Download Neoadjuvant Imatinib Therapy for Dermatofibrosarcoma Protuberans

OBSERVATION
Neoadjuvant Imatinib Therapy
for Dermatofibrosarcoma Protuberans
Anne Han, MD; Elbert H. Chen, MD; George Niedt, MD; William Sherman, MD; Désirée Ratner, MD
Background: Dermatofibrosarcoma protuberans
(DFSP) is an unusual soft-tissue tumor with a propensity for subclinical extension and local recurrence. Surgical excision, even with tissue-sparing techniques, may
cause significant deformity or disability because of the
infiltrative nature of DFSP. In this study, we evaluate
retrospective data obtained from 4 patients with locally
advanced or recurrent DFSP who received neoadjuvant
imatinib mesylate therapy before undergoing Mohs
micrographic surgery.
Observations: Patients treated with neoadjuvant imatinib therapy had an average tumor size reduction of
D
Author Affiliations:
Departments of Dermatology
(Drs Han, Niedt, and Ratner)
and Medicine–Oncology
(Dr Sherman), Columbia
University Medical Center,
New York, New York; and
Kaiser Permanente, Rancho
Cordova, California (Dr Chen).
36.9%. This clinical response was paralleled by histopathologic changes, including decreased cellularity in
100% of the total area as well as significant hyalinization. Imatinib therapy for DFSP before Mohs micrographic surgery was associated with 100% local control
at a maximum follow-up of 4 years.
Conclusions: Neoadjuvant imatinib therapy is a welltolerated, novel approach to DFSP that reduces tumor
burden and facilitates resection. Larger prospective studies are needed to confirm and expand on these results.
Arch Dermatol. 2009;145(7):792-796
ERMATOFIBROSARCOMA
protuberans (DFSP) is an
indolent soft-tissue tumor that represents approximately 0.1% of all
malignant neoplasms.1 It occurs most often on the trunk and extremities and less
frequently on the head and neck. It appears as indurated, flesh-colored or erythematous, ill-defined plaques, within
which nodules may arise. Microscopically, the tumor often extends far beyond
clinically apparent margins, infiltrating by
local extension through the dermis, subcutaneous tissue, fascia, and even muscle.
It has a high rate of local recurrence
(13%-60%)2-5 but rarely metastasizes.6 Excision using Mohs micrographic surgery
(MMS) is the standard of therapy for
DFSP.7-9 However, given the potential subclinical involvement that characterizes
DFSP, resection may still be difficult and
associated with significant deformity or
disability. In surgically challenging cases,
neoadjuvant treatment with imatinib mesylate may reduce tumor bulk, decrease local extension, and improve overall outcome, allowing excisional margins to be
reduced without sacrificing surgical cure.
Imatinib is a small molecular adenosine triphosphate analogue that competitively inhibits the adenosine triphosphate–
binding site of the platelet-derived growth
ARCH DERMATOL/ VOL 145 (NO. 7), JULY 2009
792
factor ␤ (PDGF␤) receptor tyrosine kinase in DFSP. The tumors of DFSP have
a pathologic chromosomal rearrangement that fuses the COL1A1 promoter gene
of chromosome 17 to the PDGFβ gene of
chromosome 22. Overactivation of PDGF␤
receptor tyrosine kinase leads to cellular
proliferation and tumor formation. When
imatinib binds at the receptor site, kinase
activity downregulates, resulting in growth
inhibition and increased apoptosis.10-17
Imatinib has been used successfully to treat
unresectable and metastatic lesions as well
as locally advanced primary and recurrent DFSP.1,6,18,19 This study adds to a growing body of literature showing that the use
of imatinib can reduce the tumor burden
of DFSP.
METHODS
Between 2004 and 2007, patients with a biopsy-confirmed diagnosis of DFSP who were
referred for MMS at Columbia University Medical Center, New York, New York, were evaluated to determine whether they were appropriate candidates for imatinib treatment.
