Benign Fibrous Histiocytoma (Dermatofibroma)

Benign fibrous histiocytoma refers to a heterogeneous

family of morphologically and histogenetically related
benign dermal neoplasms of uncertain lineage. These
tumors are usually seen in adults and often occur on the
legs of young and middle-aged women. Lesions are asymptomatic
or tender and may increase and decrease slightly
in size over time. Their biologic behavior is indolent.
The cause of fibrous histiocytomas remains a mystery.
Many cases have a history of antecedent trauma, suggesting
an abnormal response to injury and inflammation,
perhaps analogous to the deposition of increased amounts
of altered collagen in a hypertrophic scar or keloid. These
common yet curious tumors appear to be composed at
least partially of factor XIIIa-positive dermal dendritic
cells.
These neoplasms appear as firm, tan to brown papules (Fig.
25-16A). Most are less than 1 cm in diameter, but actively
growing lesions may reach several centimeters in diameter; with
time they often become flattened.
The most common form of fibrous histiocytoma is referred to
as a dermatofibroma. These tumors consist of benign,
spindle-shaped cells that are usually arranged in a well-defined,
nonencapsulated mass within the mid-dermis (Fig. 25-16B, C).
Extension of these cells into the subcutaneous fat is sometimes
observed. Many cases demonstrate a peculiar form of overlying
epidermal hyperplasia, characterized by downward elongation
of hyperpigmented rete ridges (pseudoepitheliomatous
hyperplasia). Numerous histologic variants are noted, such as
more cellular forms or tumors with pools of extravascular blood
and hemosiderin (aneurysmal).

What is Malignant Fibrous

Histiocytoma?

Figure 1: A histologic specimen showing a classic storiform...

Malignant fibrous histiocytoma (MFH), a type of sarcoma, is a malignant
neoplasm of uncertain origin that arises both in soft tissue and bone. It
was first introduced in 1961 by Kauffman and Stout (Ref. 22) and
controversy has plagued it since. They described MFH as a tumor rich
in histiocytes with a storiform growth pattern. By 1977, MFH was
considered the most common soft tissue sarcoma of adult life. Despite the
frequency of diagnosis, MFH has remained an enigma. No true cell of
origin has ever been identified. In 2002, the World Health Organization
(WHO) declassified MFH as a formal diagnostic entity and renamed it as
an undifferentiated pleomorphic sarcoma not otherwise specified, NOS

(Ref. 4). This new terminology has been supported by a compelling body
of evidence over the last decade to suggest that MFH represents a final
common pathway in tumors that undergo progression
towards undifferentiation (Refs. 5, 12, 15, and 19). While it remains
unclear how to most accurately organize these tumors, the term
malignant fibrous histiocytoma represents the diagnosis for thousands of
patients and is still commonly used by both patients and physicians. This
review will describe soft tissue tumors once diagnosed as MFH.

Figure 2: A histologic example of myxoid type MFH...

MFH manifests a broad range of histologic appearances with four subtypes described (Ref. 3):
1.

Storiform-pleomorphic

2.

Myxoid

3.

Giant cell

4.

Inflammatory

Of these, the storiform-pleomorphic is the most common type, accounting

for up to 70% of most cases, see Figure 1. The myxoid variant is the
second most common accounting for approximately 20% of cases, see
Figure 2.
Unlike the other sub-types of MFH, the myxoid form tends to be less
aggressive and as a result is associated with a better prognosis. Giant cell
and inflammatory types are rare. Inflammatory MFH tends to occur in the
retroperitoneum.
The myxoid subtype must contain at least 50% myxoid areas by definition. Occasionally
an entire nodule of tumor can have a myxoid appearance causing diagnostic confusion
including less aggressive entities such as myxoma or nodular fasciitis. Most myxoid
variants of MFH behave as low grade neoplasms and thus pursue a less aggressive
course.

How Does Malignant Fibrous

Histiocytoma Present?

