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Dermatofibrosarcoma Protuberans

DFSP

Dermatofibrosarcoma protuberans is a very rare slow-growing soft-tissue tumor arising from the dermis and subcutaneous tissue, most commonly in the trunk and the extremities. PDGF and collagen chain mutations are the underlying cause of tumor development. Clinical inspection and imaging studies are used in the diagnostic workup. Wide-resection surgery, radiotherapy and imatinib, a PDGF receptor antagonist, are used in therapy.

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Presentation

DFSP most commonly appears on the trunk, in approximately 40%-50% of cases, whereas the proximal extremities (more commonly in the arms) are the site of occurrence in 30-40% of patients [1]. Other less common areas include the scalp and the supraclavicular area, but in theory, this tumor may appear at any site of the body. In very rare cases, the breast area was also identified as a potential site [4]. The course of the disease is rather slow and initial appearance include a discrete, asymptomatic plaque of various colors is observed [1] [4]. Over time, the plaque grows into multiple nodules that aggressively proliferate and extend into deeper tissues [1].

Soft Tissue Mass
  • The typical appearance is that of an unmineralised, nodular soft-tissue mass involving the skin and subcutaneous adipose tissue. Ultrasound Ultrasound may show a round (67%) or ovoid lesion in the subcutaneous region.[radiopaedia.org]
  • These computed tomographic scans reveal a well-defined soft tissue mass along the superomedial aspect of the right orbit (arrows in A and B ).[jmedicalcasereports.com]
  • X-ray of the pelvis revealed a large soft tissue mass without any foci of calcification and the bones were normal. Staphylococcus aureus was cultured from the discharging ulcers.[ijdvl.com]
  • The CT appearance of DFSP is well defined, unmineralized, nodular soft tissue mass involving the skin and subcutaneous adipose tissue.[ijri.org]
Pseudotumor
  • Navarro, Pediatric Soft-Tissue Tumors and Pseudotumors: MR Imaging Features with Pathologic Correlation, RadioGraphics, 29, 4, (e36), (2009). M.-D. Vignon-Pennamen, O. Verola and C.[doi.org]
Developmental Delay
  • A 60-year-old African-American male patient with a history of seizures, developmental delay, long history of behavioural issues with psychotic episodes, heart, liver, thyroid and kidney diseases presented for evaluation of a right neck skin lesion.[ncbi.nlm.nih.gov]
Dry Cough
Ulcer
  • In contrast to DF, the epidermis overlying DFSP is usually attenuated or ulcerated. Here, we report a case of DFSP exhibiting follicular induction of the overlying epidermis.[ncbi.nlm.nih.gov]
  • Figure 1: Ulcerated mass in the left thigh (Annotated). Figure 2: Fumigating, and ulcerated mass in the left thigh (Non-annotated). Figure 3: Magnetic resonance imaging (Annotated). Figure 4: Magnetic resonance imaging (Non-annotated).[gavinpublishers.com]
  • Staphylococcus aureus was cultured from the discharging ulcers. After controlling the secondary infection with oral antibacterial therapy, biopsy was performed.[ijdvl.com]
Subcutaneous Nodule
  • The most common clinical presentation is a firm plaque with surrounding red to blue discoloration, or less often with multiple small subcutaneous nodules.[ncbi.nlm.nih.gov]
  • Regular follow-up is important to monitor for recurrence. 0008069 Subcutaneous nodule Firm lump under the skin Growth of abnormal tissue under the skin Trauma at the affected site has been reported in approximately 10-20% of patients. [3] Recent advances[rarediseases.info.nih.gov]
  • Two large subcutaneous nodules of size 7-8 cm diameter were present in the left hypochondrium and left infrascapular region. A few of these lesions were ulcerated [Figure 3].[cancerjournal.net]
  • This rare tumor usually presents during early or middle adult life as erythematous indurated firm subcutaneous nodules.[tjmrjournal.org]
  • Discussion DFSP typically presents as a slow-growing, painless, and firm subcutaneous nodule. 11 The lesions can be multiple and may coalesce to form an indurated plaque ( Fig 3 ), which on clinical examination is often violaceous. 12, 13 The growth rate[ajnr.org]
Skin Plaque
  • Occasionally, the tumor begins as a flat or depressed patch of skin (plaque). Tumors are most commonly found on the torso and can also be found on the arms, legs, head, or neck.[ghr.nlm.nih.gov]
  • D ermatofibrosarcoma protuberans usually presents as a painless thickened area of skin ( plaque ) and/or nodule that feels rubbery or firm to touch and is fixed to the underlying skin. It may be red-brown or skin coloured.[dermnetnz.org]
  • A 42-year-old woman presented with a skin plaque located on her left chest for unknown duration. A 4-mm punch biopsy was performed and sent to our institution for consultation.[journals.lww.com]
Papule
  • It usually starts in a small papule or small patch that appears anywhere in the body, but frequently on the trunk. Tumors are usually smooth and even, sclerotic and yellowish in color.[healthfoxx.com]
  • Discussion The incidence of DFSP worldwide range from 0.8 to 5 cases/million population/year. [2] Clinically, it presents as asymptomatic papule or plaque that develops into lumpy nodule that is usually ignored.[cancerjournal.net]
Apraxia
  • Timmann, “Pseudodominant inheritance” of ataxia with ocular apraxia type 2 (AOA2), Journal of Neurology, 10.1007/s00415-008-0707-z, 255, 4, (495-501), (2008). Panta Rouhani, Christopher D. M. Fletcher, Susan S. Devesa and Jorge R.[doi.org]
Ataxia
  • Timmann, “Pseudodominant inheritance” of ataxia with ocular apraxia type 2 (AOA2), Journal of Neurology, 10.1007/s00415-008-0707-z, 255, 4, (495-501), (2008). Panta Rouhani, Christopher D. M. Fletcher, Susan S. Devesa and Jorge R.[doi.org]

