# Dedifferentiated Liposarcoma of the Retroperitoneum with Extensive Leiomyosarcomatous Differentiation andβ

Authors: Michael J. Russell; Frederick L. Flynt; Allyson L. Harroff; Oluwole Fadare
Journal: Sarcoma
 (2008-02-24)

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## Abstract

Dedifferentiated liposarcomas may display a variety of “heterologous” lines of differentiation, including osseous, vascular, skeletal, and/or smooth muscular. There have been six previously reported examples of leiomyosarcomas associated with high levels of serum human chorionic gonadotropin (hCG) production, comprised of cases originating from the retroperitoneum, spermatic cord, small intestine, and uterus. This report describes the first example of a dedifferentiated liposarcoma that combined both of the aforementioned features: extensive heterologous (leiomyosarcomatous) differentiationandβ-hCG production (maximum serum levels 1046 mIU/ml, reference <5 mIU/ml). The tumor, which originated in the retroperitoneum in the region of the right kidney, was rapidly progressive and ultimately fatal within three months of its diagnosis. In addition to characteristic morphologic features, lipogenic and smooth muscle differentiation were confirmed with immunohistochemical stains for MDM2 and smooth muscle actin, respectively. The tumor also displayed diffuse immunoreactivity for β-hCG in both primary and metastatic sites. This case further expands the clinicopathologic spectrum of lipogenic tumors.


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## Body

## 1. Introduction

The term “tumor dedifferentiation” and its
underlying concepts, as used by contemporary surgical pathologists, are based
on the paradigm originally outlined by Dahlin and Beabout in low-grade chondrosarcomas [1].  Tumor dedifferentiation is characterized by
the “emergence” of an undifferentiated component (phenotypically unrecognizable
as to histogenesis) from an otherwise low-grade/borderline neoplasm, with
well-defined morphologic demarcations between the aforementioned areas and a
relatively worsened clinical course. The phenomenon of tumor dedifferentiation
has subsequently been described in a wide variety of bone, soft tissue, and
epithelial and neural neoplasms [2].Tumor dedifferentiation is probably most well
characterized in lipogenic tumors. Although it had been previously noted that
well-DDLS and pleomorphic sarcomas may be admixed [3, 4], dedifferentiated
liposarcoma (DDLS) was formally described by Evans in 1979 [5]. In a series of
55 liposarcomas, 8 cases (7 retroperitoneal, 1 spermatic cord) were noted to
display “distinct areas of well-differentiated liposarcoma and of cellular
spindle cell or pleomorphic sarcoma without recognizable lipogenesis” [5]. None
of the latter cases displayed a mitotic count of >5/10 high power fields,
and the cellular areas were often sharply demarcated from the
well-differentiated areas [5].
Subsequent reports indicated that (a) dedifferentiation in well-DDLS is
probably not anatomic site specific but time dependent [6], (b) most
retroperitoneal tumors previously classified as malignant fibrous histiocytomas
are actually DDLS [7], (c) most examples of DDLS
present as de novo lesions
rather than as a complication of a preexisting well-differentiated liposarcoma
[8], (d) DDLS may be classified into high and low grade depending on mitotic
activity and cellularity, although the prognostic significance of this
gradation is unclear [8–11].As with their clinical spectrum, the
pathologic spectrum of DDLS has been similarly expanded. Newer morphologic
observations have included a potentially poorly defined interface between the
DDLS and its well-differentiated component [8],
whorled, meningothelial-like structures [8, 12–14], a prominent inflammatory component [9], a
micronodular growth pattern [9], a hemangiopericytomatous vascular pattern
[8, 9], and heterologous differentiation [8, 9, 14–20].Chondroid metaplasia, rhabdomyosarcomatous,
and smooth muscular differentiation have been described in well-differentiated
and myxoid liposarcomas [2, 21–24]; the term lipoleiomyosarcoma is commonly used for
morphologic admixtures of well-differentiated liposarcoma and leiomyosarcoma.
[23]. However, the probability for histologic misclassification is highest when
high-grade DDLS displays heterologous differentiation [4, 5, 8, 9, 11–16]. Lines of
heterologous differentiation that have been described in DDLS include
leiomyosarcomatous, osteochondrosarcomatous, angiosarcomatous, and
rhabdomyosarcomatous and do not appear to have independent prognostic
significance [4, 5, 8, 9, 11–16, 25]This report describes an example of a retroperitoneal
DDLS with extensive leiomyosarcomatous differentiation that was accompanied by
high levels of serum beta-human chorionic gonadotropin (β-hCG).
This composite of findings has, to our knowledge, not been previously reported.


