ORTHOPAEDIC SURGERY

Surgical treatment and prognosis in patients with high-grade softtissue malignant fibrous histiocytoma of the extremities

Kontogeorgakos A. Vasileios • William C. Eward •

Brian E. Brigman

Received: 1 January 2012 / Published online: 10 April 2012

� Springer-Verlag 2012

Abstract

Background Malignant fibrous histiocytoma (MFH) of

soft tissue is one of the most common sarcoma in adult-

hood. However, only a few series have separately studied

the clinical behavior and prognosis of this malignancy.

Methods We retrospectively reviewed 61 patients treated

for extremity soft tissue high-grade MFH. Four patients

had a history of another malignancy and were excluded

from analysis. In 12 referred patients with incomplete

excision, re-excision of the tumor bed was offered. Clinical

and treatment variables were analyzed for their impact on

treatment complications, local recurrence (LR), metastatic

disease (MD) and overall survival (OS).

Results Four patients underwent primary amputation.

Twenty-three patients necessitated a primary reconstruc-

tive procedure for wound closure. Wound healing com-

plication (WHC) developed in 28.3 % of the limb sparing

group of patients. LR developed in 11 patients (19.3 %),

while 6 of them had second LR. Eighteen patients (31.5 %)

developed MD, involving lung at least. Patients who

developed MD \12 vs [12 months, died within 19.3 vs

8 months mean time (p \ 0.05). Overall survivorship was

66.7 % at 5 years. No statistically significant variables

were identified for LR, while multivariate analysis for MD

revealed tumor size [5 cm as the only statistically signif-

icant variable. For OS, development of MD and age

[70 years emerged as independent prognostic factors.

Conclusions The overall prognosis is poor. LR, although

can be managed with tumor re-excision, has high second

recurrence rate. Increased tumor size is associated with

shorter metastasis-free interval which significantly

decreases survival.

Keywords Malignant fibrous histiocytoma � Pleomorphic

sarcomas � Soft tissue extremity sarcoma � Wound healing

complications � Flap reconstruction

Introduction

Malignant fibrous histiocytoma (MFH) of soft tissue was

first described in 1963 by Ozzelo et al. [1] and then in 1964

by O’Brien and Stout [2]. Although initially MFH was

considered of histiocytic origin, recent molecular data have

failed to show evidence of true histiocytic differentiation.

According to WHO criteria, MFH is defined as an undif-

ferentiated high-grade pleomorphic sarcoma [3]. Four

subtypes have been described: undifferentiated-pleo-

morphic, myxoid, giant cell,and inflammatory [4]. Angio-

matoid fibrous histiocytoma is a lesion with low malignant

potential that has characteristic imaging and histologic

features and likely represents a clinically and morpholog-

ically distinct entity. The typical histologic appearance of

K. A. Vasileios (&)

Department of Orthopaedic Surgery, Orthopaedic Oncology,

University Hospital of Larissa, 41110 Larissa, Greece

e-mail: vaskonto@gmail.com

K. A. Vasileios � W. C. Eward � B. E. Brigman

Department of Orthopaedic Surgery, Duke Cancer Institute,

Duke University Medical Center, Duke University, 3312,

Durham, NC, USA

e-mail: william.eward@duke.edu

B. E. Brigman

e-mail: brigm003@mc.duke.edu

W. C. Eward

Division of Orthopaedic Surgery, Orthopaedic Oncology,

University of Toronto, 600 University Avenue, Toronto, ON

M4J 5A4, Canada

123

Arch Orthop Trauma Surg (2012) 132:955–961

DOI 10.1007/s00402-012-1510-y

MFH is that of a hypercellular, neoplasm with a marked

cytological and nuclear pleomorphism, bizarre stromal

cells and storiform or fascicular growth pattern [3, 4].

