|REAL WORLD DATA
|Year : 2019 | Volume
| Issue : 1 | Page : 112-118
Dermatofibrosarcoma protuberans of head and neck: Clinical outcome of nine cases treated with imatinib
Lakhan Kashyap1, Vanita Noronha1, Vijay Patil1, Amit Joshi1, Abhishek Mahajan2, Neha Mittal3, Kumar Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiodiagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||9-Sep-2019|
Department of Medical Oncology, Tata Memorial Hospital, Room 304, Homi Bhabha Block, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Dermatofibrosarcoma protuberans (DFSP) of head and neck is rare and presents a unique challenge as surgery may be associated with poor cosmetic and functional outcomes or inadequate surgical margins. There is a paucity of data regarding the use and effectiveness of imatinib in head and neck DFSP. We retrospectively analyzed head and neck DFSP cases treated with imatinib.
Patients and Methods: Data of nine head and neck DFSP cases treated with imatinib were retrieved from our hospital electronic medical records. Demographic and toxicity data were presented using descriptive statistics and simple percentages; survival was calculated using the Kaplan–Meier method.
Results: The median age was 40 years (range, 22–47 years) with almost equal male to female distribution. The site of primary tumor was scalp in seven patients, face and neck in one patient each. One-third of the patients had metastatic disease; sites of metastases included lung, lymph node, soft tissue, and brain. Fibrosarcomatous variant was present in four patients. Eight patients underwent wide local excision for the primary tumor. Three patients each received imatinib in the neoadjuvant, adjuvant, and palliative setting. The response rate to imatinib in the neoadjuvant and palliative setting was 66.7% and 33.3%, respectively. Four patients received adjuvant radiotherapy (RT) after surgery for recurrent disease and one patient received palliative hemostatic RT to the local site. The median duration of follow-up was 84 months (range, 2–148 months), and median recurrence free survival was 82 months (interquartile range, 74–83 months). All patients were alive until last follow-up.
Conclusions: Head and neck DFSP requires multimodality management with incorporation of neoadjuvant imatinib and adjuvant RT to achieve favorable clinical outcomes.
Keywords: Dermatofibrosarcoma, dermatofibrosarcoma protuberans, head and neck, imatinib, sarcoma
|How to cite this article:|
Kashyap L, Noronha V, Patil V, Joshi A, Mahajan A, Mittal N, Prabhash K. Dermatofibrosarcoma protuberans of head and neck: Clinical outcome of nine cases treated with imatinib. Cancer Res Stat Treat 2019;2:112-8
|How to cite this URL:|
Kashyap L, Noronha V, Patil V, Joshi A, Mahajan A, Mittal N, Prabhash K. Dermatofibrosarcoma protuberans of head and neck: Clinical outcome of nine cases treated with imatinib. Cancer Res Stat Treat [serial online] 2019 [cited 2021 Jan 27];2:112-8. Available from: https://www.crstonline.com/text.asp?2019/2/1/112/266458
| Introduction|| |
Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma. It accounts for 6% of all soft tissue sarcomas and 18% of cutaneous soft tissue sarcomas, second only to Kaposi sarcoma., The World Health Organization 2013 classification of soft tissue tumors categorizes it as superficial, low-grade, locally aggressive fibroblastic neoplasm. The most common locations of DFSP are on the trunk and proximal extremities; DFSP involves the head and neck region in approximately 13% of cases. DFSP is a locally aggressive tumor; the risk of distant metastasis is 2%–5%, most commonly to the lungs., Fibrosarcomatous transformation is reported in 5%–10% of DFSP cases. Fibrosarcomatous transformation in DFSP has a more aggressive course with local recurrences occurring in over 50% of patients and distant metastasis in 10%–15% of patients., Overall survival (OS) is not worse in DFSP with fibrosarcomatous transformation as long as surgical margins are adequate.