## 2. Clinical History

In 2006, a 67-year-old Caucasian female presented
with episodic right upper quadrant abdominal pain and associated nausea. Her
past medical history was significant for an infiltrating ductal breast
carcinoma (treated with radical mastectomy followed by 4 cycles of adriamycin
in 1999), a stable plasma cell dyscrasia (multiple myeloma diagnosed by a bone
marrow biopsy and serum protein electrophoresis in 2003, treated with high dose
chemotherapy, and which was associated with a mild normocytic anemia in the ensuing
period), and a hysterectomy/salpingo-oophorectomy (for benign indications). A
computed tomographic (CT) scan of the abdomen showed a heterogeneously
enhancing mass extending from the inferior right renal pole exophytically, with
significant associated inflammatory changes and some peripheral coarse
calcifications. Portocaval and mesenteric adenopathy were also present. Serum
levels of alpha-fetoprotein, carcinoembryonic antigen, CA15-3, and CA27-29 were
within normal limits. Notably, a serumβ-hCG, requested inadvertently, measured 210.3 mIU/ml
(reference value for nongestational adults <5 mIU/L).Given the high suspicion for a renal cell
carcinoma, the right kidney was resected as well as all grossly identifiable
perinephric tumor. Intraoperatively, the mass was noted to be prominently adhered to the
surrounding retroperitoneal tissue. A follow-up serumβ-hCG, which was measured 26 days after the
first measurement and 25 days after her surgical procedure, measured 1046 mIU/ml. An
abdominal CT scan performed shortly thereafter revealed multiple hypodense
liver masses measuring up to 5 cm, with an increase in the aforementioned
portocaval adenopathy.  Biopsy of one of
the hepatic masses confirmed the presence of metastatic disease. The patient
declined further therapeutic measures and expired 2 months later. An autopsy
was not performed.


## 3. Materials and Methods

Twenty sections of the retroperitoneal mass
were routinely processed for microscopic evaluation. The liver biopsy was similarly
processed. For immunohistochemistry, 4-5μ-thick sections were cut and mounted
on a glass slide, deparaffinized and rehydrated. Appropriate negative and
positive controls were included. All assays were carried out in an Axiom 36
autostainer (Lab Vision Corporation, Fremont, Calif, USA). The
following markers were evaluated in the liver biopsy and a representative
section of the retroperitoneal mass, in parallel:  β-hCG (clone
CG04+CG05, prediluted, Lab Vision), keratin cocktail comprised of clones
AE1/AE3 (Signet Corporation, Dedham, Mass, USA) and LP34 (DakoCytomation,
Carpinteria, Calif, USA), dilution 1 : 200, Smooth muscle actin: SMA (clone1A4,
prediluted, Lab  Vision), Estrogen
receptor-alpha: ER-alpha (clone ID5, dilution 1 : 50, DakoCytomation),
Progesterone receptor: PR (clone PgR 636, prediluted, DakoCytomation), Desmin
(clone D33, prediluted, Lab Vision), Epithelial membrane antigen (EMA) (clone
E29, prediluted, ThermoFisher Scientific, Fremont, Calif, USA),  MDM2 (clone IF2, dilution 1 : 100, Lab Vision),
and placental-like alkaline phosphatase: PLAP (Clone SP15, prediluted, Lab Vision).


## 4. Pathologic Features

### 4.1. Macroscopic

The kidney and associated perinephric tissue measured in aggregate21×10×7 cm.
Sectioning revealed an inferior pole mass measuring 9.5 cm in maximum
dimension, which compressed and distorted the renal pelvis and the tissue in
this region. The cut surface of the mass was largely firm and solid, tan-white
in color, with hemorrhagic areas but no grossly identifiable necrosis.