As with all sarcomas of soft tissue and bone, MFH is rare, with just a few
thousand cases diagnosed each year.
MFH of soft tissue typically presents in a patient that is approximately 50
to 70 years of age though it can appear at any age. MFH is very rare in
persons less than 20 years old.
There is a slight male predominance. Soft tissue MFH can arise in any part
of the body but most commonly in the lower extremity, especially the
thigh. Other common locations include the upper extremity and
retroperitoneum. Patients often complain of a mass or lump that has
arisen over a short period of time ranging from weeks to months. It is not
uncommon for patients to report trauma to the affected area. For
example, patients will state that they "ran into the corner of a table" and
have had a thigh lump since. Trauma as far as we know does not cause
MFH but rather the incident draws attention to the extremity. The mass
does not usually cause any pain unless it is compressing a nearby nerve.
Symptoms such as weight loss and fatigue are not typical but can present
in patients with advanced disease. Retroperitoneal tumors can become
quite large before they are detected as patients do not feel a mass per se
but rather associated constitutional symptoms such as anorexia or
increased abdominal pressure.
Because MFH is extremely rare in children, other diagnostic possibilities must be
exhausted before accepting it as a diagnosis in the pediatric population.

Figure 3: Clinical photograph of an MFH of the proximal lateral thigh...

"I feel a lump. Now what?"

Not all lumps and bumps are cancerous and in fact, most are not.
Nonetheless, all masses should be brought to the attention of a physician.
Your doctor will likely ask a series of questions regarding the mass such
as "How long has the mass been present?" and "Is it enlarging? If so,
over what period of time?" She or he will then perform a thorough
physical examination assessing the size and firmness of the mass,
examining other parts of the affected extremity, and searching for
enlarged lymph nodes.

Figure 4: Clinical picture of MFH in the hand...

Often an x-ray is obtained as the first imaging test. Usually this is
followed with an MRI. MRI is the most useful test to image soft tissue
tumors as it provides very valuable information about the mass such as
the size, location, and proximity to neurovascular structures. It is
important to note that the diagnosis of a cancerous tumor cannot be
made by MRI alone. For patients that are unable to undergo MRI because
of metallic implants such as pacemakers, a CT scanmay be obtained.
After analyzing all of the information that has been gathered, if the mass
remains suspicious for sarcoma the patient will likely be referred to a
physician who specializes in sarcoma. The specialist, usually an
orthopaedic oncologist or general surgical oncologist, will then likely
perform additional tests and arrange for a biopsy.

Figure 5a and 5b: Images of an MFH in the thigh...

When the diagnosis of sarcoma is suspected, it is important to determine
if a tumor is isolated (localized) or has spread (metastatic). When soft
tissue sarcomas spread, they most commonly metastasize to the lungs.
As such, a CT scan of the chest is routinely obtained to determine the
presence or absence of metastatic disease. While sarcomas including MFH
can spread to other sites such as lymph nodes and bones, it is fairly
uncommon. The role of tests such as bone scan and PET scan is not
totally clear (Refs. 20, 23, and 30). There is considerable variability
among physicians as to whether these additional studies are useful.
Metastasis: The vast majority of metastatic disease from sarcomas including MFH
present as pulmonary disease (90%). Involvement of extra-pulmonary sites is
uncommon: lymph nodes (10%), bone (8%), liver (1%).

PET scans exploit the high metabolic activity of cancer cells. The technique utilizes the
radiolabeled glucose analog (Ref. 18) fluoro-2-deoxy-D-glucose which is metabolized at
higher rates by the tumor cells. The uptake of the FDG is expressed as maximum
standard uptake value (SUV). While it is a very sensitive test, it is not specific for
sarcoma. Several investigations have attempted to define the role of PET scanning in soft
tissue sarcomas (refs. 13, 33, and 34). As our understanding of this new technology
develops, its diagnostic and staging capabilities will become more refined. For now, the
role and cost-effectiveness of PET scanning have yet to be clearly defined.

Biopsy

Figure 6: Needle biopsy of an MFH in the thigh...

