Pleomorphic Hyalinizing Angiectatic Tumor

Review Article
DOI: 10.17354/cr/2015/14
Pleomorphic Hyalinizing Angiectatic Tumor:
Immunohistochemical Study with Review of Literature
Vijayashree Raghavan1, K Shivaprashanth2, K Ramesh Rao3
Associate Professor, Department of Pathology, Chettinad Medical College and Research Institute, Chennai, Tamil Nadu, India, 2Post-graduate Student, Department of
Pathology, Chettinad Medical College and Research Institute, Chennai, Tamil Nadu, India, 3Professor and Head, Department of Pathology, Chettinad Medical College
and Research Institute, Chennai, Tamil Nadu, India
1
Pleomorphic hyalinizing angiectatic tumor (PHAT) is relatively a new entity that was described first in 1996. Although it is often confused
with neurilemmoma and low grade malignant fibrous histiocytoma, it is considered to be a distinctive neoplasm because of certain unique
microscopic and immunohistochemical findings. It is a low grade, slowly growing tumor that recurs after surgical removal in about a third
of all cases. It is not known to metastasize. In this review, we have immunohistochemically analyzed a case of gluteal soft tissue tumor in
a 22-year-old woman using CD 34, CD 68, CD 99, S100 and desmin. Classical histological features and positivity for only CD 34 helped in
establishing the diagnosis as PHAT. We have reviewed the available literature.
Keywords: CD 34/analysis, Extremities, Hyaline, Immunohistochemistry
INTRODUCTION
Pleomorphic hyalinizing angiectatic tumor (PHAT) is
a relatively recently recognized neoplasm. The term
was coined by Smith et al.1 to name a soft tissue tumor
that they had identified as a new entity as it exhibited
histological features distinctive enough to deserve separate
nomenclature. In their series of 14 cases, the tumor was
described as a low grade neoplasm with close resemblance
to neurilemmoma. In addition to neurilemmoma, it bears
a striking resemblance to low grade malignant fibrous
histiocytoma (MFH). WHO has categorized this tumor
as a benign neoplasm of uncertain differentiation in
its 2002 iteration of classification of tumors.2,3 Since its
recognition, less than 100 cases of this rare tumor have
been documented.4-7 From India, only one case has been
reported.8 In this article, we have analyzed a case of PHAT
immunohistochemically and reviewed the literature.
CLINICAL PRESENTATION
A 2 2 - ye a r - o l d y o u n g w o m a n p r e s e n t e d w i t h a
progressively enlarging mass in her right buttock. She
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first noticed it as a painless swelling about 2 months
prior to seeking medical attention. On examination,
her general condition was within normal limits. There
was no significant past or family history. The laboratory
investigations did not reveal anything unusual. The
swelling in the right gluteal region was painless, nontender and firm. It appeared well demarcated and mobile.
It was not adherent to overlying skin or underlying
structures. The mass was diagnosed clinically as
fibrolipoma and was surgically excised.
RESULTS
The specimen we received in pathology laboratory
consisted of an unencapsulated, firm, well-circumscribed
mass measuring 6 cm × 3 cm × 2 cm. It was partly
nodular. The cut surface was tan yellow with small foci
of brownish discoloration due to hemorrhage (Figure 1a).
The specimen was adequately sampled and processed for
paraffin embedding. A minimum of six 3 µ thick section
were cut from each block. Apart from routine hematoxylin
and eosin stain, immunohistochemistry was done using
novocastra (Leica) mouse monoclonal antibodies and
diaminobenzidine substrate to demonstrate the following
marker; CD 34. Demonstration of CD 68, CD 99, S100, and
desmin was outsourced and was done at Sri Ramachandra
University using BioGenex reagents.