Patients who were offered neoadjuvant imatinib therapy had tumors that appeared to be
at a clinically significant risk of functional or
aesthetic compromise after surgery. Because we
decided to perform this review subsequent to
the treatment of these patients, they were not
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Table. Tumor Characteristics and Imatinib Mesylate Treatment Regimens in 4 Cases of Dermatofibrosarcoma Protuberans
Variable
Tumor size, cm
Tumor site
Primary or recurrent
Daily dosage, mg
Duration, mo
Initial lesion, cm
Size of lesion after imatinib therapy, cm
Reduction in size of lesion, % a
Depth
Patient 1
Patient 2
Patient 3
Patient 4
7.3 ⫻6.5
Left frontal scalp
Recurrent
800
3
7.3 ⫻6.5
7.0 ⫻5.5
18.9
Periosteum
2.7⫻ 2.0
Left medial ankle
Primary
400
3.5
2.7⫻ 2.0
1.7⫻ 1.2
45.3
Fascia
14.0⫻ 8.6
Left lower abdominal wall
Recurrent
800
7
14.0⫻ 8.6
15.4⫻ 3.0
61.6
Fascia
4.0⫻3.2
Left thigh
Primary
600
3
4.0⫻3.2
4.0⫻2.5
21.9
Fascia
a The percentage of reduction in lesion size after imatinib therapy is calculated as follows: [(XY –XY )/XY ] ⫻ 100%, where IL is the initial lesion and PL is the
IL
PL
IL
lesion after imatinib therapy.
subject to rigid inclusion or exclusion criteria. Institutional review board approval was obtained to evaluate their records retrospectively. Informed consent was not required. Only records authorized for research use were used.
The drug was prescribed by a medical oncologist (W.S.) who
monitored all patients’ clinical responses, tolerance, and adverse effects. The standard dose was 800 mg/d based on the observation that PDGF tumors require a higher dose for inhibition than the 400-mg standard dose for BCR-ABL tumors. Doses
lower than 800 mg were given at the discretion of the medical
oncologist. The length of treatment was determined by clinical response. Treatment was administered until the decrease
in tumor size had stabilized or was minimal and continued until 4 weeks before surgery. The cost of the medication, which
is usually several thousand dollars per month, was covered by
insurance after a letter was submitted that justified the prescription of imatinib. The Mohs surgeon used a ruler to measure the extent of visible and palpable tumor in the X and Y
dimensions. The sizes of the lesions were noted at the time of
consultation and preoperatively on the day of surgery. Preoperative biopsy specimens obtained to confirm the diagnosis of
DFSP were compared with debulking specimens obtained at
the time of MMS. These specimens were used to compare the
histologic features on hematoxylin-eosin–stained sections before and after imatinib therapy.
RESULTS
A total of 4 patients with DFSP were referred from the
dermatologic surgery unit at Columbia University Medical Center to receive neoadjuvant imatinib therapy before MMS. The Table compares the tumor characteristics, treatment regimens, and percentage of tumor
reduction in the 4 patients who were treated with imatinib before surgery. The lesions, which were located on
the scalp, abdomen, thigh, and ankle, ranged from 2.0
to 8.6 cm in the X dimension and from 2.7 to 14.0 cm in
the Y dimension. Of the 4 imatinib-treated patients, 2 had
recurrent lesions and 2 had locally advanced primary
DFSP. The median duration of treatment with imatinib
was 3 months. The drug was administered at a dosage of
800 mg/d in 2 patients and at lower dosages in 2 patients. One patient requested a dose of 400 mg once a
day because she was hesitant to take a new medication.
Given the other patient’s history of multiple comorbidities, which included hypertension, diabetes, and obesity, the medical oncologist adjusted the initial dose to
600 mg/d to monitor for adverse events, with the goal of
Figure 1. Specimen from the center of the tumor showing spindle cells in a
storiform pattern typical of dermatofibrosarcoma protuberans
(hematoxylin-eosin, original magnification ⫻20).
gradually increasing to the target dose if tolerated. All 4
patients tolerated their starting doses and showed a clinical response. As a result, no further dosage changes were
made during the remainder of the treatment periods. Three
patients were treated for 3 to 31⁄2 months and experienced initial adverse effects consisting of fatigue, nausea, headache, dizziness, and diarrhea, which resolved
within several weeks. The remaining patient was treated
for 7 months and complained of dry skin and flank pain
during the treatment. Despite these adverse effects, all
patients tolerated the drug without requiring dose reduction or discontinuation. All 4 patients responded to
imatinib therapy with a reduction in tumor size and thickness, achieving a reduction in preoperative tumor size,
measured in the X and Y dimensions, between 18.9% and
61.6%, with an average size reduction of 36.9%. On pretreatment histopathologic examination, all lesions exhibited spindle-shaped cells in a typical storiform pattern. After treatment with imatinib, the histopathologic
area showing decreased cellularity approached 100%. Also,
there was production of hyalinized material throughout
the tumors (Figure 1 and Figure 2).
