Dermatofibrosarcoma Protuberans Treated at a Single Institution: A Surgical Disease With a High Cure Rate
http://www.100md.com
《临床肿瘤学》
the Department of Surgery, Istituto Nazionale per lo studio e la cura dei Tumori, and the Unit of Medical Statistics and Biometry, Istituto Nazionale per lo studio e la cura dei Tumori, and the Department of Radiation Oncology, Istituto Nazionale per lo studio e la cura dei Tumori, and the Department of Pathology, Istituto Nazionale per lo studio e la cura dei Tumori, and the Department of Cancer Medicine, Istituto Nazionale per lo studio e la cura dei Tumori, Milano, Italy
ABSTRACT
PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autocrine overproduction of the platelet-derived growth factor (PDGF) ?-chain from gene rearrangement as a key pathogenetic factor, now susceptible of molecular-targeted therapy. The aim of this retrospective analysis was to explore the outcome of patients with primary or recurrent DFSP.
PATIENTS AND METHODS: Two hundred eighteen patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy) over 20 years were reviewed. Local relapse, distant metastasis, and survival were studied.
RESULTS: One hundred thirty-six patients (62.4%) presented with a primary DFSP, while 82 patients (37.6%) had a recurrent disease. In the primary group, margins were microscopically positive in 11.8%, while in the recurrent group they were positive in 14.6% (P =.613). In the primary group, patients undergoing re-excision after inadequate previous surgery had residual disease in 62% of cases. Reconstructive surgery was needed in 30%, significantly more frequently in patients with a recurrence or a head and neck tumor. The crude cumulative incidence of local relapses was 4% at 10 years, and 2% at 10 years for distant metastases. No significant difference was found between primary and recurrent patients, as well as between positive and negative margins.
CONCLUSION: This being one of the largest mono-institutional series of DFSP, we confirm that long-term outcome is excellent, in terms of both local and distant control, after a wide excision with negative margins. Reconstructive surgery is often needed. Novel medical therapies will be of use in a limited subgroup of patients.
INTRODUCTION
Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive tumor arising from the skin. DFSP has an indolent growth and a high tendency to give local recurrences after excision.1,2,3 DFSP arises from the rearrangement of chromosomes 17 and 22, with the fusion between the collagen type I1 gene (COL1A1) and the platelet-derived growth factor (PDGF) ?-chain gene (PDGFB).4 This results in deregulation of PDGF ?-chain expression and activation of PDGF receptor ? (PDGFR?) protein tyrosine kinase, with DFSP cell growth as a result.5,6,7 More than 90% of DFSP feature the translocation between chromosomes 17 and 22.8
Standard treatment of DFSPs is wide excision, with an expected local recurrence rate of less than 10%.9 Some series suggest the use of Mohs micrographic surgery, to minimize the amount of tissue resected, especially in more visible areas.10,11
Radiation therapy (RT) has been suggested in limited series as an adjuvant for positive surgical margins, after planned marginal excision in critical anatomic sites,12 or as an exclusive treatment in advanced cases with no feasible surgical approach.13
Despite its locally aggressive behavior, DFSP rarely metastasizes. If so, the metastases-free interval is generally long, and metastases are frequently preceded by multiple local recurrences. Approximately 85% to 90% of all DFSPs are low-grade lesions; the remainder contain a high-grade fibrosarcomatous component, and have a much higher risk of metastasization.1
The present analysis of a large series of patients surgically treated at a single referral institution was carried out to further clarify the prognosis of patients with primary and recurrent disease, to investigate prognostic factors, and to identify those patients with a worse outcome, even considering that targeted medical therapy has now become available for this disease.14
PATIENTS AND METHODS
Two hundred eighteen consecutive patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy), for primary or recurrent DFSP between April 1983 and December 2003 were reviewed. They account for 10% of all patients affected by adult type soft tissue sarcoma surgically treated at our institution in the same time span. Most of the patients (approximately 85%) affected by DFSP were operated on since 1990 (50% since 1998). Clinical data were extracted from a prospective database that includes all adult patients with soft tissue sarcoma treated at our institution. Analyzed data included sex, age at diagnosis, site, size and depth of the tumor, previous treatments and recurrences, date of surgery, type of surgery, adjuvant treatments, local recurrence, and metastases occurrence.
Two different groups of patients were identified, according to whether they presented at our institution with primary or recurrent disease. Patients with primary DFSP were admitted either for initial treatment or after previous inadequate surgery, to undergo re-excision. Recurrent disease was defined as tumors arising within, or close to, the previous surgical field at least 6 months after treatment at another institution.
Standard surgery consisted of a wide local excision. Surgical resections were considered macroscopically complete in the absence of gross residual disease. All pathologic specimens of primary disease were reviewed by a dedicated pathologist if first surgery was performed elsewhere, and the diagnosis of DFSP was confirmed in all cases. Even the final pathologic examination, with assessment of margins, was done by a dedicated pathologist and prospectively recorded in the database. Surgical margins were rated as positive if tumor was present within 1 mm, negative if it was more than 1 mm from inked surface.