Diagnosis is usually made by excluding other sarcomas,

primarily leiomyosarcoma, liposarcoma and rhabdomyo-

sarcoma. Oda et al. [5] reassessed 428 soft tissue MFH

cases and revised the initial diagnosis in 32.2 %, mostly to

leiomyosarcoma and liposarcoma. Fletcher et al. [6] reas-

sessed 159 pleomorphic sarcomas and in 61 % of the cases,

a sarcoma other than MFH was diagnosed.

Epidemiologically, MFH is one of the most common

primary and secondary soft tissue tumor in adults, with a

peak incidence in the 6th decade [5, 7]. Seventy percent of

these tumors occur in the extremities (49 % lower

extremities vs 19 % upper extremities), followed by trunk

and abdomen or retroperitoneum [7, 8]. Head and neck

location is rare (1–3 %) and carries a more dismal prog-

nosis [7–9]. The inflammatory type is more commonly

encountered in the retroperitoneum [7]. Clinically, tumors

involving extremities, frequently present as a deep seated

(93 %), painless, enlarging mass for months [10]. In con-

trast, patients with retroperitoneal tumors can demonstrate

constitutional symptoms, including anorexia, weight loss,

fever and malaise [7].

On plain X-rays MFH can demonstrate abnormal soft

tissue calcifications (5–20 %) and pressure effect or ero-

sions on the adjacent bone [10]. MRI reveals a lobulated

mass, with intermediate signal on T1 and high on T2 [10].

Heterogenous signal is usually seen on all images. Areas

with tumor necrosis and hemorrhage are commonly found;

sometimes so extensive that the tumor is erroneously

interpreted as soft tissue hematoma [11].

MFH is considered as a malignant tumor with poor

prognosis. We retrospectively report on the management,

complications, local and distal recurrence and survivorship

of 57 patients diagnosed and treated for soft tissue

extremity high-grade MFH.

Materials and methods

After IRB approval, all patients from 1999 to 2005 surgi-

cally treated at our institution, for high-grade extremity soft

tissue primary MFH/undifferentiated pleomorphic sar-

coma, were retrospectively reviewed.

Tumor size was determined by the maximum dimension

measured in the pathology specimens. All patients were

classified according to the 2002 American Joint Committee

in Cancer (AJCC) staging system [12]. Histologic grade

was determined on a three tiered classification scale: low

(G1), intermediate (G2), high grade (G3). G2 and G3

tumors were considered high grade with respect to the

AJCC classification.

Surgical margins were considered positive when tumor

cells were found at the inked margins of the specimens.

WHCs were classified as minor (mWHC) when only

repetitive wound changes resulted in secondary healing and

major (MWHC) when surgical irrigation and debridement

(I&D) or a flap reconstruction were needed. Time to local

recurrence (LR) and metastatic disease (MD) defined as

time interval in months from definite surgical treatment to

detection of recurrent tumor. MD diagnosed within

12 months was characterized as early MD, while diagnosis

after 12 months as late MD. Overall survival (OS) was

estimated as time interval in months from definite surgical

treatment to death.

Patient characteristics

There were 61 patients. Four patients with MFH had pre-

vious history of carcinoma and excluded from oncological

statistical analysis. Thus, 57 patients were studied for

surgical outcome, LR, MD and OS (Table 1). Mean fol-

low-up was 51 months (range 3 months–9 years). Mean

follow-up time for the surviving patients was 60 months,

with a minimum of 30 months. Five patients presented

with pain at the involved anatomic site. One patient pre-

sented with radial nerve palsy due to tumor mass

Table 1 Clinical and pathologic characteristics of 57 patients with

extremity soft tissue primary MFH/undifferentiated pleomorphic

sarcomas

Male 35

Female 22

Mean age 61 years (range 13–87)

Mean tumor size 9 cm (range 2.5–30)

Location

Upper extremity 15

Lower extremity 42

AJCC stage

II 17

III 39

IV 1

Histologic grade

G2 5

G3 52

Depth

Superficial 3

Deep 54

Size (cm)

B0 5 17

5–10 11

C10 26

[5 3

956 Arch Orthop Trauma Surg (2012) 132:955–961

123

compression. Twelve out of 61 patients (20 %) were

referred to our department due to incomplete excision of

the tumor by an outside physician. Five of these patients

had initial diagnosis of intramuscular hematoma/abscess,

and were treated with surgical drainage at an outside

institution. Another three patients had undergone unplan-

ned excision without pre-operative adequate imaging.