Workup

Because the initial diagnosis can be made based on clinical findings, a detailed physical examination coupled with a proper patient history are most important steps in workup . MRI may be useful in assessing tumor extension, as it is able to discern the tumor from subcutaneous fat and other tissues, whereas CT is not recommended except in the case of suspected skeletal spread [1]. The role of CT in determining the size, location and depth of the tumor, however, has been established in recent studies, which determined that a solitary, superficial and subcutaneous solid mass is the most frequent finding [9]. In large tumors with high clinical suspicion of metastatic disease, the lungs are one of the most common sites of spread and plain radiography may be performed [4]. Biopsy, either needle aspiration or incision, however, is the most important diagnostic procedure [6]. Because various lesions may be included in the differential diagnosis, such as dermatofibroma (DF), benign fibrous histiocytoma and several other tumors, immunohistochemical staining is particularly useful in making a clear distinction. CD34 is positive in DFSP and negative in DF, while Stromelysin-3 (ST3), a matrix metalloproteinase (MMP) is strongly positive in DF and negative in DFSP [4]. Negative factor XIIIa is also a valid immunohistochemical staining feature, but because fibrous histiocytomas may also present with this result, the use of CD163 and apolipoprotein D, a glycoprotein component of high-density lipoprotein (HDL) that is highly expressed in DFSP, have been proposed in further workup to confirm the diagnosis [2] [10].

Treatment

Surgery is the mainstay of therapy in patients with DFSP. Mohs micrographic surgery, a procedure in which layer-by-layer resection and immediate histologic examination is performed, is considered as a favorable option in order to maximize efficacy. Wide-margin excision, if possible, is also recommended and the wider margin of excision, the lower chance of recurrence (a 3 cm margin carries a 20% chance whereas 40% of cases in whom a 2-cm margin is made develop relapses) [1] [12] [13]. However, excision of large areas of healthy tissue and unidentified subcutaneous extension of the tumor are significant risks associated with high morbidity [1]. Radiation therapy is considered as an alternative strategy, but its primary indication is in the form of adjuvant therapy after surgery [6]. Because surgery can be often mutilating and because it is not possible to resect larger or metastatic tumors, a PDFGB receptor antagonist, imatinib, has been developed [11]. In doses of 800 mg/day, up to 65% of patients exhibited tumor shrinkage, but a small subset of patients in whom classical gene translocation is not observed, imatinib has no effect on tumor tissue [4]. For these reasons, is is necessary to confirm PDFGB activity through cytogenetic studies before attempting treatment with imatinib, but its efficacy and safety surely indicates its potentially superior effects compared to surgery [7].

Prognosis

Although years and possibly decades are necessary for DFSP to produce severe and life-threatening forms of the disease, the tumor possesses high capacity for local tissue destruction [1]. The prognosis of patients with DFSP depends on two factors - promptness of the diagnosis and success of therapy. However, tumor recurrence has been observed in 17-30% of patients despite optimal surgical treatment [4]. Recurrence rates rise when tumor excision is not performed accordingly. Although metastatic DFSP is diagnosed in less than 5% of all patients, the vast majority of cases occur in the setting of recurrence and a survival rate of less than 2 years is established in such circumstances [1]. These findings point to the importance of an early diagnosis that can enable optimal therapy.