Tumor size was missing in 18 patients, because it was not specified in the original pathologic report.
All patients with the fibrosarcomatous variant of DFSP (FS-DFSP) were included in the present series.
The indication to RT was given by the radiation oncologist in cooperation with the operating surgeon when a high risk of recurrence was supposed to exist on clinical grounds. However, no prospectively selected criteria were used to this end.
Clinical follow-up of the patients was updated to March 2005, with a median follow-up of 78 months. Patients were regularly seen every 6 months for the first 5 years and then every year for at least 5 more years. A clinical exam and an ultra-sound of the operated area, along with a chest x-ray, were repeated routinely at each control.
A multiple binary logistic model was used for testing the dishomogeneity between primary and recurrent patients with respect to the common characteristics. The response variable took the value of one for recurrent patients and zero for the others. Patient’s age and tumor size were modeled as continuous variables by using 3-knot restricted cubic splines,15 whereas the other variables were modeled as categoric as shown in Table 1, by using dummy (0/1) variables. As the Wald test for the overall model was significant (P = .048), the effect of each characteristic was tested by the corresponding individual two-sided Wald test (Table 1).
Other bivariate comparisons of categoric variables, whose results in terms of P value are referred to within the text were performed by the Fisher’s exact test. The Cochran-Armitage test for trend was used whenever the comparison between patients with primary tumor and with one or more local relapses was involved.
The low number of observed events prevented us from performing reliable multivariable analyses of the end points, namely local relapse, distant metastasis, and sarcoma-specific mortality. Thus, univariable analyses were carried out in a competing risks framework by estimating the crude cumulative incidence (CCI) curves.16 Comparisons between curves, based on clinical hypotheses, were performed by means of the Gray test.17 Time to occurrence of each event was computed from the date of surgery at our institution to the date when the event was first recorded, or censored at the date of last follow-up assessment in event-free subjects. For local relapse (distant metastasis) analysis, no evidence of disease deaths, and distant metastasis (local relapse), whichever occurred first, were regarded as competing events. Concomitant local relapses and distant metastases were included in the estimation of the CCI curves as distant metastases. In the analysis of sarcoma-specific mortality, death caused by conditions unrelated to the disease was regarded as a competing event.
We used SAS software (SAS Institute Inc, Cary, NC) and the S-Plus Design (StatSci, MathSoft, Seattle, WA; available at: http://lib.stat.cmu.edu) and Cmprsk (available at: http://biowww.dfci.harvard.edu/gray/) libraries to perform the modeling and statistical calculations. We considered two-sided P values below the 5% conventional threshold as significant.
RESULTS
Study population consisted of 218 patients whose main characteristics are summarized in Table 1.
The median age was 37 years (range, 14 to 77). One hundred thirty-six patients (62.4%) presented with primary disease, while 82 patients (37.6%) had a recurrent DFSP at the time of referral to our institution. In the recurrent group, 48 patients (58.5%) presented after one previous local relapse, while 34 patients (41.5%) presented with a second or further local relapse (up to six relapses). Median follow-up was 55.5 months for the primary group and 98 months for the recurrent group.
The most common localization was the trunk (72.0%). DFSP was located in the extremities in 16.5% of patients and in the head or neck in 11.5% of patients. Almost all patients (96.8%) presented the classic histologic features, while FS-DFSP variant was present in seven patients. Two hundred and nine patients had a superficial localization, while only nine patients had a deep involvement (muscle, bone, or neurovascular structures invasion), seven of whom had classic DFSP, while two patients had FS-DFSP variant. None of these patients had distant metastases at the time of diagnosis.
On the basis of the logistic model results, no significant differences between primary and recurrent tumors were found according to age, sex, tumor site, tumor size, histologic variant, or RT (Table 1). Primary and recurrent patients were found to be significantly different as far as tumor depth (P = .042) and need of reconstructive surgery (P = .007) were concerned. In particular, a deep tumor was observed in nine patients, of whom one of 136 patients (0.7%) had primary tumor, two of 48 patients (4.2%) had a single previous local relapse, and six of 34 patients (17.7%) had two or more local relapses (P < .001). Sixty-six patients (30.3%) underwent reconstructive surgery, with a different distribution according to tumor presentation (ie, 32 of 136 primary patients [23.5%], 16 of 48 patients [33.3%] with one local relapse, and 18 of 34 patients [52.9%] with two or more local relapses; P = .001). Reconstructive surgical procedures are detailed in Table 2. The execution of reconstructive surgery was found to be associated with the site of tumor, with 14 of 36 reconstructions (38.9%) performed in patients with tumors of extremities, 19 of 25 reconstructions (76.0%) in patients with head and neck tumors, and 33 of 157 reconstructions (21.0%) in patients with their tumor in the trunk (P < .001).
All patients underwent macroscopically complete resection, save for one of the supraclavicular region presenting after four previous recurrences. This patient had intralesional surgery, followed by radiotherapy and chemotherapy, and eventually died of local disease 10 months after surgery.