Surgical Treatment and Adjuvant Therapy modalities

All patients were treated surgically. Fifty-three underwent

limb salvage with tumor excision (Fig. 1). Four patients

(7 %) underwent primary amputation. The 12 patients, who

were referred to our institution due to incomplete initial

excision, all had re-resection of the tumor bed. The mean

time to re-excision was 2 months (range 1–4 months).

Twenty-nine out of 53 patients treated with limb salvage

received pre-operative and 10 post-operative radiation

therapy (RT). RT was offered to all the patients treated

with tumor bed re-resection before definite surgical exci-

sion and was considered as pre-operative for analytic

purposes. Five patients had post-operative chemotherapy.

Statistical analysis

Variables entered into the univariate analysis were gender,

tumor size (B5 vs C10 vs 5–10 cm), age (B50 vs 50–70 vs

C70 years), location (upper vs lower extremity), RT (yes

vs no), (pre-op vs post-op vs no), type of tumor resection

(tumor bed re-resection vs primary tumor resection vs

amputation), type of wound closure (primary wound

closure vs primary reconstructive procedure), WHC (yes vs

no), LR (yes vs no), MD (no vs early MD vs late MD) and

AJCC stage (II vs III vs IV).

Differences in proportions were assessed using

Chi-square test. Multiple logistic regression analysis was

applied to examine the effect of measured variables on

WHC. The effect of independent variables on time to LR,

time to MD and OS was initially examined with the Kap-

lan–Meier method using the log–rank test and factors with

a p value \0.05 were subsequently analyzed for indepen-

dent prognostic significance by the Cox (proportional

hazards) model. The results of the Cox regression analysis

were reported with 95 % confidence intervals (CI). Statis-

tical significance level was in all cases set at p \ 0.05.

Results

Surgical treatment

Negative surgical margins on final pathology report were

achieved in all patients. In one patient treated primarily at

our institution, pathologic examination reported micro-

scopic positive margins and tumor bed resection was

performed. Thus including 12 patients referred with

incomplete resection, 13 patients underwent second surgi-

cal procedure in order to achieve clear margins. Of the 53

patients treated with limb salvage, 30 patients (56 %) had

primary wound closure. The other 23 patients (44 %) had a

primary reconstructive procedure. No major nerve or vessel

had to be reconstructed in the re-resection group, but more

reconstructive procedures were necessary compared to the

primary resection group (46 vs 35 %, p[ 0.05). A total of

3 spilt thickness skin grafts and 27 free or rotational flaps

were performed for primary wound closure, skeletal

reconstruction, MWHC and limb salvage after LR. Flap

congestion due to decreased venous outflow occurred in 2

free flaps. Surgical exploration and venous anastomosis

redo was performed in one case because of thrombosis.

The overall WHC for 53 patients treated with limb

salvage surgery was 28.3 %. The rate for WHC for tumors

Fig. 1 MRI T1 FS with Gadolinium axial image. a Heterogeneous

mass of the volar and radial side of the forearm with peripheral

enhancement. b Closed biopsy was consistent with MFH. The patient

underwent pre-op radiation therapy and 3 weeks later, excision of the

tumor to negative margins

Arch Orthop Trauma Surg (2012) 132:955–961 957

123

\10 vs C10 cm, RT yes vs RT no, primary wound closure

vs primary reconstructive procedure, lower vs upper

extremities and AJCC stage II vs III, was 18 vs 38.5 %,

33.4 % vs 14.3 %, 23.3 % vs 34.8 %, 31 % vs 13.3 % and

11.8 % vs 40 %, respectively. The rate of MWHC was

17 %. All MWHCs were associated with RT, while 50 %

of these were complicated with local infection. 90 % of all

MWHC were involved the lower extremity. However, no

statistically significant factors were revealed.