A biopsy is a procedure in which diagnostic tissue is obtained. Biopsies
can be performed by different methods. A needle biopsy involves inserting
a small needle into the tumor to obtain a specimen (Refs. 17 and 45).
Needle biopsies, see Figure 6, can often be performed in the physicians
office. If the tumor is in a location that is difficult to feel or there are
structures near the tumor that could be damaged, then a CT-guided
needle biopsy might be arranged.
An open biopsy is a surgical procedure that is usually performed in the
operating room under sedation or anesthesia. With incisional biopsies,
just a small part of the tumor is removed for analysis. With excisional
biopsies, the entire mass is removed. Excisional biopsies are usually
reserved for small tumors (less than 3 cm).

Figure 7: Limb sparing incision in the upper extremity for a sarcoma of the...
The decision to remove part of the mass or the entire mass at the time of
biopsy is extremely critical. The importance of having a sarcoma specialist
either perform the actual biopsy or guide the treating surgeon in planning
a biopsy cannot be overstated.
The biopsy is often the first step to a successful limb-sparing procedure.
The location of the biopsy incision and technical aspects of obtaining
tissue can have a major impact on subsequent operations (Ref. 28).

The tissue obtained from the biopsy is evaluated by a pathologist. The

pathologist uses a number of diagnostic tools including light
microscopy, immunohistochemistry, electron microscopy, and molecular
studies to make the diagnosis. In addition to making a diagnosis, the
pathologist also provides an important piece of information called the
grade. The grade refers to a tumors appearance under the microscope
and is a reflection of a tumors aggressiveness. High grade tumors behave
more aggressively meaning they have a higher tendency to recur and
spread. Low grade tumors are less aggressive and have a lower tendency
to recur and spread. The grade is not a guarantee of a tumors behavior
but rather is one of the factors that helps the treatment team make
recommendations.
Several cytogenetic abnormalities have been described for STS including MFH. More
than 80% of MFH tumors display mutations affecting 1q31, 9q31,5p14, and 7q32.
Abnormalities at 3p12, 11p11, and 19p13have also been described. In a multivariate
analysis of tumor grade and size, gains at 7q32 predicted a worse survival (Ref. 24).

Staging
Once all of the imaging studies and biopsy have been performed, the
stage of disease can be assigned. The most commonly used staging
system is the AJCC (American Joint Commission on Cancer) system for
soft tissue sarcoma, see Table 1 (Ref. 1). Patients often inquire about the
stage of their disease. It must be kept in mind that stage is not a
guarantee of a tumors behavior. Staging merely provides guidelines for
the treatment team on how best to manage a given tumor to optimize
clinical outcome.
Table 1: The American Joint Committee on Cancer (AJCC) Staging
System for Soft Tissue Sarcoma, 6th Edition
Stage

Size

Depth

Grade

Metastases

Any

Any

Low

No

II

< 5cm, any depth OR > 5cm

Superficial

High

No

III

> 5cm

Deep

High

No

IV

Any

Any

Any

Yes

*Depth is termed superficial (above the deep fascia) or deep (deep to the deep fascia). Retroperitoneal
tumors are considered deep.

"I have MFH. What are the next

steps?"
Once the diagnosis of MFH has been confirmed, an individual treatment
plan is made for each patient. Sarcoma treatment requires a

multimodality approach and hence a team of physicians will participate in

a patients care. There are essentially three main types of treatment that
will need to be coordinated to treat the MFH:
1.

Surgery

2.

Radiation

3.