Microscopically, the lesion was well demarcated but
without a capsule. It was highly vascular with a variable
cellularity. There were many large ectatic thin-walled
Corresponding Author:
Dr. K Ramesh Rao, Department of Pathology, Chettinad Medical College and Research Institute, Kelambakkam, Chennai - 603 103, Tamil Nadu,
India. Phone: +91-9884616318/9841829000. E-mail: [email protected]
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IJSS Case Reports & Reviews | January 2015 | Vol 1 | Issue 8
Raghavan, et al.: Pleomorphic Hyalinizing Angiectatic Tumor
blood vessels, often lying in clusters. Lumen of many of
these vessels was narrowed by subendothelial deposition
of fibrin like material. Some vessels were partially or
completely occluded by fresh or partially organizing
thrombi (Figure 1b). Many of the vessels were surrounded
by a zone of hyalinization that extended in between tumor
cells (Figure 2b). The tumor cells were either highly
pleomorphic or spindle-shaped. Many large cells with
multilobated nuclei or multiple nuclei were seen. Some
of these nuclei showed large intranuclear inclusions
(Figure 2c). The tumor exhibited variable cellularity. In
low cellularity areas, the tumor cells were dispersed in a
myxoid background with clusters of inflammatory cells
(Figure 2d). In spindle cell areas, tumor appeared more
cellular and resembled schwannoma. Despite the sinister
looking histology, mitotic figures were uncommon (<1/50
high power fields). Focal aggregates of hemosiderin and
siderophages were present (Figure 2a).
The tumor cells showed a strong membranous positivity
for CD 34 (Figure 3a). CD 68 stained only a few scattered
background leucocytes, but tumor cells remained unstained
(Figure 3b). The tumur cell nuclei failed to show any staining
with S100 (Figure 3c). They were completely negative for
desmin (Figure 3d) and CD 99 (Figure 3e).
a
b
Figure 1: (a) Gross appearance of the tumor, (b) Low power view of the tumor
showing ectatic blood vessels with mural fibrin and luminal thrombi (H and E, ×40)
a
b
c
d
Figure 2: Characteristic histologic features, (a) Hemosiderin pigment, (b)
perivascular hyaline, (c) intranuclear pseudo-inclusion (arrow), and cellular
pleomorphism, (d) inflammation and focal myxoid background (H and E, ×100
[B and D], ×400 [A and D])
IJSS Case Reports & Reviews | January 2015 | Vol 1 | Issue 8
The characteristic histology and distinctive immunological
profile were diagnostic of PHAT. Following surgical
excision, the patient has remained symptom-free for last
4 months.
DISCUSSION
PHAT was first recognized as a distinctive morphological
entity in 1996 by Smith et al.1 Majority of their cases arose
in the subcutaneous plane of lower extremities. Apart
from the presence characteristic thin walled ectatic blood
vessels, the authors noted a close resemblance to MFH and
neurilemmoma. Occasional expression of CD 34 by PHAT
helped it to be distinguished from MFH, while the absence
of S100 expression separated it from neurilemmoma. The
authors suggested that PHAT is a “low grade sarcoma of
uncertain lineage.” But, PHAT was included in 2002 WHO
classification of soft tissue tumors under “benign tumors
of uncertain differentiation.”2
Since its recognition, only about 100 cases of PHAT have
been documented. Folpe and Weiss9 have published the
largest series so far in which they analyzed 41 reported
cases. The clinical presentation of PHAT has been
summarized in several articles.9-11 The tumor affects broad
age-range. Youngest patient recorded to be affected by
the tumor so far was 10 years old, while oldest patient
was 89 years of age. Average age of incidence is 55 years.
Women are more frequently affected by the tumor than men
(F:M = 4:3). In the present study, the patient was 24-yearold female. The lesion presented as slowly enlarging,
painless, non-tender, unencapsulated mass in the gluteal
region. Almost all the cases reported in the literature have
been unencapsulated, slowly growing, painless masses
affecting lower extremities in nearly two-thirds of cases.
Sites of predilection include foot and ankle (~28%) and legs.
Less frequently affected sites include upper extremities,
chest, gluteal region, groin and back. The tumor has also
been reported in oral cavity,12 mesorectal soft tissue4 and
a
b
c
d
e
Figure 3: Immunohistochemistry, (a) CD 34, strong membranous positivity, (b)
CD 68, tumor cells negative, (c) S100, negative, (d) desmin, negative, (e) CD
99, negative (H-diaminobenzidine, ×100)
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Raghavan, et al.: Pleomorphic Hyalinizing Angiectatic Tumor
male breast.13 Size of the tumor may vary from less than a
centimeter to almost 20 cm.3,9,10
The morphological features of PHAT are now well
established.1,3,8,9,14 The major features include ectatic thinwalled vessels with subendothelial fibrin deposition and
luminal thrombi, perivascular hyalinization, pleomorphic
cells, intranuclear inclusions, inflammatory cells and
myxoid areas. All these features were present in our case
(Figures 1 and 2). The most characteristic histological
feature is the presence of ectatic thin-walled vessels in
clusters (Figure 1b). Smith et al. 1 speculated that the
vascular changes are probably secondary to release of
vasoactive amines by the large number of mast cells found
in the tumor. It may be also be due to slow encroachment
of the vessels by the tumor cells. According to Folpe and
Weiss,9 these vascular changes are seen even in early PHAT
and might lead to leakage and progression of the lesion.
