# Multiple Bone Metastasis of Sclerosing Epithelioid Fibrosarcoma 12 Years after Initial Surgery—Increasing Ki-67 Labeling Index

Authors: Atsuko Kanno; Masahito Hatori; Masami Hosaka; Koshi N. Kishimoto; Munenori Watanuki; Mika Watanabe; Eiji Itoi
Journal: Sarcoma
 (2009)

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## Abstract

Sclerosing epithelioid fibrosarcoma (SEF) is a rare sarcoma of low-grade malignancy. There has been no report to describe the comparison of histological features of SEF between primary and metastatic lesions in spite of high local recurrence rate. We report the histological changes and increasing Ki-67 labeling index of the primary and metastatic lesions of SEF. The patient was a 31-year-old man. At 18, a tumor in the abdominal wall was excised. At 23, the tumor recurred which was removed again. At 30, he was referred to our hospital because of swelling and pain in the chest. Histological examination of the chest wall tumor showed epithelioid cells arranged like alveolar pattern with dense collagen stroma. These findings were consistent with those of SEF. Abdominal and the rib tumors showed the same immunohistochemistrical expression. It is noteworthy that the tumor cells of the rib lesion showed increased cellularity, and its Ki-67 activity was higher as compared with the abdominal tumor, suggestive of progression of malignancy of SEF.


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## Body

## 1. Introduction

Sclerosing
epithelioid fibrosarcoma (SEF) is a very rare sarcoma which occurs in the deep
musculature. Extensive English literature survey reveals that there have been
only fifteen reports so far. There is wide age of spectrum and median age is 45
and equal sex distribution [1].It is first reported by Meis-Kindblom in 1995.
The author described SEF as a variant of fibrosarcoma simulating carcinoma. This
tumor is characterized by epithelioid cells arranged in nest and strands in highly
sclerosing matrix. SEF is a relatively low-grade fibrosarcoma histologically [2].On the other hand, high rate of
recurrence and metastasis has been reported.  Meis-Kindblom et al. reported that local recurrence
occurred in 53% and metastasis occurred in 43%. Their interval of metastasis
was 4.7 to 14 years. In some other cases, uncontrollable recurrence and
metastasis occurred after uneventful some years. They stated that SEF is a clinically
malignant sarcoma [3–5].There is no report about the comparison
of histological characteristics of SEF between primary and metastatic lesions
in spite of high local recurrence rate. In some case reports, the biopsy from the
metastasis lesion was performed, and the pathology was consistent with the primary
lesion [4–7]. However, there was no detailed description about the grade
of malignancy change except one report [6]. We report an SEF patient, who had metastasis
to the bones twelve years after the initial operation, and the metastatic
lesion of SEF showed higher grade of malignancy than the primary lesion.