Chemotherapy

Surgery
Surgery is the cornerstone of treatment for all soft tissue sarcomas. The
goal of surgery is to eradicate all disease in the affected area. For
extremity sarcomas, surgical options fall into two categories: limb-sparing
and amputation. Historically, soft tissue sarcomas were treated with
amputation. As our understanding of sarcoma has evolved, so has the
treatment. Several studies have demonstrated no difference in patient
survival with amputation versus limb-salvage (Refs. 46 and 47). In a
randomized clinical trial run by the National Cancer Institute (ref. 40),
there was no difference in overall survival for patients with soft tissue
sarcoma that had amputation (70%) versus those that had amputation
(71%). Currently at least 90% of tumors are now removed using limbsparing surgery meaning that the tumor is removed while saving the
extremity. Limb sparing surgery should only be performed if the surgeon
is confident that the tumor can be completely removed and that the
remaining extremity provides reasonable function. Obviously balancing
oncologic and functional outcomes is a very complex and subjective
undertaking. It is very important that the patient and treating surgeon
discuss the expectations of all options preoperatively. Reconstruction
following tumor resection is sometimes necessary depending on the size
of the tumor and what structures need to be sacrificed. For example, a
bone or joint may need to be reconstructed or soft tissue flaps may be
needed for wound coverage.

Figure 8: Intra-operative photograph of an MFH of the scapula...

Once a tumor has been removed, the pathologist analyzes the entire
specimen to confirm the tumors grade and margins. The
term margin refers to the outermost edges of a resection specimen.
A negative marginindicates that there are no tumor cells on the periphery
of the tumor implying that a complete resection was achieved. A positive

margin means that tumor cells were found on the periphery of the
resection specimen which implies there is likely residual microscopic
disease. Obviously one hopes to achieve negative margins at the time of
surgery. Unfortunately it is not always possible to accomplish this.
Surgical procedures for sarcoma are classified as outlined in Table 2.
When possible, wide and radical procedures are attempted in order to
obtain negative margins.
Table 2: Classification of surgical resections for the treatment of
sarcoma
Intralesional

Partial removal of the tumor

Marginal

Through the reactive zone; may leave residual microscopic disease

Wide

Entire tumor removed with a cuff of normal tissue

Radical

Entire compartment containing the tumor removed

Radiation
Radiation therapy is administered by a radiation oncologist. The purpose
of radiation is to improve local tumor control by killing residual
microscopic disease. Radiation has been clearly shown to improve the
incidence of local recurrence and has become an integral part of the
treatment for MFH (Refs. 6 and 27). Typical radiation doses vary from 45
Gy to 65 Gy.
In a prospective randomized trial from NCI, 91 patients with high grade tumors were
randomized to surgery alone or surgery with post-operative external beam radiation
therapy, XRT (Ref. 48). Patients in the surgery alone group experience 20% local
recurrence rates compared to 0% for the surgery plus XRT group. For both groups, there
was no difference in overall survival. In general, patients treated with adequate limbsparing surgery supplemented with radiation have a likelihood of experiencing over 85%
local control.

There are several different ways to administer radiation. The most

commonly used form of radiation is external beam radiation which can be
given pre-operatively, intra-operatively, post-operatively, or in some
combination. Each has advantages and disadvantages, see Table 3. For
tumors that are in contact with major nerves and blood vessels, preoperative radiation can potentially shrink the tumor, making limb-sparing
surgery possible or easier. The main disadvantage to pre-operative
radiation is its association with post-operative wound complications (Refs.
10 and 35). Post-operative radiation is probably the most commonly used
modality. Typically pre- and post-operative radiation is administered over
a 5 week period. Intra-operative has the advantage of delivering a large
dose of radiation directly to an area of concern while sparing nearby
organs such as the bowel or bladder. It is particularly useful for treating

large retroperitoneal sarcomas in which it is difficult to obtain local tumor

control (Ref. 43).
Table 3: The advantages and disadvantages
of the timing of radiation therapy
Delivery
Method

Advantages

1.

Disadvantages

1.

potentially shrinks tumor

complications

Pre-operative

2.

smaller volume required

1.

