithelioid sarcoma
- Metastatic adenocarcinoma
- Epithelioid angiosarcoma/epithelioid hemangioendothelioma
- High-grade plasma cell dyscrasia
- True histiocytic lymphoma
Vascular neoplasms with an epithelioid morphology vary considerably in clinical behavior. These
neoplasms vary in aggressiveness from the benign epithelioid hemangioma (histiocytoid hemangioma) to
epithelioid hemangioendothelioma and epithelioid angiosarcoma.
of these lesions into benign, intermediate and malignant forms is based on the presence or absence of
cellular pleomorphism and architectural pattern. Recently, an apparently specific translocation has been
identified in epithelioid hemangioendotheliomas. These neoplasms appear to be characterized by a
non-random abnormality represented by t(1;3)(p36;3q25).
Epithelioid hemangiomas and epithelioid angiomatous nodules pursue a benign course but the former may
have considerable clinical and histologic overlap with Kimura's disease.  Kimura's disease
is a chronic inflammatory condition most commonly seen in the Asian population. While initially confused
with epithelioid hemangiomas, current data indicate that they are two entirely separate lesions with only
a few superficial histologic similarities.
Intermediate and high-grade epithelioid vascular neoplasms are usually easily separable histologically
from epithelioid hemangiomas. Epithelioid hemangioendotheliomas are characterized by a distinctive
architecture with definitive angiocentricity and a myxohyaline or chondroid background.
The cells of epithelioid hemangioendothelioma are arranged in short cords or chains rather than
surrounding vascular channels as seen in hemangiomas. Low-grade epithelioid hemangioendotheliomas are
characterized by bland cells without mitotic activity. This aids in their distinction from epithelioid
angiosarcomas. However, in approximately 20-25% of cases, the neoplastic cells of epithelioid
hemangioendotheliomas will show significant nuclear atypia and mitotic activity. These tumors may also
show focal spindling of the cells and/or necrosis. Such cases are difficult to separate from
angiosarcomas as well as some examples of soft tissue metastases from carcinomas and melanomas. In
distinction from epithelioid hemangioendotheliomas, epithelioid angiosarcomas are usually composed of
solid sheets of highly atypical and mitotically active neoplastic epithelioid cells. Necrosis is a
common finding in angiosarcomas. Vascular differentiation is demonstrated by the formation of irregular
sinusoidal vascular channels and occasional cells showing intracytoplasmic lumen formation or small
clusters of cells surrounding abortive lumens.
Immunohistochemical demonstration of CD31
and CD34 expression is helpful in defining the endothelial direction of differentiation for both
epithelioid hemangioendothelioma and epithelioid angiosarcoma. Unfortunately, some epithelioid vascular
neoplasms express cytokeratins.  This complicates separation of these neoplasms from poorly
differentiated metastatic adenocarcinomas.
The cytologic diagnosis of malignant spindle-cell vascular neoplasms (angiosarcomas and
hemangioendotheliomas) can be challenging. The cytologic differential diagnosis of the epithelioid
varieties of malignant vascular neoplasms appears even more complicated with a wide range of clinically
significant differential diagnoses. Epithelioid hemangioendotheliomas and epithelioid angiosarcomas may
be inseparable by purely cytologic evaluation. In general, however, epithelioid hemangioendotheliomas
contain a cellular component with less nuclear atypia than is characteristic of epithelioid
Smear specimens obtained from epithelioid angiosarcomas have been reported to vary considerably in
Liu and Layfield reported low cellularity in their
cases of epithelioid angiosarcoma. Minimo et al  reported smears obtained from epithelioid
angiosarcomas to be highly cellular. In a large series of angiosarcomas reported by Klijanienko et
the majority of angiosarcomas were cell rich (59%). The presence of a hemorrhagic
background is likewise variably present in published reports. Klijanienko found that only 31% of their
cases were characterized by a hemorrhagic background. Minimo et al  and Liu and
Layfield  reported that a hemorrhagic background was characteristic of epithelioid
angiosarcomas. Other authors have also reported a prominent bloody background.
Cytologic features characteristic of epithelioid angiosarcoma include single neoplastic cells and
small cell clusters, abortive vasoformative structures, papillary cell groups, rare intracytoplasmic red
blood cells and a dominant population of neoplastic polygonal or epithelioid cells.
The cytoplasm may show vacuolations or lumina.  Nuclear atypia
is of moderate to marked degree. In epithelioid forms of angiosarcoma, the cells are often grouped in
clusters including papillary and gland-like groups. High power examination of the cells reveals the
nuclei to have smooth membranes or membrane folds and irregularities. The cytoplasm stains dark blue in
Diff-Quik preparations. Giant cells are seen in approximately a quarter of cases of epithelioid
angiosarcoma.  Erythrophagocytosis is a common finding being present in approximately 40% of
cases. Erythrophagocytosis occurs both in isolated cells and in cells forming clusters. Mitotic figures
are found in only 20% of cases but may be of atypical form. Nucleoli are of variable character but are
often large and multiple. 