Clear margins were achieved with MMS in 3 of the 4
patients. The fourth patient had a large, multiply recurrent, abdominal lesion that, after preoperative debulking, required 1 stage of MMS with a margin of 2 cm to
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Figure 2. Specimen from the center of the tumor showing decreased
cellularity in 100% of the total area as well as significant hyalinization after
imatinib mesylate therapy (hematoxylin-eosin, original magnification ⫻20).
Figure 3. Lesion on the scalp of patient 1 before imatinib mesylate therapy.
clear its peripheral extent. The patient subsequently underwent further resection by surgical oncology. At the
time of writing, all patients were free of disease, with follow-up ranging from 1.5 to 4.0 years.
COMMENT
While MMS and other surgery with complete peripheral and deep margin control are standard therapies for
DFSP, neoadjuvant treatment with imatinib can offer considerable advantages. It is striking to note that imatinibtreated patients had an average 36.9% reduction in preoperative tumor size (Figure 3 and Figure 4). Therefore,
neoadjuvant imatinib therapy has the potential to facilitate excision of large or difficult tumors. For example,
the smallest pretreatment lesion in this case series was a
3-cm, freely movable, exophytic nodule on the medial
aspect of the ankle. A complicated surgical course was
anticipated owing to the proximity of tendons, muscles,
and nerves lying below the lesion. Neoadjuvant treatment with imatinib significantly reduced the preoperative lesion size, resulting in a less extensive surgical defect, and allowed placement of a full-thickness skin graft
over a wound that extended to the periosteum. As a re-
Figure 4. Lesion on the scalp of patient 1 after imatinib mesylate therapy.
Note the reduction in the size and thickness of the tumor at its surface.
sult, the patient did not suffer the potential comorbidity
of functional damage to her ankle as a result of surgery.
Imatinib therapy is also useful in patients with recurrent DFSP. One of the study patients who had a large anterior abdominal wall lesion had previously undergone
2 incomplete resections. He responded well to adjuvant
treatment with imatinib but adhered to the regimen for
only 4 months. Six years later, the lesion had progressed to a fungating, foul-smelling mass that measured at least 10 cm at the base, with smaller nodules noted
at its periphery. After a 7-month neoadjuvant course of
imatinib, the size of the mass had decreased to less than
7 cm at the base and the nodules had also decreased in
size. The patient then underwent palliative debulking by
surgical oncology before MMS both to control bleeding
and to minimize the risk of infection. On the day of surgery, 1 surgical stage was taken for peripheral margin
clearance; the remaining resection was performed by surgical oncology the next day with the patient under general anesthesia. The resulting defect extended to the fascia, with residual tumor at the deep margin. The wound
was left open until clear margins were confirmed. An additional Mohs surgical stage was required after a positive deep margin was discovered extending toward the
scrotum. As a result of the combined effort, complete resection with clear margins was ultimately achieved.
The clinical response of DFSP to imatinib therapy is
paralleled by the changes seen histopathologically. Biopsy specimens of DFSPs from imatinib-treated patients showed a decrease in cellularity in 100% of the total
area as well as significant hyalinization. These observations correlate with a recently published novel histologic finding in DFSP after treatment with imatinib: that
of copious amounts of hyalinized collagen.20 A potential
pitfall of neoadjuvant treatment with imatinib is the possibility that imatinib exerts its effect in a discontiguous
fashion, resulting in skip areas of histologically normal
tissue interspersed with persistent tumor. Such an effect
would make MMS less reliable in achieving true tumorfree margins and could lead to more recurrences. To our
knowledge, no such findings have been reported in the
literature to date, and we have not seen any evidence of
skip areas after imatinib therapy in patients with DFSP
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at our institution. In our series, the positive margin occurred in the patient who had a multiply recurrent tumor, and that margin was contiguous with a deep pocket
of tumor.