Over 90% cases of DFSP are characterized by either supernumerary ring chromosomes, derived from chromosome 22 and contain low-level amplified sequences from 17q22-qter and 22q10-q13.1, or t(17;22). This places the expression of platelet-derived growth factor subunit β (PDGF β) gene under the activating control of the COL1A1 promoter., The constitutive activation of the PDGF pathway provides an attractive therapeutic target for inhibition in DFSP. Surgery is the mainstay of treatment in DFSP; however, in advanced and unresectable DFSP, imatinib [a platelet-derived growth factor receptor (PDGFR) inhibitor] has shown efficacy. Imatinib has also been used as neoadjuvant therapy in patients with unresectable disease and where surgery may entail an unacceptable cosmetic or functional outcome.
DFSP in the head and neck region presents a unique challenge as surgery may be associated with poor cosmetic and functional outcomes or inadequate surgical margins, thus increasing the local recurrence rate. Besides, the head and neck location in DFSP is associated with a worse prognosis. There is a paucity of data regarding the use and effectiveness of imatinib in head and neck DFSP. We present a retrospective analysis of patients with advanced head and neck DFSP treated with imatinib at our institution.
| Patients and Methods|| |
This is retrospective analysis of prospectively maintained data of head and neck DFSP at Tata Memorial Center (a tertiary level oncology hospital in Mumbai, India) who received imatinib as part of their treatment. We screened 183 DFSP patients who were registered at our institution between January 2007 and December 2018. We identified 33 patients with head and neck DFSP, 9 of them received imatinib. Written consent for therapy was obtained from each patient before the start of treatment.
Therapy and follow-up
Therapy for all the patients was decided in the multidisciplinary head and neck cancer meetings. Patients received neoadjuvant or palliative imatinib as per standard treatment guidelines. Adjuvant treatment with imatinib was given as per decision in the multidisciplinary clinic. Treatment in the palliative setting was continued until disease progression or unacceptable toxicity as per clinician judgment, while in the neoadjuvant or adjuvant setting, it was continued for a specified duration as decided in the multidisciplinary clinic or until unacceptable toxicity. Patients received radiotherapy (RT) if indicated as per standard treatment guidelines. Patients were followed up routinely in our outpatient department as per our usual clinical practice. The response evaluation was done by clinical evaluation and radiologic imaging every 3 months or as per clinician discretion. Response to treatment was based on clinical assessment and radiologic imaging as per Response Evaluation Criteria in Solid Tumors 1.1 criteria.
The analysis was performed in February 2019. The data were entered and analyzed in the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, Version 24.0. IBM Corp., Armonk, NY, USA). Demographic and toxicity data were presented using descriptive statistics and simple percentages; survival was calculated using the Kaplan–Meier method. Overall disease control rate (DCR) was calculated as the proportion of patients who received imatinib with neoadjuvant or palliative intent and were found to have stable disease or partial response on disease reassessment. Progression-free survival (PFS) was calculated from the date of start of imatinib to the date of disease progression or last follow-up, in patients who had not progressed. Recurrence-free survival (RFS) was calculated from the date of diagnosis to the date of first recurrence or death or last follow-up in patients who had not recurred. OS was calculated from the date of diagnosis to the date of death or the last date of follow-up in surviving patients. Duration of follow-up was calculated from the date of registration at our institution to the date of last follow-up; median follow-up was calculated in the surviving patients by the reverse Kaplan–Meier method. Patients who could not be contacted for over 6 months were considered as lost to follow-up. Lost to follow-up was considered as an event for OS.
| Results|| |
There were nine patients of head-and-neck DFSP who received imatinib as part of their treatment. Patient and treatment characteristics are summarized in [Table 1] and [Table 2], respectively. The clinical course of all 9 patients is summarized in [Table 3].