## 2. Case Report

A 30-year-old
man presented with 2-year history of bump and pain in his left chest. In 1995,
the soft tissue tumor of abdominal wall was excised. In 2000, the recurrent tumor
was excised again. In January of 2007, he was referred to our hospital. There
was tenderness in the left chest. Radiological examination revealed a lesion
with bone destruction in the left 6th rib (Figure1(a)). CT revealed a pleural
lesion. Bone scintigraphy and positron emission tomography (PET) showed
increased uptake in the bilateral humeral shaft and left rib (Figure 1(b)). Plain
X-ray films demonstrated an osteolytic lesion in the humeral shaft (Figure 1(c)).
The cortex was thinned. MRI revealed the lesion in the left humeral shaft with
low signal intensities on T1 weighted images and iso to high signal intensities
on T2 weighted images. The mass was enhanced after gadolinium injection (Figure
1(d)).(a) Plain radiogram showing bone destruction of the rib (arrow). (b) Bone scintigram showing increased spots in the bilateral humerus and the left rib (arrow). (c) Plain radiogram of the left humerus showing an osteolytic lesion (arrow). (d) T1 weighted magnetic resonance imaging showing gadolinium enhancement (arrow).
(a)(b)(c)(d)Retrospective histological
examination of the specimen removed in 1995 revealed that the lesion was composed
of many spindle cells admixed with abundant collagen matrix (Figure2(a)). Epithelioid
cells arranged in an alveolar pattern (Figure 2(b)). Mitosis was conspicuous. It
was consistent with SEF.the specimen of the abdominal tumor excised in 1995 showing abundant collagen proliferation (a) and alveolar pattern (b).
(a)(b)The tumor removed from abdominal
wall in 2000. There was richness in abundant collagen. The features of the
tumor were similar to those of the previous surgery specimen. However, this
tumor showed increased cellularity. In this specimen, epithelioid cells were more dominant than spindle
cells, and the epithelioid cells were arranged in alveolar pattern (Figure3).
These cells showed nuclear polymorphism, and increased frequency of mitosis 15
cells per 10 high-power fields (HPF). Necrosis was found in the specimen. This
area revealed ghost-like figures. These features well corresponded to SEF showing
higher-grade malignancy compared to the primary lesion.Figure 3
The specimen of the abdominal tumor excised in 2000 showing epithelioid cells arranged in an alveolar pattern, too.To confirm the diagnosis, excisional
biopsy of the 6th rib was performed. Macroscopically, the bone marrow was occupied
by a white solid tumor. Microscopically, the specimen was composed of dysplastic
cells in the hyalinized stroma. These cells were arranged in epithelioid and
alveolar patterns too. In contrast to the primary lesion, this lesion was
characterized by much higher cellularity, high nuclear/cell rate, and more prominent
nuclear polymorphism (Figure4). Mitosis was more prominent with 30 to 40 cells
per 10 HPF. Necrosis was frequently found in the lesion. Ghost-like figures were
also present too.Figure 4
The specimen of the rib excised in 2007 showing cellular atypia and prominent nuclear pleomorphism.Immunohistochemical examination
revealed vimentin-positive cells. Although it was focal, tumor cells were
positive for HHF-35. CD99 had a weak immunostaining pattern. Tumor cells were
negative forα-SMA, desmin, CD34, S-100
protein, cytokeratin (AE1/AE3), and epithelial membrane antigen (EMA). All
three specimens showed same features by immunohistochemistry.Ki-67 labeling indices were7~8%, 20%, and 60%
in the tumor excised in 1995, in 2000, and in 2007, respectively, (Figures 5, 6,
and 7). In conclusion, the primary lesion was SEF and that the lesion of the
rib was bone metastasis from SEF in the abdomen.Figure 5
Ki-67 staining of the specimen resected in 1995. There are few Ki-67 positive cells. Ki-67 labeling index was 7 to 8%.Figure 6
The specimen resected in 2000. There were more Ki-67 positive cells than Figure5. Ki-67 labeling index was 20%.Figure 7
The specimen resected in 2007. More cells were stained by Ki-67. Ki-67 labeling index was 60%.In February 2007, pathological
fracture occurred in the left humeral shaft. Since it was a metastatic lesion, chemotherapy
using ifosfamide and adriamycin was performed. However, this chemotherapy
was discontinued because of acute myocardial infarction. Since the tumor size
is increasing, the patient was treated by radiation therapy to the left
humerus. After that, he hoped the second opinion, so he was referred to another
hospital.


## 3. Discussion

### 3.1. Histology of the SEF

SEF is characterized by uniform, small, and round
to ovoid epithelioid cells with clear cytoplasm arranged in distinct nest and
cords, embedded in a hyalinized fibrous stroma. This histology stimulates
infiltrating carcinoma. In contrast, there are hypocellular and fibromatous
areas which contain spindle cells and abundant collagen, simulating fibroma [2].
There is the morphologic variance in the sclerosing matrix. Antonescu et al. also pointed out this, so the author described that “there was a patchwork of zones of varying size, shape, and cellularity”
in the SEF [3].  Eyden et al. described
that all the SEF showed variable cellularity in five cases [8].  In some other reports variable cellularity was
described [9, 10]. Hemorrhage and necrosis were also occasionally seen [2, 6–8, 11].In addition, the SEF is characterized
by a range of other morphologic appearance. Meis-Kindblom et al. described that
there were myxoid zones with cyst formation in the SEF and that more cellular
myxoid zones stimulated myxoid fibrosarcoma [2].  Antonescu et al. also reported that poorly
delineated myxoid area were present in four cases [3]. In some reports there
were fibromatous zones which resemble classic fibrosarcoma [2, 3, 12, 13]. In
addition, the staghorn vessels, which were hemangiopericytoma pattern in some
reports [7, 11]. So, there are many
differential diagnoses: nodular fasciitis, desmoid, infiltrating carcinoma,
monophasic synovial sarcoma, clear cell sarcoma, hemangioperiendothelioma,
sclerosing lymphoma, myxoid fibrosarcoma, and osteosarcoma.In our case, polymorphic epithelioid
cells arrange in nest and strand, and there is much abundant collagen and
fibroblasts. There is nuclear polymorphism too. It is consistent with
Meis-Kindblom's report [2]. In addition, histological analysis showed that
mitosis and necrosis area were much more frequently seen in the rib tumor than
the abdominal wall tumors resected in 1995 and in 2000. Cellularity increased,
which strongly suggests increasing malignancy.