Imatinib appears to be a safe oral medication with the
ability to significantly shrink the lesions of DFSP. Among
our patients, adverse effects, including fatigue, nausea,
headache, dizziness, diarrhea, dry skin, and flank pain,
were minimal, and all of them resolved. The mean decrease in size of our patients’ tumors after imatinib pretreatment was 36.9%. All study patients were confirmed
to be tumor-free after a follow-up of 1.5 to 4.0 years. To
our knowledge, there are no known long-term effects of
imatinib therapy, although it should be noted that it is
still a relatively new drug, having been first approved for
use in 2001 for chronic myeloid leukemia.21 Imatinib has
been reported to be efficacious only in tumors exhibiting the chromosomal translocation (17;22), which occurs in 90% of all DFSP lesions.22,23 While the patients
in our study did not receive pretreatment evaluation by
fluorescence in situ hybridization, routine screening with
fluorescence in situ hybridization before imatinib therapy
may be useful in identifying this rearrangement, so that
patients with DFSP without this translocation will not
be pretreated unnecessarily.
In the future, adjuvant use of imatinib could also be
considered in patients with DFSP who have undergone
an incomplete surgical excision and therefore have a high
probability of recurrence. Several reports already document a partial or complete response to imatinib in cases
of metastatic, recurrent, and locally advanced disease. Five
groups have described a total of 7 patients with metastatic DFSP, 5 of whom had partial or complete remission.6,18,24-26 The 2 patients with metastatic DFSP who did
not to respond to imatinib therapy were found to be without r(17;22) or t(17;22) chromosomal rearrangements.
One imatinib-treated case of recurrent DFSP achieved a
good response,22 and a total of 11 patients with locally
advanced primary DFSP also had some degree of success.1,19,27,28
Our study documents the utility of imatinib therapy
in decreasing tumor size before surgery in 2 locally advanced and 2 recurrent cases of DFSP and shows that imatinib therapy has the potential to transform patients with
surgically challenging or recurrent tumors into better operative candidates. However, there are several limitations to our study, including its retrospective design, small
sample size, and short-term follow-up. Larger prospective studies are needed to confirm and expand on our results. Furthermore, tumor bulk, or the extent of invasion, is notoriously difficult to assess in DFSP. Tumors
can behave differently, even at the same anatomical location; therefore, the surface area may not be indicative
of the total tumor volume. Currently, several phase 2 clinical trials are under way to assess the response of DFSP
to varying durations of imatinib treatment.
Preoperative imatinib therapy may provide a means
of decreasing morbidity and recurrence rates for patients with locally aggressive or recurrent cases of DFSP
that are surgically challenging but still respectable. While
imatinib is currently approved only for treatment of nonsurgical adult candidates with unresectable, recurrent,
and/or metastatic DFSP, studies like this one may help
to expand the Food and Drug Administration’s indications for its use.
In conclusion, neoadjuvant treatment of locally advanced and recurrent DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult
tumors. Oral imatinib therapy is a well-tolerated, novel
approach to the treatment of DFSP that does not appear
to have any long-term sequelae. It offers patients with
DFSP with highly infiltrative lesions the possibility of reducing their tumor size before surgery, thereby resulting in a smaller postsurgical defect and a less complicated repair.
Accepted for Publication: January 6, 2009.
Correspondence: Anne Han, MD, Department of Dermatology, Columbia University Medical Center, 161 Fort
Washington Ave, 12th Floor, New York, NY 10032 (dr
[email protected]).
Author Contributions: All authors had full access to all
the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Han, Chen, Niedt, and Ratner.
Acquisition of data: Han, Chen, Niedt, Sherman, and Ratner. Analysis and interpretation of data: Han, Chen, Niedt,
and Ratner. Drafting of the manuscript: Han and Niedt.
Critical revision of the manuscript for important intellectual content: Han, Chen, Niedt, Sherman, and Ratner. Administrative, technical, and material support: Han, Chen,
Niedt, and Sherman. Study supervision: Ratner.
Financial Disclosure: None reported.
Additional Contributions: Spiros Manolidis, MD, and Bret
Taback, MD, generously offered their expertise and support in the treatment of these patients.
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Announcement
Volunteering With Health Volunteers Overseas
The American Academy of Dermatology partnered with
Health Volunteers Overseas (HVO) in 2004 to match interested dermatologists with overseas volunteer opportunities. Through HVO programs, volunteer dermatologists train local health care providers, giving them the
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The major goal of the HVO dermatology programs
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Sites with volunteer opportunities for dermatologists include Costa Rica, Palau, India, Peru, Uganda, Cambodia, and Saint Lucia. Volunteers generally serve for 2
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