Local recurrence

LR developed in 11 out of the 57 patients (19.3%) (Fig. 2)

with a mean time of 38 months (SD ± 19.6, range 7–70)

from surgery to detection of recurrence. Two out of the 13

(15.4 %) who underwent tumor bed re-excision demon-

strated LR, and 9 out of the remaining 44 patients (20.5 %)

received initial tumor resection at our institution

(p [ 0.05). No patient with amputation developed LR.

Mean tumor size was 9.7 vs 9.3 cm (p [ 0.05) for patients

with and without LR, respectively. Of the 11 patients, 1

denied any sort of further treatment. The remaining ten

underwent surgical excision of the recurrent tumor and

eight received adjuvant RT. Five out of these 10 patients

(50 %) developed MWHC. Six out of the 10 patients

(60 %) developed second LR treated with new local

resection and 5 of these 10 patients underwent amputation,

either due to LR or MWHC.

Patients with local recurrence were analyzed for gender,

age, tumor size, tumor location, WHC, RT, type of resec-

tion, type of wound closure and AJCC stage. No statisti-

cally significant parameters were detected.

Metastatic disease

Eighteen of the 57 patients (31.5 %) developed MD

(Fig. 3). Seventeen patients were classified as AJCC stage

III and one as IV at initial presentation. All four patients

treated initially with amputation developed metastases.

Mean time to metastases detection after tumor excision was

16.5 months (SD ± 21, range 1–78). The mean tumor size

for patients with metastases was 13 cm vs 7 cm for the

patients without metastases. Patients with a tumor

size C10 cm had a metastatic rate of 58 %, while patients

with tumor size 5–10 cm had a rate of 27 % (p = 0.029).

Ninety-two percent of patients with early lung metastasis

had tumor size [10 cm. Two out of 11 patients with LR

developed metastatic disease. Only 1 out of 13 patients

treated with tumor bed re-excision demonstrated metastasis

(7.7 %), compared to 36.4 % of patients with primary

tumor resection (p [ 0.05). Seventeen patients had

metastases in the lung as the first site of metastatic disease,

while one patient had nodal metastasis then later demon-

strated lung disease. Metastases were managed in 13

patients with a combination of chemotherapy, RT and/or

surgical excision, while 5 did not receive a specific type of

treatment other than symptomatic management. Patients

with metastatic disease were analyzed for gender, age,

tumor size, tumor location, WHC, RT, type of resection,

type of wound closure, LR and AJCC stage. On univariate

analysis, tumor size [5 cm age [50 years, WHC, AJCC

stage III, and primary amputation were statistically sig-

nificant factors for development of MD. Multivariate

analysis of these parameters showed that only tumor

size C5 cm (95 % CI 1.13–1.47; p = 0.000) was a statis-

tically significant factor. For each 1 cm increase in tumor

size, there was 29 % increase in the risk for developing

MD.Fig. 2 Kaplan–Meier local recurrence curve of 57 high-grade

extremity MFH patients

Fig. 3 Kaplan–Meier metastatic disease curve of 57 high-grade

extremity MFH patients

958 Arch Orthop Trauma Surg (2012) 132:955–961

123

Overall survival

Overall survivorship at the time of follow-up was 66.7 %

(Fig. 4). All the 18 patients with metastases and 1 patient

(AJCC II) with extensive proximal thigh LR, who refused

further treatment, were dead at the time of last follow-up.