### 3.2. Immunohistochemical Feature

Meis-Kindblom described that in most fibrosarcoma,
immunohistochemical staining was of limited value although it was useful for
excluding other lesions [2]. From past available reports described in English [2–16], the only consistent finding
is diffuse reactivity for vimentin. Some cases express NSE [2, 6] and S-100
protein [2, 12, 14] although they were weak or focal. In some cases, tumor
cells were positive for EMA, although most of them were focal positive [2, 6, 10, 13, 14].In the cases which were difficult to
diagnose, ultrastructural examination was performed and the features displayed
the features of fibroblasts [2–8, 10, 11, 14].In our case, vimentin was diffusely positive.
Cytokeratin andα-SMA were negative. Carcinoma,
synovial sarcoma, and epithelioid sarcoma were ruled out, and, CD34 was
negative, so hemangiopericytoma is less likely. Moreover, three specimens (tumor
resected in 1995, 2000, and 2007) showed same feature by immunohistochemistry.
So, we concluded that these tumors are the same.


### 3.3. Proliferation Marker

Ki-67 is a nuclear antigen which is
expressed in late G1, S, M, G2 growth phases. In other words, Ki-67 is
expressed only when mitosis occur. There is a correlation between high Ki-67
labeling index, especially, more than 20%, and poor clinical diagnosis in soft
tissue sarcoma [17]. In some cases of SEF Ki-67 labeling index is performed [2, 7, 10, 11, 13], Ki-67 labeling index was 1 to 5%. It is consistent of low
mitotic rate, which were 0 to 10 mitoses per 10 high-power fields. On the other
hand, high rate of local recurrence and distant metastasis are reported. Meis-Kindblom concluded that neither proliferation markers nor mitotic rate correlated with
prognosis [2].In our case, Ki-67 labeling index
has changed among three specimens.
The abdominal tumor resected in 1995 showed 7 to 8% labeling index. The
abdominal tumor resected in 2000 showed 20%, the bone tumor of the rib showed
60% Ki-67 labeling index, respectively. We concluded that malignancy grade has increased.


### 3.4. Clinical Feature

Clinically, in many cases of SEF
local recurrence [2–4, 7, 8, 12] and distant metastasis occurred [2–8, 14]. Especially, uncontrollable local recurrence and distant
metastasis occur after the uneventful years. It is not uncommon that metastasis
occurs some years after primary surgery [2, 3, 5, 14]. Meis-Kindblom reported
that eight patients had local recurrence in 15 patients and that the median
interval to the first local recurrence was 4.8 years (2.3 to 11 years). The
author also reported that six patients had distant metastasis in 14 patients whose
data were available and that the median interval to metastases was 7.7 years
(4.7 to 14 years)  [2].In our case, metastasis has occurred
after 12 years. This feature is consistent with these reports.