After definitive surgery, margins were microscopically negative in 87.2% of patients and positive in 12.8% of patients. Among the primary group, margins were microscopically positive in 11.8% of patients, while they were positive in 14.6% of the recurrent patients (Wald test P = .613).
Adjuvant external beam radiation was given in 17 cases, with doses ranging from 45 Gy to 65 Gy.
In the primary group, 103 patients (75.7%) initially presented after inadequate surgery performed elsewhere and underwent re-excision, with 92.2% of microscopically negative margins. After re-excision, residual disease was detected in the pathologic specimen in 62.1% of these patients, including eight patients with macroscopic residual disease (7.8%).
During the follow-up period, a local relapse was the first event for eight patients (three patients from the primary group and five patients from the recurrent group), and in one of them it was concomitant to a distant metastasis. Overall, five patients experienced distant metastases, mainly to the lungs; in two of these patients, it was the only event. Four patients died because of disease, while seven patients died for reasons other than DFSP. The characteristics of these patients are detailed in Table 3.
Overall CCI of sarcoma-specific mortality was 1.5% (SE, 0.8%) at 5 years and 2.8% (SE, 1.6%) at 10 years. No disease-related death was observed in primary patients, while CCI of sarcoma-specific mortality was 3.7% (SE, 2.1%) at 5 years and 6.2% (SE, 3.3%) at 10 years in patients presenting with a locally recurrent tumor.
Overall CCI of local relapse and distant metastasis is shown in Figure 1. Local relapse CCI was 3.0% (SE, 1.2%) at 5 years and 4.2% (SE, 1.7%) at 10 years. CCI of distant metastasis was 1.7% (SE, 1.0%) at both 5 years and 10 years.
According to tumor presentation (Fig 2), 5-year and 10-year CCI of local relapse in primary group were 1.9% (SE, 1.3%) and 4.1% (SE, 2.6%), respectively. In the recurrent group, both 5-year and 10-year CCI were 5.0% (SE, 2.5%). The difference between primary patients and recurrent patients was not significant (P = .368). CCI of distant metastasis was 1.3% (SE, 1.3%) at both 5 years and 10 years in the primary group, and 2.5% (SE, 1.7%) in the recurrent group (P = .382).
According to surgical margins (Fig 3), 5-year and 10-year CCI of local relapse in the negative margins group were 2.3% (SE, 1.2%) and 3.7% (SE, 1.8%), respectively. In the positive margins group, both 5-year and 10-year CCI were 8.0% (SE, 5.6%). The difference between negative and positive margins patients was not significant (P = .195). CCI of distant metastasis was 1.4% (SE, 1.0%) at both 5 years and 10 years in the negative margin group, and 3.6% (SE, 3.6%) in the positive margin group (P = .311).
DISCUSSION
To our knowledge, this series is one of the largest mono-institutional series of patients with DFSP. DFSP was confirmed to be a relatively indolent tumor, with a cause-specific mortality of less than 2% at 5 years and less than 3% at 10 years. No disease-related deaths occurred in patients presenting at our institution with a primary tumor. However, in those patients who presented with a locally recurrent tumor, the CCI of sarcoma-specific mortality was 6.2%.
The latter difference may well reflect a selection bias, but might suggest that local recurrences need to be carefully followed, because they bear a five-fold risk of dying of the disease. However, the management of DFSP has mainly to face its tendency to locally recur. In published literature, many series reported local recurrence rates widely ranging from 0% to 60%.3 Recurrence rates from the major published series are summarized in Table 4. 18-21 Even in a recent, large, and well-characterized series from the Memorial Sloan-Kettering Cancer Center, local recurrence rate were considerable, accounting for up to 21% of the cases, though a relatively high rate of positive surgical margin (42%) and FS-DFSP variant (16%) were found. Moreover, multivariable analysis of this series found FS-DFSP variant and positive/close (< 1 mm) surgical margins to be of prognostic relevance for recurrence-free survival.20
In our series, the CCI of local recurrence and distant metastases are quite low (4.2% and 1.7% at 10 years, respectively; Fig 1). This might reflect an aggressive surgical policy, since only 13% of patients had pathologically positive surgical margins, or a referral bias, since only 3% of patients were diagnosed with the more aggressive FS-DFSP variant.
The small number of local relapses and distant metastases in our series prevented us from performing reliable multivariable analyses of prognostic factors, though a trend towards a higher risk for local relapse in recurrent cases and in the positive margin group was confirmed. Interestingly, events seem to occur earlier both in recurrent and positive margin patients (Figs 2 and 3), and a trend towards a better prognosis in negative margin cases was observed.
It is generally recognized that negative margins are a key-point in the treatment of DFSP, as is the case for most soft tissue sarcomas. The microscopically infiltrating pattern of the tumor might lead to high rates of unexpected positive margins. A policy of re-excision to obtain negative margins should always be followed, save in selected instances in which reconstructive difficulties are expected. In our series, all patients were operated on with the intent to obtain negative margins, achieving similar rates for primary and recurrent tumors.