Mean time survivorship of these patients was 28 months

(SD ± 22.7, range 4–82). OS for size B 5 cm, 5–10 cm

and [ 10 cm was 100 %, 72 % and 38 %, respectively

(p \ 0.05). Mean time to death after metastases detection

was 12.5 months (range 3–38). Six patients demonstrated

metastases in a delayed fashion with a mean time of

39 months (range 16–84). The mean tumor size in these

patients was 10.9 cm. These six patients died in a mean

time of 19.3 months (range 7–38 months) after metastases

presentation. Eleven patients demonstrated early metasta-

ses with a mean time of 5 months after the operation (range

1–12). These 11 patients died after a mean time of

8 months (range 1–19) after metastasis detection. Mean

tumor size of these patients was 14.2 cm (p \ 0.05).

Parameters inserted in univariate analysis were gender,

age, tumor size, WHC, AJCC, LR, type of resection, RT,

extremity location, and MD. Statistically significant factors

with negative impact were tumor size [5 cm, MD, age

[70 years, WHC, AJCC stage III, and primary amputa-

tion. These parameters tested in multivariate analysis and

MD and age [70 years remained significant variables.

Discussion

MFH constitutes a subgroup of STSs with high potential to

locally and systematically recur associated with dismal

prognosis [13–17]. Tumor resection with negative margins

is the goal of surgical treatment [18]. Unplanned biopsies

or inadequate surgical procedures are a common problem

when STSs are not treated in specialized sarcoma centers.

Twenty percent of the patients treated in this study had an

unplanned surgical excision with positive margins.

Unplanned resections frequently leave microscopic resid-

ual disease, despite what may have seemed to be a gross

total resection [19, 20]. Giuliano and Eilber [20] com-

mented on the rationale for planned reoperation after

unplanned total excision of STS. In our study, although no

statistical significance emerged between primary tumor

resection vs secondary tumor bed resection in terms of LR,

MD and OS, a trend for better results was noticed with

re-resection. However this finding could be related to the

fact that unplanned resections were performed in smaller

tumors.

Reconstructive procedures are considered as an integral

part in STS operative treatment [21, 22]. Barwick et al.

[21] compared conventional primary closure with flap

reconstructive procedures, for STS treated with pre-op RT

(61 vs. 37 %). In our study, 28.3 % of the patients treated

with limb salvage, developed WHCs. Almost half of our

patients had a primary reconstructive procedure for wound

closure. This surgical strategy follows our rationale to

avoid any tension at the sutured wound edges. However, in

the present study patients treated with primary wound

closure developed less WHCs (p [ 0.05). Although this

finding may seem contradictory, it is probably a reflection

of size differences in the excised soft tissues. Patients with

a primary flap were those in whom initial closure could not

be accomplished with locally available tissue transposition.

Patients with tumor size C10 cm had twice the rate of

WHCs compared to those with tumors \10 cm, although

this was not statistically significant. It seems that, although

vascularized flaps reduce the healing complications com-

pared to the conventional wound closure, still there are a

percentage of flaps that fail to heal with surrounding tissue,

especially when pre-op RT is used. Probably this is

explained by the fact that vascular ingrowth from vascu-

larized flap into the recipient bed may not occur, secondary

to the devascularized state of the recipient bed [22, 23].

Furthermore WHCs development was associated with

worse MD and OS in the univariate analysis only. How-

ever, this finding does not imply that WHC is a causative

factor, as this probably reflects the differences in tumor

size. No association was found between the reconstructive

procedure and oncologic outcome, suggesting that the

biologic component of reconstructive procedures (vascu-

larized tissue transfers vs conventional wound closure)

does not promote LR or dissemination of primary tumor.