## 3.1. Histology of the SEF

SEF is characterized by uniform, small, and round
to ovoid epithelioid cells with clear cytoplasm arranged in distinct nest and
cords, embedded in a hyalinized fibrous stroma. This histology stimulates
infiltrating carcinoma. In contrast, there are hypocellular and fibromatous
areas which contain spindle cells and abundant collagen, simulating fibroma [2].
There is the morphologic variance in the sclerosing matrix. Antonescu et al. also pointed out this, so the author described that “there was a patchwork of zones of varying size, shape, and cellularity”
in the SEF [3].  Eyden et al. described
that all the SEF showed variable cellularity in five cases [8].  In some other reports variable cellularity was
described [9, 10]. Hemorrhage and necrosis were also occasionally seen [2, 6–8, 11].In addition, the SEF is characterized
by a range of other morphologic appearance. Meis-Kindblom et al. described that
there were myxoid zones with cyst formation in the SEF and that more cellular
myxoid zones stimulated myxoid fibrosarcoma [2].  Antonescu et al. also reported that poorly
delineated myxoid area were present in four cases [3]. In some reports there
were fibromatous zones which resemble classic fibrosarcoma [2, 3, 12, 13]. In
addition, the staghorn vessels, which were hemangiopericytoma pattern in some
reports [7, 11]. So, there are many
differential diagnoses: nodular fasciitis, desmoid, infiltrating carcinoma,
monophasic synovial sarcoma, clear cell sarcoma, hemangioperiendothelioma,
sclerosing lymphoma, myxoid fibrosarcoma, and osteosarcoma.In our case, polymorphic epithelioid
cells arrange in nest and strand, and there is much abundant collagen and
fibroblasts. There is nuclear polymorphism too. It is consistent with
Meis-Kindblom's report [2]. In addition, histological analysis showed that
mitosis and necrosis area were much more frequently seen in the rib tumor than
the abdominal wall tumors resected in 1995 and in 2000. Cellularity increased,
which strongly suggests increasing malignancy.


## 3.2. Immunohistochemical Feature

Meis-Kindblom described that in most fibrosarcoma,
immunohistochemical staining was of limited value although it was useful for
excluding other lesions [2]. From past available reports described in English [2–16], the only consistent finding
is diffuse reactivity for vimentin. Some cases express NSE [2, 6] and S-100
protein [2, 12, 14] although they were weak or focal. In some cases, tumor
cells were positive for EMA, although most of them were focal positive [2, 6, 10, 13, 14].In the cases which were difficult to
diagnose, ultrastructural examination was performed and the features displayed
the features of fibroblasts [2–8, 10, 11, 14].In our case, vimentin was diffusely positive.
Cytokeratin andα-SMA were negative. Carcinoma,
synovial sarcoma, and epithelioid sarcoma were ruled out, and, CD34 was
negative, so hemangiopericytoma is less likely. Moreover, three specimens (tumor
resected in 1995, 2000, and 2007) showed same feature by immunohistochemistry.
So, we concluded that these tumors are the same.


## 3.3. Proliferation Marker

Ki-67 is a nuclear antigen which is
expressed in late G1, S, M, G2 growth phases. In other words, Ki-67 is
expressed only when mitosis occur. There is a correlation between high Ki-67
labeling index, especially, more than 20%, and poor clinical diagnosis in soft
tissue sarcoma [17]. In some cases of SEF Ki-67 labeling index is performed [2, 7, 10, 11, 13], Ki-67 labeling index was 1 to 5%. It is consistent of low
mitotic rate, which were 0 to 10 mitoses per 10 high-power fields. On the other
hand, high rate of local recurrence and distant metastasis are reported. Meis-Kindblom concluded that neither proliferation markers nor mitotic rate correlated with
prognosis [2].In our case, Ki-67 labeling index
has changed among three specimens.
The abdominal tumor resected in 1995 showed 7 to 8% labeling index. The
abdominal tumor resected in 2000 showed 20%, the bone tumor of the rib showed
60% Ki-67 labeling index, respectively. We concluded that malignancy grade has increased.


## 3.4. Clinical Feature

Clinically, in many cases of SEF
local recurrence [2–4, 7, 8, 12] and distant metastasis occurred [2–8, 14]. Especially, uncontrollable local recurrence and distant
metastasis occur after the uneventful years. It is not uncommon that metastasis
occurs some years after primary surgery [2, 3, 5, 14]. Meis-Kindblom reported
that eight patients had local recurrence in 15 patients and that the median
interval to the first local recurrence was 4.8 years (2.3 to 11 years). The
author also reported that six patients had distant metastasis in 14 patients whose
data were available and that the median interval to metastases was 7.7 years
(4.7 to 14 years)  [2].In our case, metastasis has occurred
after 12 years. This feature is consistent with these reports.



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*Source: 953750-2009-03-29.xml*