Etiology

In more than 90% of identified tumors, genetic translocation involving chromosomes 17 and 22 is identified as the underlying cause [5]. Specifically, fusion of PDGFB and COL1A1 genes triggers increased PDGFB production through up-regulation of its functional ligand through autocrine and paracrine signaling [1]., which is directly responsible for DFSP differentiation and growth [4]. In a small subset of patients, however, the classical translocation is not seen and the presumed cause remains to be elucidated. Additionally, the underlying trigger that causes these mutations remains unknown.

Epidemiology

DFSP is quite rarely encountered in clinical practice, as it is responsible for approximately 1% of all soft tissue sarcomas and less than 0.1% of all malignant diseases [4]. In the United States, the estimated incidence rates are between 0.8-5 per 1 million individual per year [1]. In France, a 3 per 1 million annual incidence rate was established, while similar results were obtained in Sweden [2] [6]. This tumor is equally distributed between genders and is most frequently noted between the second and fifth decade of life [4]. For unknown reasons, DFSP is more commonly seen in African Americans than in Caucasians, but in general, this tumor is diagnosed in all races [1]. In terms of risk factors, previous trauma on the site of tumor development has been proposed, as it was documented in approximately 10-20% of patients [1].

Sex distribution
Age distribution

Pathophysiology

The pathogenesis starts with fusion of the COL1A1-PDGFB genes from chromosomes 22 and 17, respectively. Transcription of this mutated gene in the extracellular tissue results in production of mitogen-activating PDGFB through activity of its tyrosine kinase receptors [7]. In fact, the overexpression of PDGF beta receptors has been well-documented [8]. Once the intracellular triggering cascade is activated, the processes of proliferation, apoptosis and further differentiation are initiated, eventually causing tumor growth.

Prevention

Although the exact genetic defects that trigger development of this tumor have been identified, prevention is currently not possible. One of the main goals regarding DFSP is long-term follow-up of treated patients, since tumor recurrence may occur years or even decades after therapy [2].

Summary

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous soft tissue tumor that possesses an intermediary malignant potential [1]. In virtually all patients, a translocation t(17;22) that consequently leads to fusion of genes that code for the B chain of the platelet derived growth factor (PDGFB) on chromosome 22 and collagen I α1 chain (COL1A1) on chromosome 17, respectively, is the underlying cause [2]. As a result, transcription of PDGFB-COL1A1 mutated gene stimulates up-regulation of PDGFB receptors, the essential constituents in tumor growth and proliferation [3]. It is estimated that DFSP develops in approximately 0.5-8 per 1 million individuals per year, making it a very rare occurrence in clinical practice [1]. Apart from prior trauma at the site of tumor development, other potential risk factors have not been proposed, whereas gender predilection has not been established [4]. In patients between 20-50 years, an initially asymptomatic plaque of pink to red-violet progressing into multiple nodules is the hallmark of clinical presentation. These nodules have significant potential for local invasion and tissue destruction. Most common sites are the trunk and the proximal extremities [2]., while the head and neck are less common regions, but the tumor may develop at any site of the body. To make the diagnosis, a high clinical suspicion after a meticulous physical examination with careful inspection of the lesion should be supported by studies such as magnetic resonance imaging (MRI) [2]. Fine-needle aspiration or incision biopsy followed by immunohistochemical staining is, however, the definite diagnostic method [2]. Treatment principles are based around surgery, either through Mohs micrographic surgery or wide-margin complete excision, but the introduction of imatinib, a PDGF receptor antagonist, has substantially changed the therapeutic approach and its role in both preoperative and isolated management has been solidified [3]. Radiation is often used as adjuvant therapy after surgery. The prognosis is fairly good with proper treatment, but despite all measures, recurrence rates reach up to 30% if the surgical margin around the tumor is less than 2 cm or if inadequate response to therapy is observed [4]. Although metastatic DFSP is seen in less than 5% of patients, it carries a very poor prognosis. For these reasons, it is imperative to obtain the diagnosis early on, which is feasible due to the slow-growing nature of the tumor.