### 4.2. Morphologic Features

The retroperitoneal tumor displayed the characteristic morphologic features of
DDLS. In the well-differentiated component, large coarse fibrotic bands were
observed irregularly, coursing through lobules of well-differentiated
adipocytes. Within the fibrous bands, the perivascular regions and within the
adipocytic lobules were scattered cells with large irregular and hyperchromatic
nuclei (Figure1). The mitotic
index in these regions was low. The dedifferentiated component comprised
approximately 80% of the tumor mass. The interface between the
well-differentiated and dedifferentiated components was variable: the interface
was well demarcated in some regions (Figure 2), and highly
irregular/infiltrative in others. The central portion of the mass was necrotic,
while the surrounding areas, comprising approximately 10% of the mass were
hypocellular and hyalinized. However, atypical cells well still recognizable in
these regions. The remainder of the mass displayed a spectrum of pathologic
changes with respect to cellularity, mitotic activity and atypia. Nonetheless,
the tumor was predominantly a high-grade pleomorphic spindle cell sarcoma. In
the most hypocellular regions, scattered atypical cells were clearly evident in
a hyalinized background and displayed a maximum mitotic index of 11 MF/10 high
power fields. Other areas were significantly more cellular, and were comprised
of cells with hyperchromatic nuclei arranged in vague fascicles (Figure 3).
These areas displayed the highest mitotic activity (maximum 36 MF/10 high power
fields). Constituent cell displayed variable amounts of eosinophilic cytoplasm
(Figure 4). The growth pattern of the tumor relative to the adjacent kidney was
largely to displace it. However, there were areas where the tumor appeared to
infiltrate in an interstitial pattern, with glomeruli encircled by tumor cells.
The portions of the tumor not comprised of spindle cells were comprised of
nondescript pleomorphic cells. Lipoblasts were evident throughout the tumor and
there were no morphologically-recognizable syncytiotrophoblasts. The portion of
the liver mass that was sampled was comprised predominantly of spindle cells as
described above.Figure 1
Well-differentiated component of the liposarcoma, showing atypical cells
with nucleomegaly and hyperchromasia scattered within mature adipocytes and
intervening fibrous septae.Figure 2
The interface between the well-differentiated and dedifferentiated
components.Figure 3
Cellular areas of the dedifferentiated component.Figure 4
Some areas of the dedifferentiated component were comprised of cells with varying amounts of
eosinophilic cytoplasm.


### 4.3. Immunophenotypic Features

The retroperitoneal tumor and liver mass
displayed an identical immunoprofile, consistent with the latter being a
metastatic deposit from the former. Both displayed diffuse immunoreactivity for
desmin, SMA,β-hCG (Figure 5),
and MDM2 (Figure 6). The tumors were
negative for ER, PR, EMA, PLAP, and keratins.Figure 5
The tumor cells displayed diffuse immunoreactivity forβ-hCG.Figure 6
The tumor cells displayed diffuse immunoreactivity for MDM2.


## 4.1. Macroscopic

The kidney and associated perinephric tissue measured in aggregate21×10×7 cm.
Sectioning revealed an inferior pole mass measuring 9.5 cm in maximum
dimension, which compressed and distorted the renal pelvis and the tissue in
this region. The cut surface of the mass was largely firm and solid, tan-white
in color, with hemorrhagic areas but no grossly identifiable necrosis.