MFH is considered as a tumor with higher potential to

recur locally [24]. It is well accepted that positive histo-

logical margins are associated with increased rate of LR [8,

17, 18, 25]. The adjuvant role of radiation for improving

local control is well established [26]. LR rate at 5 years

Fig. 4 Kaplan–Meier overall survival curve of 57 high grade

extremity MFH patients

Arch Orthop Trauma Surg (2012) 132:955–961 959

123

follow up was 19.3 %. In the literature, LR rate of MFH

ranges from 19.2 to 44 % [14–17, 27, 28]. Our favorable

results are probably the combined result of negative

resection margins and supplementary RT. When surgical

margins were expected to be close with important struc-

tures, we offered pre-op RT to enhance tumor resectability.

We did not offer RT for primarily treated patients, when a

wide margin could be achieved based on the pre-op MRI

and final pathology confirmed a resection margin of at least

2.5 cm at all directions.

LR is considered a negative prognostic factor for sub-

sequent re-recurrence [16, 29]. Detection of LR is very

challenging. Usually on clinical examination a firm nodule

can be palpated. A MRI in these cases frequently reveals a

heterogenous nodule. A core needle biopsy of the nodule

can facilitate the diagnosis in questionable cases. Although

limb salvage is feasible in over than 90 % of primary STS,

the salvage rate after recurrence drops abruptly [30]. The

decision when to amputate or not, in primary or recurrent

cases, is a balance between tumor resectability, ability for

reconstruction of the resected tissues, and expected com-

plications; and functional outcome, keeping in mind that

these patients frequently need or have already received RT,

are old and may have comorbidities. In our series, while

initial amputation incidence was 7, 60 % of the patients

who developed LR eventually underwent an amputation

either for tumor local control or due to MWHC.

The relation of LR to MD and OS in soft-tissue sarco-

mas is still unclear. Local recurrence can be a result of

inadequate local treatment or a sequel of an aggressive

tumor phenotype [31, 32]. The nature of LR, rather than its

presence per se is a more useful guide to prognosis. In our

study no causal association between LR and MD or OS was

found.

For localized untreated extremity STSs, the two most

important tumor-related prognostic factors regarding MD

and OS are the histologic grade and tumor size [18, 25, 32].

The most important treatment-related factor is surgical

margins [25]. The MD rate in our study was similar to the

reported rate for high grade extremity soft tissue MFH [15,

16, 29]. In multivariate analysis, size emerged as the only

significant factor for the development of MD. It seems that

there is a linear increase in the risk for developing MD as

size of the tumor increases. Additionally, shorter metasta-

sis-free interval was noticed with larger tumor size.

Metastatic disease is closely related to disease-specific

survival. This is clearly seen in our study as all the patients

with MD were not alive at latest follow-up. The OS rate in

our study was 66.7 %, which is identical to survival for

high-grade STSs. In our study, size, age, WHC, AJCC

stage III, and primary amputation were statistically sig-

nificant variables in univariate analysis for both MD and

OS. For OS, the development of MD and time of

development were also significant Salo et al. [16] pointed

out the significance of tumor size as a shorter metastasis

free and disease-specific survival rates were reported with

increasing size category. In their study as in ours, patients

with tumor size[10 cm were in a significantly greater risk

for developing early MD and experienced worse OS. Za-

gars et al. [33] reported that for patients presenting with

metastasis as the first relapse, the time to metastasis was

the major determinant of survival ([12 vs B12 months).

When we performed multivariate analysis for OS, time to

MD and age [70 years remained independent prognostic

factors.

In conclusion, this is a retrospective study of 57 patients

treated for soft tissue high-grade extremity MFH. Complete

tumor excision is the cornerstone of surgical treatment.

Almost half of the patients needed a reconstructive pro-

cedure for wound closure. Patients with tumor size larger

than 10 cm and pre-op RT tend to develop more WHCs.

Tumors with initial incomplete resection undergoing tumor

bed re-resection behaved like tumors with initial negative

margins with respect to LR, MD and OS. Overall prognosis

is poor. Increased tumor size is associated with shorter

metastasis-free interval which significantly decreases

survival.

Conflict of interest The authors declare that they have no conflict

of interest.

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