|Table 1: Patient characteristics of nine patients with head and neck dermatofibrosarcoma protuberans treated with imatinib|
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|Table 2: Treatment characteristics of nine patients with head and neck dermatofibrosarcoma protuberans treated with imatinib|
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|Table 3: Details of nine patients with head and neck dermatofibrosarcoma protuberans treated with imatinib|
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Eight (89%) patients (two metastatic and six non-metastatic) underwent surgery for the primary tumor. One metastatic patient with unresectable primary tumor received imatinib alone with palliative intent. Six patients (66.6%) underwent upfront surgery while two patients with unresectable primary tumor (22.2%) underwent surgery after neoadjuvant imatinib. Five patients (55.5%) developed recurrence. Three patients had only local recurrences, one patient had only distant recurrence, and one metastatic patient who underwent surgery for primary tumor had a local recurrence. The median RFS was 82 months (interquartile range [IQR], 74–83 months). Three non-metastatic recurrent patients underwent surgery, one had received neoadjuvant imatinib while other two patients received adjuvant imatinib. All three patients received adjuvant RT with a median dose of 50 Gy. Of the three metastatic recurrent patients, the first patient was continued on imatinib as she had recurrence after she had stopped treatment by herself for 2 years after which she developed lung metastases, the second patient received weekly paclitaxel for 24 months which was changed to sorafenib 400 mg daily on progression while the third patient received pazopanib 800 mg daily.
All nine patients received imatinib as part of their treatment. Three patients received neoadjuvant imatinib, two for borderline resectable disease while one patient had an indeterminate lung nodule and was therefore planned for upfront systemic therapy and then re-evaluation for radical therapy. The disease reassessment in the three patients who received imatinib with neoadjuvant intent included two partial responses and one stable disease; thus, the response rate was 66.7%. All three patients underwent surgery. Complete excision of tumor could be achieved in all three patients with negative margins. Three patients received adjuvant imatinib, and the median RFS in the adjuvant setting was 90 months.
Of the three patients who received palliative intent imatinib, one patient had stable disease, one patient progressed after an initial partial response following dose reduction of imatinib due to grade 3 toxicity, and one patient had progressive disease. The median PFS was 10 months (IQR, 10–14 months), and all the patients were alive at a median follow-up of 12 months. The overall DCR (stable disease or partial response) was 66.7% in patients who received imatinib as neoadjuvant or palliative treatment. Median time to response to imatinib was 5 months in the neoadjuvant and palliative settings.
All grade toxicities as a result of imatinib occurred in three patients (33.3%), and grade 3 toxicities occurred in one patient (11%). Adverse effects included fatigue, anorexia, anemia, nausea, and facial puffiness. The grade 3 toxicities from imatinib in our nine DFSP patients included fatigue in 1 (11%), anorexia in 1 (11%), and anemia in 1 (11%) patient. One patient who received imatinib 800 mg daily with palliative intent required imatinib to be withheld for 2 months for grade 3 toxicities. Imatinib was restarted at a lower dose of 300 mg daily on which the patient had progression and imatinib was stopped, and the patient was started on pazopanib. This patient developed grade 3 anemia and grade 2 fatigue at the lower dose of imatinib.
Follow-up details were available for eight patients, while one patient was lost to follow-up. The median duration of follow-up was 84 months (range, 2–148 months). [Figure 1] highlights the representative histological features of our patient cohort. The median RFS was 82 months (IQR, 74–83 months). The median PFS on imatinib was 79 months (IQR, 14–79 months). The median time to progression on palliative imatinib treatment was 10 months (IQR, 10–14 months). All patients were alive until the last follow-up; OS ranged between 15 months and 258 months. OS at 10 years was 89% (8/9). Due to the small number of patients, it was not possible to evaluate for differences in the outcomes based on the presence of various prognostic features.
