Dermatofibrosarcoma protuberans (overview) C44.-

Authors: Prof. Dr. med. Peter Altmeyer, Dr. med. Stephan Große-Büning

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Last updated on: 23.07.2021

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Synonym(s)

Bednar tumor; DFSP; Sarcoma Dermatofibrosarcoma protuberans

History
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Darier and Ferrand, 1924; Hoffmann, 1925; Bednar, 1957

Definition
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Rare, fibroblastic, intermediate, locally aggressively growing, rarely metastasizing tumor of the skin connective tissue, occurring exclusively in the skin. DFSP is the most common skin sarcoma.

Classification
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A binding classification has not yet been proposed. Therefore one can roughly distinguish 3 stages:
  • Stage I: only primary tumor present
  • Stage II: locoregional recurrences
  • Stage III: Remote metastasis.

Occurrence/Epidemiology
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Rare; the proportion of all malignant neoplasias is < 0.1%. Incidence: 0,8-5/1.000.000 inhabitants/year. Panethnically occurring. A larger population-based study in the USA showed an increased incidence in African Americans and in women (Kreicher KL et al. 2016).

Etiopathogenesis
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The aetiology is not clear in detail. Chromosomal translocation mutations ("ring chromosomes"), which result from a fusion of chromosome regions 17q22 and 22q13, have been described. These are the genloci, which also encode the alpha chain of collagen A1 (COL1A19) and the beta chain of platelet derived growth factors (see below growth factors), a functional growth factor. The now fused COL1A1-PDGFß gene is segregated as a "ring chromosome" from the other genes. As a result, under the influence of transcription factors, excessive amounts of functional growth factor PDGF-beta are produced, which drive the tumour to grow autocrine via PDGF receptor stimulation. This dysfunction is highly characteristic of DFSP (detection in >90%) and is also the key to molecularly targeted therapy with tyrosine kinase inhibitors of the imatinib type (Gleevec ).

Manifestation
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Occurrence possible at any stage of life, age peak between 20 and 50 years. Average age at diagnosis: 43 years. Men and women are affected about equally often (m:w = 1.2:1.0). The tumour rarely occurs in children (5% of cases).

Localization
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Mainly occurring on the trunk (approx. 50-60%), extremities (20-30%), head and neck (10-15%).

Clinical features
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1-10 cm in size, very coarse, usually skin-colored to brownish livid, bumpy, plate-like spread, promontory like conglomerate knot, which consists of a knotty and a plate-like part underneath. Typical is an "iceberg phenomenon" (only a part of the tumour protrudes above the skin level, only by careful palpation can the actual size below the surface be measured).

The growth takes place in two stages: First, a rough cutaneous-subcutaneously situated plate-like induration is formed (stage 1); then a "tumor stage" with the formation of very firm nodes of varying size (stage 2).

A clinical variant is rare in which the tumour appears as a circumscribed, skin-coloured or brownish, slightly sunken (scar-like) area ("atrophic dermatofibrosarcoma protuberans" [pseudo-scar]).

Imaging
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6 dermatoscopic criteria for DFSP can be identified by incident light microscopy (by experienced examiners) ( Bernard 2013):

  • delicate pigment network (90%)
  • ramified/branched vessels (80%)
  • structureless light brown areas (70%)
  • luminous, white stripes (70% only detectable with polarization)
  • pink background (70%)
  • structureless hypo- or depigmented areas (60%)

Histology
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Infiltrating, polymorphous, connective tissue tumour, which usually completely covers the dermis and also affects the subcutis in broad strands. More rarely, the muscle fascia is also affected. The tumor parenchyma consists of tightly interwoven spindle cell bundles. The fascicular or radial arrangement results in the typical cartwheel pattern. Also typical is the so-called "honeycomb pattern", i.e. the flowing around of adipose tissue globules and adipocytes by spindle cell tumor formations. Moderate cell polymorphism as well as clearly increased mitosis rate characterize the tumor cells. Characteristic is a discontinuous growth of the tumor, so that the evaluation of the lateral tumor margins (tumor freedom) is only possible in serial sections.