## 4.2. Morphologic Features

The retroperitoneal tumor displayed the characteristic morphologic features of
DDLS. In the well-differentiated component, large coarse fibrotic bands were
observed irregularly, coursing through lobules of well-differentiated
adipocytes. Within the fibrous bands, the perivascular regions and within the
adipocytic lobules were scattered cells with large irregular and hyperchromatic
nuclei (Figure1). The mitotic
index in these regions was low. The dedifferentiated component comprised
approximately 80% of the tumor mass. The interface between the
well-differentiated and dedifferentiated components was variable: the interface
was well demarcated in some regions (Figure 2), and highly
irregular/infiltrative in others. The central portion of the mass was necrotic,
while the surrounding areas, comprising approximately 10% of the mass were
hypocellular and hyalinized. However, atypical cells well still recognizable in
these regions. The remainder of the mass displayed a spectrum of pathologic
changes with respect to cellularity, mitotic activity and atypia. Nonetheless,
the tumor was predominantly a high-grade pleomorphic spindle cell sarcoma. In
the most hypocellular regions, scattered atypical cells were clearly evident in
a hyalinized background and displayed a maximum mitotic index of 11 MF/10 high
power fields. Other areas were significantly more cellular, and were comprised
of cells with hyperchromatic nuclei arranged in vague fascicles (Figure 3).
These areas displayed the highest mitotic activity (maximum 36 MF/10 high power
fields). Constituent cell displayed variable amounts of eosinophilic cytoplasm
(Figure 4). The growth pattern of the tumor relative to the adjacent kidney was
largely to displace it. However, there were areas where the tumor appeared to
infiltrate in an interstitial pattern, with glomeruli encircled by tumor cells.
The portions of the tumor not comprised of spindle cells were comprised of
nondescript pleomorphic cells. Lipoblasts were evident throughout the tumor and
there were no morphologically-recognizable syncytiotrophoblasts. The portion of
the liver mass that was sampled was comprised predominantly of spindle cells as
described above.Figure 1
Well-differentiated component of the liposarcoma, showing atypical cells
with nucleomegaly and hyperchromasia scattered within mature adipocytes and
intervening fibrous septae.Figure 2
The interface between the well-differentiated and dedifferentiated
components.Figure 3
Cellular areas of the dedifferentiated component.Figure 4
Some areas of the dedifferentiated component were comprised of cells with varying amounts of
eosinophilic cytoplasm.


## 4.3. Immunophenotypic Features

The retroperitoneal tumor and liver mass
displayed an identical immunoprofile, consistent with the latter being a
metastatic deposit from the former. Both displayed diffuse immunoreactivity for
desmin, SMA,β-hCG (Figure 5),
and MDM2 (Figure 6). The tumors were
negative for ER, PR, EMA, PLAP, and keratins.Figure 5
The tumor cells displayed diffuse immunoreactivity forβ-hCG.Figure 6
The tumor cells displayed diffuse immunoreactivity for MDM2.


## 5. Discussion

hCG, a glycoprotein with a molecular weight of
38 000, is comprised of two subunits—α and β—that are noncovalently bound
to form a heterodimer [26, 27]. The α subunit of hCG is identical to the
α subunits of luteining hormone, follicle stimulating hormone, and thyrotropin; the β
subunit therefore provides hormonal specificity [26, 27]. The measurement of
serum β-hCG has its greatest clinical utility in the
diagnosis of gestation, congenital disorders, and germ cell neoplasia. However,
it has long been recognized that a wide variety of other nongerm cell
neoplasms, predominantly carcinomas, may be associated with elevated
serum β-hCG, in which it appears to function as an
autocrine growth factor by inhibiting apoptosis [28, 29]. The expression of hCG has also been found
to be an adverse prognostic factor in some specific histotypes such as small cell lung
carcinoma, transitional cell carcinoma of the urinary bladder, and prostatic
and colorectal adenocarcinoma [30–33]. Rare examples of osteosarcoma [28, 34–36],
chondrosarcoma [37], and leiomyosarcoma [38–43] have been
associated with elevated serum β-hCG. Amongst the six
previously reported examples of β-hCG-producing leiomyosarcomas, two originated in the
retroperitoneum [42, 43], two in the spermatic cord [39, 41], one in the uterus
[40], and one in the small intestine [38]. Notably, five of the six patients
succumbed to their disease within one year of their diagnoses. However, the
sarcomas were high grade; thus the independent prognostic significance of β-hCG remains unclear.In the present case, a DDLS with extensive leiomyosarcomatous differentiation was associated
withβ-hCG production, as evidenced by demonstration of  β-hCG expression in the tumor and its
metastatic deposit by immunohistochemistry, and an elevation of serum β-hCG that
was temporally related to tumor progression. The diagnostic utility of MDM2, a
recently described marker reportedly useful for distinguishing DDLS from their
histologic mimics [44], was confirmed, as this marker helped to establish, in
addition to morphologic features, underlying lipogenic differentation.β-hCG production by DDLS has
not been previously reported to our knowledge and is presumed to represent
“aberrant” differentiation in a high-grade tumor. Nonetheless, this finding
expands the clinicopathologic spectrum of lipogenic tumors in general.
Furthermore, it suggests that liposarcoma should be a differential
consideration when elevated serum β-hCG is associated with a radiographic mass lesion, especially
when the mass is retroperitoneal.



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*Source: 658090-2008-03-12.xml*