Epithelioid angiosarcomas are high grade lesions and a large number of neoplasms must be considered in
the differential diagnosis. Other epithelioid sarcomas must be considered including clear cell sarcomas
of tendon sheath (melanoma of soft parts), epithelioid sarcomas, some rhabdomyosarcomas and alveolar soft
part sarcomas. Because of the epithelioid appearance and cellular anaplasia, metastatic malignant
melanoma must also be excluded. This is especially true when golden-brown to black pigment is present
within some cells. Other significant considerations include metastatic poorly differentiated
adenocarcinoma and metastatic renal cell carcinoma.
Epithelioid sarcomas enter the differential diagnosis of malignant epithelioid vascular neoplasms.
Epithelioid sarcomas occur predominately in the extremities of young adults. These neoplasms
have a histiocytic appearance often with an inflammatory background. Epithelioid sarcomas are
characteristically keratin positive  but occasional angiosarcomas also express
cytokeratins.  This can result in misdiagnosis of epithelioid angiosarcomas. However, the
vacuolization and intracytoplasmic lumen formation seen within an epithelioid malignant vascular neoplasm
aids in the exclusion of epithelioid sarcoma from the differential diagnosis. Additionally, the presence
of hemosiderin in the background as well as phagocytized red blood cells supports the diagnosis of an
epithelioid malignant vascular neoplasm (angiosarcoma).
Rhabdomyosarcomas may be confused with epithelioid angiosarcomas. Both may show marked variation in
cell size and shape. Rhabdomyosarcomas are reactive with antibodies directed against muscle markers
including desmin, caldesmin, myogenin and muscle specific actin. Rhabdomyosarcomas are non-reactive
with antibodies directed against CD31 and CD34. Immunohistochemistry is of great aid in separating these
lesions. Additionally, most rhabdomyosarcomas occur in the pediatric age group while epithelioid
angiosarcomas are neoplasms of adults. Pleomorphic rhabdomyosarcomas are the most difficult to separate
from epithelioid angiosarcomas but the presence of intracytoplasmic lumina and vacuolization of the
cytoplasm favors the diagnosis of angiosarcoma.
Separation of epithelioid angiosarcomas from metastatic malignant melanoma and melanoma of soft parts
is particularly difficult. Both neoplasms can present as cellular smears composed of both single cells
and small cell clusters. Angiosarcomas and melanomas show marked nuclear atypia as well as
intracytoplasmic and/or extracytoplasmic pigment. Melanomas frequently show intranuclear cytoplasmic
pseudoinclusions and often greater degrees of nuclear irregularity than seen in epithelioid
angiosarcomas. Moreover, malignant melanomas are immunoreactive with antibodies directed against S-100
protein, melan-A and HMB45. These markers are not expressed in epithelioid angiosarcomas. Also helpful
in the separation of epithelioid angiosarcomas from malignant melanomas is the presence of
intracytoplasmic lumina and small vasoformative structures in angiosarcomas.
Separation of epithelioid angiosarcomas from metastatic adenocarcinomas can be challenging. Both
lesions may contain individual cells as well as small cell clusters. Similarly, both neoplasms may
contain cells with intracytoplasmic vacuoles/lumina and may form small cell clusters with a central
lumina or papillary fragments. Adenocarcinomas often form larger cell clusters or sheets which are not
seen in epithelioid angiosarcomas. Special stains are also helpful in that adenocarcinomas may contain
intra- or extracytoplasmic mucins which are absent from epithelioid angiosarcomas. Immunohistochemistry
is helpful. While some angiosarcomas may express cytokeratins,  differential staining for
cytokeratins including CK7, CK20, CK5/6 as well as epithelial membrane antigen may aid in establishing
the presence of an adenocarcinoma. The immunoreactivity of the neoplastic cells for CD31, CD34 and
FVIII-RA definitively demonstrates the endothelial direction of differentiation and establish the
diagnosis of a vascular malignancy.
The cytologic recognition of epithelioid malignant vascular neoplasms can be challenging. These
neoplasms are characterized by variable smear cellularity as well as a population of non-cohesive cells
and cells forming small clusters. The presence of intracytoplasmic lumina occasionally containing red
blood cells and small vasoformative cell clusters strongly suggests the diagnosis of epithelioid
angiosarcoma. Immunohistochemical staining for CD31, CD34 and FVIII-RA is helpful in separating these
malignancies from a variety of carcinomas, melanoma and other epithelioid sarcomas.
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