A higher need for reconstructive procedures was observed both in the recurrent group as well as in head and neck tumors. Patients with DFSP had a higher rate of reconstructive surgery procedures overall (30.3%), when compared with other soft tissue sarcomas operated on at our own institution in the same time span.22
Mohs micrographic surgery–suggested by some authors–was not performed in this series, even for the most exposed regions. In our series, this challenge was dealt with by an extensive use of reconstructive surgery, with all patients receiving one time surgery and without delayed closing procedures.
As far as primary presenting DFSPs are concerned, 76% of patients came to our institution following a previous inadequate surgery. This referral pattern reflects the clinical characteristics of the disease, which mimics a benign tumor. Pathologic residual disease was detected in 62% of re-excisions, a relatively high rate in comparison to a similar population of re-excised extremity soft tissue sarcoma patients at our own institution (23.6%).23 In any case, the presence of residual disease did not influence the local or distant outcomes, the only determinant of local recurrence being the final quality of surgical margins.
Five patients developed distant metastases, which are rarely described in this disease. Four of these patients were recurrent at presentation at our institute, two patients had a FS-DFSP, three patients had a deep tumor, two patients had positive surgical margins, and three patients locally recurred after surgery (one patient had a concomitant local and distant relapse). Three patients with lung disease underwent metastasectomy, one of them died of disease (FS-DFSP variant), and two patients have no evidence of disease at 98 months and 130 months after lung surgery (classic DFSP). Aggressive surgical treatment might be important in the metastatic setting, especially when metastases originate from a classic DFSP. As a matter of fact, distant metastases often behave as low-grade lesions, with long intervals before further progression after surgical resection. On the contrary, the FS-DFSP variant has a much less indolent course, with a far higher tendency to give metastases and a much faster growth. Overall, two of seven patients who presented at our center with a FS-DFSP developed distant metastases and both died, while this happened in only three of 211 patients with a classic DFSP and two of them are still progression-free following metastasectomy.
While there are anecdotal reports of sensitivity to vinblastine and oral methotrexate,24 recent studies have created interest in DFSP because of the activation of PDGFR?, which is treatable with imatinib mesylate.5,6,25 A series of 10 patients with locally advanced and/or metastatic DFSP were recently reported, with a 50% complete response rate in the locally advanced disease setting. As far as metastatic DFSP is concerned, only two patients have been reported, one with a partial response followed by disease progression after 7 months of therapy, the other with a FS-DFSP lacking the t(17;22) translocation and no clinical response.14 In brief, this novel approach might be of great interest in a limited subset of DFSP patients, but further studies are needed to identify whether it is effective even in the FS-DFSP variant, which is expected to be more aggressive and thus, more in need of medical therapy. However, it should be stressed that classic DFSP, even when advanced, should be surgically treated whenever feasible, given the good results surgery can provide.
In summary, an aggressive surgical approach is able to cure the vast majority of DFSP. Local recurrences should be avoided, to limit the need for reconstructive procedures. A liberal policy of re-excision after inadequate surgical margins seems justified, whenever feasible, because of the high rate of residual disease found in these cases. Metastatic disease is rare, and surgery may well play a role even in this setting, for isolated lung lesions. Only a limited subset of patients will have a need for novel approaches with molecular-targeted therapies, but further studies are needed to better identify the role of these therapies in the most aggressive FS-DFSP variant.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Mendenhall WM, Zlotecki RA, Scarborough MT: Dermatofibrosarcoma protuberans. Cancer 101:2503-2508, 2004
Stamathis G: Fibrohistiocytic Tumors of Intermediate Malignancy, in Enzinger FM, Weiss SW (eds): Soft tissue tumors. St Louis, MO, Mosby, 1988, pp 252-268
Gloster HM Jr: Dermatofibrosarcoma protuberans. J Am Acad Dermatol 35:355-374, 1996
Shimizu A, O’Brien KP, Sj?blom T, et al: The dermatofibrosarcoma protuberans-associated collagen type I1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res 59:3719-3723, 1999
McAuthur G: Molecularly targeted treatment for dermatofibrosarcoma protuberans. Semin Oncol 31:30-36, 2004
Sj?blom T, Shimizu A, O’Brien KP, et al: Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis. Cancer Res 61:5778-5783, 2001
Kiuru-Kuhlefelt S, El-Rifai W, Fanburg-Smith J, et al: Concomitant DNA copy number amplification at 17q and 22q in dermatofibrosarcoma protuberans. Cytogenet Cell Genet 92:192-195, 2001
Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: Dermatofibrosarcoma protuberans and giant cell fibroblastoma. Cancer Genet Cytogenet 140:1-12, 2003
Lindner NJ, Scarborough MT, Powell GJ, et al: Revision surgery in dermatofibrosarcoma protuberans of the trunk and extremities. Eur J Surg Oncol 25:392-397, 1999
DuBay D, Cimmino V, Lowe L, et al: Low recurrence rate after surgery for dermatofibrosarcoma protuberans. A multidisciplinary approach from a single institution. Cancer 100:1008-1016, 2004
Khatri VP, Galante JM, Bold RJ, et al: Dermatofibrosarcoma protuberans: Reappraisal of wide local excision and impact of inadequate initial treatment. Ann Surg Oncol 10:1118-1122, 2003
Ballo MT, Zagars GK, Pisters P, et al: The role of radiation therapy in the management of dermatofibrosarcoma protuberans. Int J Radiat Oncol Biol Phys 40:823-827, 1998