|Figure 1: Spectrum of histological and immunohistochemical findings of our dermatofibrosarcoma cases. (a) (×200), classical storiform pattern of dermatofibrosarcoma with monotonous appearing oval to spindle cells. CD34 is diffusely positive (c). Sarcomatous transformation in the form of patternless sheets of malignant spindle cells with brisk mitoses (b). CD34 shows patchy positivity indicating partial loss of CD34 in areas of fibrosarcomatous transformation (d)|
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| Discussion|| |
We present the data of a series of nine patients with DFSP of the head and neck region who were treated with imatinib. The median age was 40 years (range, 22–47 years) with almost equal male to female distribution (M:F = 5:4). The site of primary tumor was scalp in seven patients, face and neck in one patient each. 66.7% patients had localized disease; 33.3% had metastatic disease. Sites of metastases included lung, lymph node, soft tissue, and brain. Fibrosarcomatous variant was present in 44.4% of patients. Patients received imatinib in neoadjuvant setting (three patients; two for borderline resectable disease and one for possible oligometastatic disease), in the adjuvant setting (three patients for recurrent disease and close margin) and metastatic setting. The response rate to imatinib in the neoadjuvant and palliative setting was 66.7% and 33.3%, respectively. In the neoadjuvant setting, all patients could undergo resection with negative margins and none recurred till the last follow-up. In the metastatic setting, the median PFS was 10 months; all patients were alive at last follow-up.
In our series, the median age of presentation was 40 years with almost equal male to female distribution and patients typically presented with insidious onset painless mass. This is consistent with DFSP at head and neck and other sites, where the typical age of presentation is in the thirties with similar frequencies in male and female., Most of the tumors are indolent and are <5 cm at presentation; however, in our series, almost half of the patients had tumor size >5 cm., Scalp has been reported as the most common location of head and neck DFSP, which was observed in our series too. The reported incidence of the fibrosarcomatous variant is 16%, which is associated with an adverse prognosis and higher rate of metastasis. In our series, almost half of the patients demonstrated fibrosarcomatous variant. There is 1%–5% incidence of metastases in DFSP with lung being the most frequent metastatic site., In our series, one-third of patients presented with metastatic disease; this could be due to greater proportion of fibrosarcomatous variant in our series or due to referral bias since we are a tertiary care center.
Surgery is the mainstay of treatment of DFSP. Depending on clinical feasibility, the National Comprehensive Cancer Network and the European interdisciplinary group recommend a surgical margin of 2–4 cm. However, such wide margins are difficult to achieve with good functional and cosmetic outcomes, especially in head and neck DFSP. Eight of nine patients underwent surgery for the primary site in our series. All the patients underwent wide local excision (WLE); reconstruction with flap was done in five of eight resected patients. Moh's micrographic surgery (MMS) was not performed in any of the patients. MMS involves sequential examination of the frozen section of the margins during resection until clear margins are obtained. DFSP has an infiltrative pattern of growth with the tumor cells invading in the form of irregular tentacles through septa and fat lobules of subcutaneous tissue. Hence, MMS can achieve resection with clear margins while maintaining good cosmetic outcomes; this is particularly applicable in the head and neck region. A systematic review of 23 non-randomized trials that reported on the efficacy of MMS in DFSP showed a recurrence rate of 1.11% with MMS versus 6.32% with WLE. More than half of the patients in our series developed recurrence. This could be due to close resection margin (<0.5 cm) in three-fourth of resected patients, higher proportion of fibrosarcomatous variant, and MMS not being done.