2.

delay in definitive surgery

can concentrate very high

1.
doses to close margins

Intraoperative

2.

minimal injury to normal

tissue
1.

requires a special operating

room with exposure to O.R. staff
2.

wound complications

fewer wound
complications

Postoperative

increase in wound

1.

larger volume required

secondary to operative contamination

2.

immediate surgery

Another means of administering radiation is a technique

called brachytherapy. After the surgeon has removed the tumor, a
radiation oncologist then places empty catheters in the operative bed.
Once the wound is starting to heal (approximately 5 days after surgery),
the catheters are filled with radioactive material which sits in the surgical
bed for 5 days. This allows for high doses of radiation over a short period
of time obviating the need to travel daily for radiation treatments over
several weeks.
In a prospective randomized trial conducted at the Memorial Sloan-Kettering Cancer
Center, 164 patients with extremity or superficial axial sarcomas were randomized to
surgery alone versus surgery plus brachytherapy (Ref. 38). For patients with high grade
tumors, the 5-year local control rate was 89% in the brachytherapy group, compared to
66% in the surgery only group. There was no difference in overall survival between the
groups. A retrospective review from the same institution examined small (<5cm) high
grade sarcomas treated with brachytherapy (Ref. 37). There was no advantage in local
control or overall survival for this subgroup of patients.

Figure 9: Brachytherapy catheters traversing the operative field...

Unfortunately radiation does have well known side effects. Problems with
wound healing have already been described above. Problems including
scarring of the tissue resulting in firm stiff muscles, as well as skin
discoloration, have also been well described. The most serious
complication arising from radiation is the development of a second cancer
within the radiated field (Refs. 8, 29, and 32). This is called a postradiation or radiation-induced sarcoma. Radiation-induced sarcomas are
rare and occur in less than 5% of long-term survivors.

Chemotherapy
The role of chemotherapy in the treatment of MFH is not entirely clear.
Several clinical trials incorporating the chemotherapy
drug doxorubicin have shown trends in improved event-free survival
without a major impact on overall survival. The results of a large metaanalysis which included almost 1,600 soft tissue sarcoma patients
concluded that the addition of chemotherapy improved overall survival by
less than 10% (Ref. 2). Results were better in patients with extremity
tumors than in patients with axial or retroperitoneal tumors. More
recently, clinical trials incorporating ifosfamide and doxorubicin have
demonstrated an improvement in disease-free survival (Refs. 26 and 36).
One of the major limitations of chemotherapy is the associated toxicities
with the doses necessary to have a significant impact on disease-specific
survival. The addition of supportive drugs such as hematopoietic growth
factors has allowed for higher doses and trends in improved survival are
being observed.
Unfortunately, the interpretation of these and other chemotherapy trials
results has varied so much that it has become difficult for patients to
decipher the information in order to make decisions regarding
chemotherapy as part of their treatment. The decision to incorporate
chemotherapy in the treatment of MFH must be made with the guidance
of a medical oncologist. Chemotherapy probably should be given to
patients who already have metastatic disease or who are at the highest
risk for developing metastatic disease. Most often, chemotherapy will
likely be administered in the setting of a clinical trial.

Prognosis and Outcome

Prognostic factors that are known to correlate with survival in patients
with MFH include tumor grade, depth, size, metastatic status, patients
age, and histologic subtype (Refs. 11, 16, and 39). Favorable prognostic
factors include age less than 60 years old, tumor size less than 5 cm,
superficial location, low grade, the absence of metastatic disease, and a
myxoid subtype. Older patients with large (> 5cm), deeply seated, high

grade tumors do not have as favorable an outcome. For example, patients

with a small low grade tumor are likely to achieve complete cure. For
patients with large, deep, high grade tumors (Stage III), the 5 year
survival estimates range from 34 to 70% (Refs. 25, 42, and 49).

Sarcoma Nomogram
On the basis of a prospectively followed cohort of adult patients with primary soft tissue
sarcoma (STS) who were treated at Memorial Sloan-Kettering Cancer Center, a
nomogram for predicting sarcoma-specific mortality at 12 years was developed (Ref. 21).
Nomogram predictor variables included age at diagnosis, tumor size (< or = 5, 5 to 10,
or > 10 cm), histologic grade (high or low), histologic subtype (fibrosarcoma,
leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral
nerve tumor, synovial, or other), depth (superficial or deep), and site (upper extremity,
lower extremity, visceral, thoracic or trunk, retrointraabdominal, or head or neck. The
accuracy of the nomogram has been validated by both internal and external standards
(Ref. 14). The tool is meant to be used in adult patients who are less than 6 months
from their index surgical procedure and are without evidence of metastatic disease. The
sarcoma nomogram may be useful for patient counseling, follow-up scheduling, and
clinical trial eligibility determination. It is available to health care professionals by clicking
here.