Suit H, Mankin HJ, Efrid J, et al: Radiation in management of patients with dermatofibrosarcoma protuberans. J Clin Oncol 14:2365-2369, 1996
McArthur GA, Demetri GD, van Oosterom A, et al: Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib target exploration consortium study B2225. J Clin Oncol 23:866-873, 2005
Durrleman S, Simon R: Flexible regression models with cubic splines. Stat Med 8:551-561, 1989
Marubini E, Valsecchi MG: Analyzing Survival Data for Clinical Trials and Observational Studies. Chichester, UK, John Wiley and Sons, 1995
Gray RJ: A class of k-sample tests for comparing the cumulative incidence of a competing risk. The Annals of Statistics 16:1141-1154, 1988
Taylor HB, Helwig EB: Dermatofibrosarcoma protuberans. A study of 115 cases. Cancer 15:717-725, 1962
Rutgers EJ, Kroon BB, Albus-Lutter CE, et al: Dermatofibrosarcoma protuberans: Treatment and prognosis. Eur J Surg Oncol 18:241-248, 1992
Bowne WB, Antonescu R, Leung DH, et al: Dermatofibrosarcoma protuberans. A clinicopathologic analysis of patients treated and followed at a single institution. Cancer 88:2711-2720, 2000
Chang CK, Jacobs IA, Salti GI: Outcomes of surgery for dermatofibrosarcoma protuberans. Eur J Surg Oncol 30:341-345, 2004
Gronchi A, Casali PG, Mariani L, et al: Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: A series of patients treated at a single institution. J Clin Oncol 23:96-104, 2005
Fiore M, Casali PG, Miceli R, et al: Prognostic effect of re-excision in adult soft tissue sarcoma of the extremity. Ann Surg Oncol (in press)
Antony N, Hiroshi N, Anthony L, et al: Chemosensitivity in pediatric dermatofibrosarcoma protuberans. J Pediatr Hematol Oncol 27:100-102, 2005
Rubin BP, Schuetze SM, Eary JF, et al: Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 20:3586-3591, 2002(Marco Fiore, Rosalba Mice)
ABSTRACT
PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autocrine overproduction of the platelet-derived growth factor (PDGF) ?-chain from gene rearrangement as a key pathogenetic factor, now susceptible of molecular-targeted therapy. The aim of this retrospective analysis was to explore the outcome of patients with primary or recurrent DFSP.
PATIENTS AND METHODS: Two hundred eighteen patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy) over 20 years were reviewed. Local relapse, distant metastasis, and survival were studied.
RESULTS: One hundred thirty-six patients (62.4%) presented with a primary DFSP, while 82 patients (37.6%) had a recurrent disease. In the primary group, margins were microscopically positive in 11.8%, while in the recurrent group they were positive in 14.6% (P =.613). In the primary group, patients undergoing re-excision after inadequate previous surgery had residual disease in 62% of cases. Reconstructive surgery was needed in 30%, significantly more frequently in patients with a recurrence or a head and neck tumor. The crude cumulative incidence of local relapses was 4% at 10 years, and 2% at 10 years for distant metastases. No significant difference was found between primary and recurrent patients, as well as between positive and negative margins.
CONCLUSION: This being one of the largest mono-institutional series of DFSP, we confirm that long-term outcome is excellent, in terms of both local and distant control, after a wide excision with negative margins. Reconstructive surgery is often needed. Novel medical therapies will be of use in a limited subgroup of patients.
INTRODUCTION
Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive tumor arising from the skin. DFSP has an indolent growth and a high tendency to give local recurrences after excision.1,2,3 DFSP arises from the rearrangement of chromosomes 17 and 22, with the fusion between the collagen type I1 gene (COL1A1) and the platelet-derived growth factor (PDGF) ?-chain gene (PDGFB).4 This results in deregulation of PDGF ?-chain expression and activation of PDGF receptor ? (PDGFR?) protein tyrosine kinase, with DFSP cell growth as a result.5,6,7 More than 90% of DFSP feature the translocation between chromosomes 17 and 22.8
Standard treatment of DFSPs is wide excision, with an expected local recurrence rate of less than 10%.9 Some series suggest the use of Mohs micrographic surgery, to minimize the amount of tissue resected, especially in more visible areas.10,11
Radiation therapy (RT) has been suggested in limited series as an adjuvant for positive surgical margins, after planned marginal excision in critical anatomic sites,12 or as an exclusive treatment in advanced cases with no feasible surgical approach.13
Despite its locally aggressive behavior, DFSP rarely metastasizes. If so, the metastases-free interval is generally long, and metastases are frequently preceded by multiple local recurrences. Approximately 85% to 90% of all DFSPs are low-grade lesions; the remainder contain a high-grade fibrosarcomatous component, and have a much higher risk of metastasization.1
The present analysis of a large series of patients surgically treated at a single referral institution was carried out to further clarify the prognosis of patients with primary and recurrent disease, to investigate prognostic factors, and to identify those patients with a worse outcome, even considering that targeted medical therapy has now become available for this disease.14
PATIENTS AND METHODS
Two hundred eighteen consecutive patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy), for primary or recurrent DFSP between April 1983 and December 2003 were reviewed. They account for 10% of all patients affected by adult type soft tissue sarcoma surgically treated at our institution in the same time span. Most of the patients (approximately 85%) affected by DFSP were operated on since 1990 (50% since 1998). Clinical data were extracted from a prospective database that includes all adult patients with soft tissue sarcoma treated at our institution. Analyzed data included sex, age at diagnosis, site, size and depth of the tumor, previous treatments and recurrences, date of surgery, type of surgery, adjuvant treatments, local recurrence, and metastases occurrence.