Patient Information

Dermatofibrosarcoma protuberans (DFSP) is a rare tumor developing from the skin and subcutaneous tissues as a result of genetic mutations involving genes from chromosomes 17 and 22. For still unknown reasons, a fusion of platelet derived growth factor b (PDGFB) and collagen 1α1 chain (COL1A1) genes and subsequent production of PDGFB, which directly stimulates tumor growth, is the underlying pathophysiological mechanism seen in this tumor, which is diagnosed in approximately 0.5-8 per 1 million individuals every year, depending on the country. It is most frequently seen in patients between 20-50 years and both sexes are equally affected. Some studies have determined that a predilection toward African Americans exists compared to Caucasians, but individuals of any race may be affected. DFSP is characterized by the appearance of an indurated and initially asymptomatic skin lesion of either pink or red-violer color. As the tumor slowly progresses, the lesion transforms into multiple nodules that both extend outward and inward, causing extensive tissue destruction. In more than 50% of patients, this tumor develops on the trunk, whereas the extremities and the head and neck are other less common sites. To make the diagnosis, the physician must carefully inspect the tumor and identify its typical features, using data from the patients such as the course of the disease and presence of symptoms (since DFSP is initially asymptomatic). Magnetic resonance imaging (MRI) and computed tomography (CT scan) may be used to determine the size and scope of tissue involvement, but a definite diagnosis is made by obtaining a sample of the tumor through biopsy. To successfully treat DFSP, complete surgical excision is recommended, either through a procedure called Mohs micrographic surgery, in which the tumor is resected layer by layer followed by immediate microscopic evaluation in order to confirm that no residual tumor is left, or excision with removal of a few centimeters of healthy tissue as a margin. Radiotherapy is often performed post-operatively to eliminate the remaining tumor tissue, but recent approval of imatinib, a PDGFB receptor antagonist with good therapeutic effects, is slowly shifting the focus of therapy toward this drug. When tumors are detected early on, appropriate therapy may result in cure, but recurrence may be observed in up to 20% of patients, especially in those in whom larger tumors are not excised properly. Although DFSP gives metastases in only 5% of cases, the mean survival rate in these patients is only two years, indicating that an early diagnosis is detrimental in ensuring good patient outcomes.

References

Article

  1. Sanmartín O, Llombart B, López-Guerrero JA, et al. Dermatofibrosarcoma Protuberans. Actas Dermosifiliogr. 2007;98:77-87.
  2. Mendenhall W, Zlotecki R, Scarborough M. Dermatofibrosarcoma Protuberans. Cancer. 2004;101:2503-2508.
  3. Kerob D, Porcher R, Verola O, et al. Imatinib mesylate as a preoperative therapy in dermatofibrosarcoma: results of a multicenter phase II study on 25 patients. Clin Cancer Res. 2010;16(12):3288–3295.
  4. Dragoumis DM, Katsohi LA, Amplianitis IK, et al. Late local recurrence of dermatofibrosarcoma protuberans in the skin of female breast. World J Surg Oncol. 2010;8:48.
  5. Shimizu A, O'Brien KP, Sjoblom T, et al. The dermatofibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res. 1999;59(15):3719-3723.
  6. Miller SJ, Alam M, Andersen JS, et al. Dermatofibrosarcoma protuberans. Journal of the National Comprehensive Cancer Network. 2012; 10(3):312–318.
  7. McArthur G. Molecularly targeted treatment for dermatofibrosarcoma protuberans. Semin Oncol. 2004;31(2 Suppl 6):30-36.
  8. Gisselsson D, Hoglund M, O'Brien KP, et al. A case of dermatofibrosarcoma protuberans with a ring chromosome 5 and a rearranged chromosome 22 containing amplified COL1A1 and PDGFB sequences. Cancer Lett. 1998;133(2):129-134.
  9. Li X, Zhang W, Xiao L et-al. Computed tomographic and pathological findings of dermatofibrosarcoma protuberans. J Comput Assist Tomogr. 2012;36(4): 462-468.
  10. Monnier D, Vidal C, Martin L, et al. Dermatofibrosarcoma protuberans: a population-based cancer registry descriptive study of 66 consecutive cases diagnosed between 1982 and 2002. J Eur Acad Dermatol Venereol. 2006;20(10):1237-1242.
  11. Lisovsky M, Hoang M, Dresser K, et al. Apolipoprotein D in CD34-positive and CD34-negative cutaneous neoplasms: a useful marker in differentiating superficial acral fibromyxoma from dermatofibrosarcoma protuberans Mod Pathol. 2008;21:31-38.
  12. Fiore M, Miceli R, Mussi C, et al. Dermatofibrosarcoma protuberans treated at a single institution: a surgical disease with a high cure rate. J Clin Oncol. 2005;23:7669-75.
  13. Gloster HM, Jr., Harris KR, Roenigk RK. A comparison
    between Mohs micrographic surgery and wide surgical excision for the treatment of dermatofibrosarcoma protuberans. J Am Acad Dermatol. 1996;35:82-7.

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Last updated: 2019-07-11 20:09