Local recurrence (LR), recurrence of the tumor in the same location, will
occur in approximately 20-30% of all patients with soft tissue sarcomas
(Refs. 25, 42, and 49). LR is lowest in extremity sarcomas and highest in
retroperitoneal and head and neck sarcomas. This distribution is directly
related to the ability to completely resect a tumor at the time of surgery.
Higher LR rates are observed in the setting of positive surgical margins,
which are more difficult to achieve in anatomic locations outside of the
extremity (Ref. 18). Whether local control has an impact on overall
survival is unclear and remains controversial. Several well designed
investigations have been reported that support both sides of the
argument.
It is very important for patients to understand that the data on outcomes
and survival is derived from mostly heterogeneous, retrospective analyses
that lack strict inclusion criteria. The survival statistics that are quoted are
most useful to the treating physician to guide therapy and probably of
limited value for an individual patient.
Table 4: Clinical Outcome of Malignant Fibrous Histiocytoma
from Large Cancer Centers
Center

# of
Patients

Local Recurrence
(%)

Metastasis
(%)

5-Year
Survival

Memorial Sloan-Kettering
Cancer Center

230

19

35

65

MD Anderson Cancer Center

271

21

31

68

French Federation of Cancer

Centers

216

31

33

70

Follow-up Care and Surveillance

Probably about 1/3 of patients with extremity MFH and closer to of
patients with retroperitoneal MFH will experience recurrence either in the
primary site (local recurrence) or at a distant site (distant recurrence or
metastasis). Most recurrences usually develop in the first 2 years
following treatment but may occur at any time during a patients lifetime.
The frequency and length of follow-up vary according to the number of
risk factors an individual has for developing a recurrence. On average
patients are followed for approximately 10 years. Patients with large or
high grade tumors will likely be evaluated every few months initially
where as patients with low grade or small tumors will probably be seen
annually. A follow-up exam consists of a physical examination and a chest
evaluation in the form of an x-ray or CT-scan. Depending on the
circumstances, an MRI of the primary site may be obtained.
If a recurrence is detected, the treatment team collaborates again to
determine the roles of surgery, radiation, and chemotherapy. Most local
recurrences can be effectively treated with additional surgery. For
recurrent local disease that is resectable, approximately 2/3 of patients
experience long term survival (Refs. 31 and 44). If no prior radiation was
administered, the affected area should receive radiation for the
recurrence. Metastatic disease represents the most serious type of
recurrence and most commonly occurs in the lungs. Individual treatment
plans vary significantly depending on a host of patient and disease factors
as well as the limitations imposed by previous treatments. For patients
that have isolated resectable pulmonary metastases, it is possible to
achieve extended survival in approximately 20% to 50% of patients (Refs.
7, 9, and 41). Chemotherapy is often incorporated into the treatment of
patients with distant recurrence. Unfortunately, patients with unresectable
recurrent disease have a uniformly poor prognosis.

Summary

MFH is a curable disease.

The term "Malignant Fibrous Histiocytoma" has been changed by the WHO to
Undifferentiated Pleomorphic Sarcoma Not Otherwise Specified.

The mainstays of treatment for MFH are complete surgical excision most often
supplemented with adjuvant radiation therapy.

Chemotherapy is reserved for patients at the highest risk of disease recurrence or

patients that already have recurrence.

Patients with recurrent MFH can still be cured.

Favorable prognostic factors that correspond to superior survival include small

tumor size, low grade, extremity location, superficial location, and localized disease.
Last revision and medical review: 4/2005
By Carol D. Morris, MD, MS
Attending Orthopaedic Surgeon
Memorial Sloan-Kettering Cancer Center
Assistant Professor of Orthopaedic Surgery
Weill Medical College
Cornell University
New York, NY
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