Two different groups of patients were identified, according to whether they presented at our institution with primary or recurrent disease. Patients with primary DFSP were admitted either for initial treatment or after previous inadequate surgery, to undergo re-excision. Recurrent disease was defined as tumors arising within, or close to, the previous surgical field at least 6 months after treatment at another institution.
Standard surgery consisted of a wide local excision. Surgical resections were considered macroscopically complete in the absence of gross residual disease. All pathologic specimens of primary disease were reviewed by a dedicated pathologist if first surgery was performed elsewhere, and the diagnosis of DFSP was confirmed in all cases. Even the final pathologic examination, with assessment of margins, was done by a dedicated pathologist and prospectively recorded in the database. Surgical margins were rated as positive if tumor was present within 1 mm, negative if it was more than 1 mm from inked surface.
Tumor size was missing in 18 patients, because it was not specified in the original pathologic report.
All patients with the fibrosarcomatous variant of DFSP (FS-DFSP) were included in the present series.
The indication to RT was given by the radiation oncologist in cooperation with the operating surgeon when a high risk of recurrence was supposed to exist on clinical grounds. However, no prospectively selected criteria were used to this end.
Clinical follow-up of the patients was updated to March 2005, with a median follow-up of 78 months. Patients were regularly seen every 6 months for the first 5 years and then every year for at least 5 more years. A clinical exam and an ultra-sound of the operated area, along with a chest x-ray, were repeated routinely at each control.
A multiple binary logistic model was used for testing the dishomogeneity between primary and recurrent patients with respect to the common characteristics. The response variable took the value of one for recurrent patients and zero for the others. Patient’s age and tumor size were modeled as continuous variables by using 3-knot restricted cubic splines,15 whereas the other variables were modeled as categoric as shown in Table 1, by using dummy (0/1) variables. As the Wald test for the overall model was significant (P = .048), the effect of each characteristic was tested by the corresponding individual two-sided Wald test (Table 1).
Other bivariate comparisons of categoric variables, whose results in terms of P value are referred to within the text were performed by the Fisher’s exact test. The Cochran-Armitage test for trend was used whenever the comparison between patients with primary tumor and with one or more local relapses was involved.
The low number of observed events prevented us from performing reliable multivariable analyses of the end points, namely local relapse, distant metastasis, and sarcoma-specific mortality. Thus, univariable analyses were carried out in a competing risks framework by estimating the crude cumulative incidence (CCI) curves.16 Comparisons between curves, based on clinical hypotheses, were performed by means of the Gray test.17 Time to occurrence of each event was computed from the date of surgery at our institution to the date when the event was first recorded, or censored at the date of last follow-up assessment in event-free subjects. For local relapse (distant metastasis) analysis, no evidence of disease deaths, and distant metastasis (local relapse), whichever occurred first, were regarded as competing events. Concomitant local relapses and distant metastases were included in the estimation of the CCI curves as distant metastases. In the analysis of sarcoma-specific mortality, death caused by conditions unrelated to the disease was regarded as a competing event.
We used SAS software (SAS Institute Inc, Cary, NC) and the S-Plus Design (StatSci, MathSoft, Seattle, WA; available at: http://lib.stat.cmu.edu) and Cmprsk (available at: http://biowww.dfci.harvard.edu/gray/) libraries to perform the modeling and statistical calculations. We considered two-sided P values below the 5% conventional threshold as significant.
RESULTS
Study population consisted of 218 patients whose main characteristics are summarized in Table 1.
The median age was 37 years (range, 14 to 77). One hundred thirty-six patients (62.4%) presented with primary disease, while 82 patients (37.6%) had a recurrent DFSP at the time of referral to our institution. In the recurrent group, 48 patients (58.5%) presented after one previous local relapse, while 34 patients (41.5%) presented with a second or further local relapse (up to six relapses). Median follow-up was 55.5 months for the primary group and 98 months for the recurrent group.