Groisman et al.15 found increased expression of vascular
endothelial growth factor (VEGF) in perivascular tumor
cells and endothelial cells of normal vessels but not in the
endothelial cells of hyalinized vessels. They hypothesized
that the progressive hypoxia induced by hyalinized
vessels might trigger enhanced VEGF production and
neovascularization.
Despite the sinister looking histology, low or nearly absent
mitotic activity has been recorded in most reports. Cell
proliferation marker MIB-1 (Ki67) expression was found
to be very low by Ke et al.11 Flow cytometric analysis has
resulted in a diploid DNA histogram and an absence of
aneuploidy.11,15 These findings suggest that the cytological
pleomorphism is not related to tumor growth but is a
reflection of progressive degenerative change.9
Additional morphological changes that are seen sometimes
include areas resembling “hemosiderotic fibrohisticytic
lipomatous lesion” (HFLL), which Folpe and Weiss
considered to be an early form of PHAT and not as a
reactive lesion it was once thought to be.9 Similar view
was also expressed by Luzar et al.16 in their report on an
ankle swelling in a 47-year-old woman. That lesion had
the histological features of both HFLL and PHAT. They
too thought that HFLL is an early form of PHAT. In a more
recent report, Suzuki et al.17 documented a case of PHAT in
a 68-year-old woman that was completely surrounded by
HFLL. In our case, areas resembling HFLL were not found.
A variety of immunohistochemical stains have been used
to characterize the tumor immunologically. Only CD 34 has
been found to be fairly consistently but variably expressed
by the tumour.3,11,13,14,18-20 Some reports have claimed positive
immunohistochemical reaction for CD 99,8,13,15 VEGF11
and factor XIIIa,15 but in most of the studies, the tumor is
48
negative for CD 99. The tumor is also consistently negative
for CD 68, desmin and S100. This is particularly relevant
as lack of expression of CD 68 is useful in distinguishing it
from MFH with which it is most often confused. Similarly,
S100 helps to differentiate it from neurilemmoma, which is
usually strongly positive for S100. In our study, only CD 34
showed a strong membranous positivity. All other markers
used (CD 68, CD 99, S100 and desmin) were negative.
Other conditions with which PHAT might be confused
include solitary fibrous tumor, giant cell angiofibroma18
and cutaneous myxofibrosarcoma.21
Biological behavior of these tumors is predominantly
indolent. About one-third of these tumors is known to
recur after surgical removal. Although no cases of overt
metastasis have been reported, Kazakov et al.22 recorded
an instance of recurrence as a malignant neoplasm. In
their report, a 76-year-old woman initially presented with
a solitary axillary mass that was diagnosed as PHAT.
Seven months after its excision, the patient came back
with a rapidly growing tumor that had all the features of
myxofibrosarcoma.
Immunohistochemical analysis and ultrastructural studies
have so far failed to establish the histogenesis of this tumor.
While one electron microscopic study of the tumor cells
revealed features of primitive fibroblast with no specific
differentiation,11 another study has shown the presence
of ganglion like cells.20 For the present, this tumor is to be
considered a low grade, locally aggressive mesenchymal
neoplasm of uncertain histogenesis.
CONCLUSION
A case of PHAT in a 22-year-old woman has been analyzed
immunohistochemically using CD 34, CD 68, CD 99, S100
and desmin. It was found that it was positive only for CD
34, thus helping to differentiate it from neurilemmoma and
MFH, the two tumors with which it is often confused. At
present, its histogenesis remains uncertain.
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How to cite this article: Raghavan V, Shivaprashanth K, Ramesh Rao K.
Pleomorphic hyalinising angiectatic tumour: Immunohistochemical study with
review of literature. IJSS Case Reports & Reviews 2015;1(8):46-49.
Source of Support: Nil, Conflict of Interest: None declared.
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