More than 90% of DFSP cases demonstrate unique translocation t(17;22) (q22;q13), which places normally inhibited PDGFβ-R, gene under the activating control of the COL1A1 promoter. This results in production of platelet-derived growth factor beta polypeptide (PDGFβ) and constitutive activation of PDGFβ-R, a tyrosine kinase., Imatinib, an orally active small molecule tyrosine kinase inhibitor (TKI), inhibits PDGF receptors. Tumors lacking t(17:22) show poor clinical response; therefore, molecular testing for t(17:22) should be considered in DFSP cases. However, as >90% of DFSP cases carry this translocation, imatinib can be used to treat DFSP without performing this test, if molecular testing is not available. Molecular testing was not done in our patients. A pooled analysis of two phase II trials has shown benefit of imatinib in advanced DFSP cases in which around one-third cases were head and neck DFSP, with median time to progression of 1.7 years. There was no advantage of imatinib 800 mg over 400 mg daily dose. In our series, the median time to progression on palliative imatinib treatment was 12 months, and there was no difference in outcome with dose or duration of imatinib. Neoadjuvant imatinib has been evaluated in two phase II trials. Patients received imatinib 600 mg daily for 12 weeks in the German trial and for 2 months in the French trial. Clinical response occurred in 75% and 36% of patients in the German trial and the French trial, respectively., Neoadjuvant imatinib could be combined with MMS to achieve good cosmetic outcomes with negative surgical margins in head and neck DFSP. However, the optimal dose and duration of imatinib in the neoadjuvant setting are still not defined. In our series, all the patients who received neoadjuvant imatinib demonstrated clinical response and underwent surgery. Two patients received imatinib 600 mg daily while one received imatinib 400 mg daily for a median duration of 4 months (range, 3–12 months). At a median follow-up of 18 months (range, 17–148 months), all three patients were disease free. The role of imatinib in the adjuvant setting is still not defined. In our series, three patients who received adjuvant imatinib had resection margin <0.5 cm and had recurrent tumors. They received imatinib 400 mg daily for a median duration of 24 months (range, 6–48 months). At a median follow-up of 100 months (range, 92–124 months), two patients were disease free while one patient developed lung metastasis after 7.5 years. Thus, adjuvant imatinib may help in achieving long-term local control in patients who are at high risk of recurrence. However, impact on OS may be modest, considering the good prognosis and the option of using imatinib at the time of recurrence.,,
On progression with imatinib in locally advanced or metastatic disease, other TKIs targeting PDGF-R have been tried. Fu et al. demonstrated DCR of 73% with sunitinib after imatinib failure in locally advanced or metastatic DFSP. A multicentric phase II study of pazopanib in patients with unresectable or recurrent DFSP showed objective response rate of 30%. There is a case report of response to sorafenib in a patient with imatinib failure. Patients with DFSP do not usually respond to conventional anthracycline-based chemotherapy used for other soft tissue sarcomas. In our series, two patients progressed on imatinib, one patient received pazopanib and had disease control for 1 month till last follow-up while the other received weekly paclitaxel which resulted in control of the disease for 24 months and was then started on sorafenib after progression on chemotherapy.
RT may be used as adjuvant or palliative treatment in DFSP. A meta-analysis on the efficacy of adjuvant RT in DFSP concluded that adjuvant RT is highly recommended in large or recurrent tumors, especially when WLE with negative margins would result in a significant functional or cosmetic deficit. In our series, four patients received adjuvant RT after surgery for recurrent disease. Surgical margins in these patients was <2 cm. At a median follow-up of 112 months (range, 92–124 months), none of the four patients had local recurrence. Thus, adjuvant RT in recurrent disease and for close margins may help in achieving long-term tumor control. One patient received palliative hemostatic RT to the primary site. There was control of bleeding and decrease in size of tumor after RT.
There is a paucity of reported studies in head and neck DFSP, and as such, our study adds to the available literature. There were certain limitations to our study. It was a retrospective analysis although data were prospectively collected, the number of patients is small, and it was a single-center study; thus, statistically robust conclusions cannot be derived from the study. Molecular testing for t(17:12) was not available, and MMS was not done, which may have affected the outcome of our patients. However, considering the rarity of head and neck DFSP, our study provides insights into the treatment and outcome of these patients. Imatinib should be considered as neoadjuvant treatment in borderline resectable cases and as adjuvant treatment in recurrent cases or with close margins.
| Conclusions|| |
Head and neck DFSP is associated with a worse prognosis as compared to DFSP of other sites. Head and neck DFSP requires multimodality management with incorporation of neoadjuvant imatinib, and adjuvant RT to achieve favorable RFS with acceptable functional and cosmetic outcomes. Imatinib results in a good clinical response in the palliative setting; however, its role in the adjuvant setting still needs to be defined.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]