The most common localization was the trunk (72.0%). DFSP was located in the extremities in 16.5% of patients and in the head or neck in 11.5% of patients. Almost all patients (96.8%) presented the classic histologic features, while FS-DFSP variant was present in seven patients. Two hundred and nine patients had a superficial localization, while only nine patients had a deep involvement (muscle, bone, or neurovascular structures invasion), seven of whom had classic DFSP, while two patients had FS-DFSP variant. None of these patients had distant metastases at the time of diagnosis.
On the basis of the logistic model results, no significant differences between primary and recurrent tumors were found according to age, sex, tumor site, tumor size, histologic variant, or RT (Table 1). Primary and recurrent patients were found to be significantly different as far as tumor depth (P = .042) and need of reconstructive surgery (P = .007) were concerned. In particular, a deep tumor was observed in nine patients, of whom one of 136 patients (0.7%) had primary tumor, two of 48 patients (4.2%) had a single previous local relapse, and six of 34 patients (17.7%) had two or more local relapses (P < .001). Sixty-six patients (30.3%) underwent reconstructive surgery, with a different distribution according to tumor presentation (ie, 32 of 136 primary patients [23.5%], 16 of 48 patients [33.3%] with one local relapse, and 18 of 34 patients [52.9%] with two or more local relapses; P = .001). Reconstructive surgical procedures are detailed in Table 2. The execution of reconstructive surgery was found to be associated with the site of tumor, with 14 of 36 reconstructions (38.9%) performed in patients with tumors of extremities, 19 of 25 reconstructions (76.0%) in patients with head and neck tumors, and 33 of 157 reconstructions (21.0%) in patients with their tumor in the trunk (P < .001).
All patients underwent macroscopically complete resection, save for one of the supraclavicular region presenting after four previous recurrences. This patient had intralesional surgery, followed by radiotherapy and chemotherapy, and eventually died of local disease 10 months after surgery.
After definitive surgery, margins were microscopically negative in 87.2% of patients and positive in 12.8% of patients. Among the primary group, margins were microscopically positive in 11.8% of patients, while they were positive in 14.6% of the recurrent patients (Wald test P = .613).
Adjuvant external beam radiation was given in 17 cases, with doses ranging from 45 Gy to 65 Gy.
In the primary group, 103 patients (75.7%) initially presented after inadequate surgery performed elsewhere and underwent re-excision, with 92.2% of microscopically negative margins. After re-excision, residual disease was detected in the pathologic specimen in 62.1% of these patients, including eight patients with macroscopic residual disease (7.8%).
During the follow-up period, a local relapse was the first event for eight patients (three patients from the primary group and five patients from the recurrent group), and in one of them it was concomitant to a distant metastasis. Overall, five patients experienced distant metastases, mainly to the lungs; in two of these patients, it was the only event. Four patients died because of disease, while seven patients died for reasons other than DFSP. The characteristics of these patients are detailed in Table 3.
Overall CCI of sarcoma-specific mortality was 1.5% (SE, 0.8%) at 5 years and 2.8% (SE, 1.6%) at 10 years. No disease-related death was observed in primary patients, while CCI of sarcoma-specific mortality was 3.7% (SE, 2.1%) at 5 years and 6.2% (SE, 3.3%) at 10 years in patients presenting with a locally recurrent tumor.
Overall CCI of local relapse and distant metastasis is shown in Figure 1. Local relapse CCI was 3.0% (SE, 1.2%) at 5 years and 4.2% (SE, 1.7%) at 10 years. CCI of distant metastasis was 1.7% (SE, 1.0%) at both 5 years and 10 years.
According to tumor presentation (Fig 2), 5-year and 10-year CCI of local relapse in primary group were 1.9% (SE, 1.3%) and 4.1% (SE, 2.6%), respectively. In the recurrent group, both 5-year and 10-year CCI were 5.0% (SE, 2.5%). The difference between primary patients and recurrent patients was not significant (P = .368). CCI of distant metastasis was 1.3% (SE, 1.3%) at both 5 years and 10 years in the primary group, and 2.5% (SE, 1.7%) in the recurrent group (P = .382).
According to surgical margins (Fig 3), 5-year and 10-year CCI of local relapse in the negative margins group were 2.3% (SE, 1.2%) and 3.7% (SE, 1.8%), respectively. In the positive margins group, both 5-year and 10-year CCI were 8.0% (SE, 5.6%). The difference between negative and positive margins patients was not significant (P = .195). CCI of distant metastasis was 1.4% (SE, 1.0%) at both 5 years and 10 years in the negative margin group, and 3.6% (SE, 3.6%) in the positive margin group (P = .311).
DISCUSSION
To our knowledge, this series is one of the largest mono-institutional series of patients with DFSP. DFSP was confirmed to be a relatively indolent tumor, with a cause-specific mortality of less than 2% at 5 years and less than 3% at 10 years. No disease-related deaths occurred in patients presenting at our institution with a primary tumor. However, in those patients who presented with a locally recurrent tumor, the CCI of sarcoma-specific mortality was 6.2%.
The latter difference may well reflect a selection bias, but might suggest that local recurrences need to be carefully followed, because they bear a five-fold risk of dying of the disease. However, the management of DFSP has mainly to face its tendency to locally recur. In published literature, many series reported local recurrence rates widely ranging from 0% to 60%.3 Recurrence rates from the major published series are summarized in Table 4. 18-21 Even in a recent, large, and well-characterized series from the Memorial Sloan-Kettering Cancer Center, local recurrence rate were considerable, accounting for up to 21% of the cases, though a relatively high rate of positive surgical margin (42%) and FS-DFSP variant (16%) were found. Moreover, multivariable analysis of this series found FS-DFSP variant and positive/close (< 1 mm) surgical margins to be of prognostic relevance for recurrence-free survival.20
In our series, the CCI of local recurrence and distant metastases are quite low (4.2% and 1.7% at 10 years, respectively; Fig 1). This might reflect an aggressive surgical policy, since only 13% of patients had pathologically positive surgical margins, or a referral bias, since only 3% of patients were diagnosed with the more aggressive FS-DFSP variant.
The small number of local relapses and distant metastases in our series prevented us from performing reliable multivariable analyses of prognostic factors, though a trend towards a higher risk for local relapse in recurrent cases and in the positive margin group was confirmed. Interestingly, events seem to occur earlier both in recurrent and positive margin patients (Figs 2 and 3), and a trend towards a better prognosis in negative margin cases was observed.
It is generally recognized that negative margins are a key-point in the treatment of DFSP, as is the case for most soft tissue sarcomas. The microscopically infiltrating pattern of the tumor might lead to high rates of unexpected positive margins. A policy of re-excision to obtain negative margins should always be followed, save in selected instances in which reconstructive difficulties are expected. In our series, all patients were operated on with the intent to obtain negative margins, achieving similar rates for primary and recurrent tumors.
A higher need for reconstructive procedures was observed both in the recurrent group as well as in head and neck tumors. Patients with DFSP had a higher rate of reconstructive surgery procedures overall (30.3%), when compared with other soft tissue sarcomas operated on at our own institution in the same time span.22
Mohs micrographic surgery–suggested by some authors–was not performed in this series, even for the most exposed regions. In our series, this challenge was dealt with by an extensive use of reconstructive surgery, with all patients receiving one time surgery and without delayed closing procedures.
As far as primary presenting DFSPs are concerned, 76% of patients came to our institution following a previous inadequate surgery. This referral pattern reflects the clinical characteristics of the disease, which mimics a benign tumor. Pathologic residual disease was detected in 62% of re-excisions, a relatively high rate in comparison to a similar population of re-excised extremity soft tissue sarcoma patients at our own institution (23.6%).23 In any case, the presence of residual disease did not influence the local or distant outcomes, the only determinant of local recurrence being the final quality of surgical margins.
Five patients developed distant metastases, which are rarely described in this disease. Four of these patients were recurrent at presentation at our institute, two patients had a FS-DFSP, three patients had a deep tumor, two patients had positive surgical margins, and three patients locally recurred after surgery (one patient had a concomitant local and distant relapse). Three patients with lung disease underwent metastasectomy, one of them died of disease (FS-DFSP variant), and two patients have no evidence of disease at 98 months and 130 months after lung surgery (classic DFSP). Aggressive surgical treatment might be important in the metastatic setting, especially when metastases originate from a classic DFSP. As a matter of fact, distant metastases often behave as low-grade lesions, with long intervals before further progression after surgical resection. On the contrary, the FS-DFSP variant has a much less indolent course, with a far higher tendency to give metastases and a much faster growth. Overall, two of seven patients who presented at our center with a FS-DFSP developed distant metastases and both died, while this happened in only three of 211 patients with a classic DFSP and two of them are still progression-free following metastasectomy.
While there are anecdotal reports of sensitivity to vinblastine and oral methotrexate,24 recent studies have created interest in DFSP because of the activation of PDGFR?, which is treatable with imatinib mesylate.5,6,25 A series of 10 patients with locally advanced and/or metastatic DFSP were recently reported, with a 50% complete response rate in the locally advanced disease setting. As far as metastatic DFSP is concerned, only two patients have been reported, one with a partial response followed by disease progression after 7 months of therapy, the other with a FS-DFSP lacking the t(17;22) translocation and no clinical response.14 In brief, this novel approach might be of great interest in a limited subset of DFSP patients, but further studies are needed to identify whether it is effective even in the FS-DFSP variant, which is expected to be more aggressive and thus, more in need of medical therapy. However, it should be stressed that classic DFSP, even when advanced, should be surgically treated whenever feasible, given the good results surgery can provide.
In summary, an aggressive surgical approach is able to cure the vast majority of DFSP. Local recurrences should be avoided, to limit the need for reconstructive procedures. A liberal policy of re-excision after inadequate surgical margins seems justified, whenever feasible, because of the high rate of residual disease found in these cases. Metastatic disease is rare, and surgery may well play a role even in this setting, for isolated lung lesions. Only a limited subset of patients will have a need for novel approaches with molecular-targeted therapies, but further studies are needed to better identify the role of these therapies in the most aggressive FS-DFSP variant.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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