Immunohistology: The tumor cells are consistently CD34 positive (see CD classification below), CD99 weakly positive and S100 and SMA (smooth-muscle actin) negative. Large absence of FXIIIa (DD: deep penetrating dermatofibroma). Important CD34 loss in sarcomatous and myxoid parts; in Bednar tumor: evidence of S100 positive dendritic cells.

Electron microscopy: Strongly segmented nuclei (labyrinth nucleus).

Histological variants:

  • Atrophic (morphea-like) DFSP (delineation controversial).
  • Plaque-like DSPF
  • Granular cellular DFSP
  • Fibrosarcomatous DSFP (10-15% metastasis!) with fishbone-like (herring-bone), mitosis-rich parenchymal formations.
  • Myxoid DSFP
  • Pigmented DSFP (Bednar tumor), interspersing dendritic melanocytes.
  • Giant cell fibroblastoma (juvenile variant of DFSP; characterized by bizarre giant cells, mucin, and vascular-like clefts).
  • DSFP with myoid differentiation.

Differential diagnosis
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  • Clinical:
    • Lymphoma, cutaneous B-cell lymphoma: Can occur solitary with exophytic growth; the decisive difference is the consistency of the node, which is "woody" hard in DFSP and rather elastic and firm in CBCL. CBCL also does not show any iceberg phenomenon.
    • Dermatofibroma: hardly reaches the size of the DFSP. The so-called deep infiltrating dermatofibroma is primarily found on the trunk and extremities of younger people. At 1.0-2.0 cm in diameter, they are larger than the usual forms.
    • Other sarcomas (see below): Very rare. Not clinically differentiable.
    • Keloid: Occurring in young patient population; bright red, fast growing, painful mostly plate-like nodules with a smooth surface. Usually preceded by scarring.
    • Metastases of the skin: Mostly fast growing exophytic nodules: Rarely hard like wood.
    • Basal cell carcinoma: In rare cases, BCC, especially after insufficient pre-therapy, present as plate-like, very rough indurations of the skin. In these cases clinical DD is difficult. Histological clarification!
    • Neurofibroma: Mostly multiple within the scope of a neurofibromatosis. Size: 0.2-0.5 cm or >; skin-coloured to bluish, broad or stalked, conspicuously soft tumours, possibly with wrinkles or as a dewlap-like structure (clinically this is clearly different).
  • Histological:

Therapy
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Early generous excision in healthy tissue using microscopically controlled surgery (MKC). Safety distance with each step approx. 1 cm. Local recurrence rate of 50-80%, probably due to subclinical, finger-like spurs. Adequate, complete histological border controls are therefore essential, two or more steps may be necessary.

In the case of a one-stage excision, a sufficiently large safety margin of 2.0-3.0 cm (DDG guideline) must be maintained (47% local recurrences at safety margins < 3.0 cm vs. 7% at safety margins > 3.0 cm). For the fibrosarcomatous variant of Dermatofibrosarcoma protuberans a safety distance of 3.0-5.0 cm is required. Some authors recommend to take the fascia with you. Lymph node evacuation is usually not indicated, it only has to be considered in case of de-differentiated DFSP which have the ability to metastasize.

Radiation therapy (high-energy photon radiation) of the primary tumor manifestation with 2 Gy ED 5 times/week and 60-70 Gy GD and a sufficiently large safety distance of 3-5 cm is only carried out in patients who are not capable of surgery. The radiotherapy has a high recurrence rate!

Radiation therapy
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Radiation therapy is indicated in cases of primary inoperability, R1 or R2 resection, and in cases of multiple relapses. The target volume includes the primary tumor, postoperative scars and a safety margin of 3-5 cm. The single dose is 2 Gy and is applied 5 times/week. Total dose: 60 Gy (microscopic tumor) to 70 Gy (macroscopic tumor) with curative targeting. Palliative and depending on the localisation with corresponding surrounding risk structures, a total dose of 50 Gy should be aimed for. The safety distance is about 3-5 cm.

Internal therapy
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There is no known effective chemotherapy.

The tyrosine kinase inhibitor Imatinib (Gleevec®) is approved for the treatment of unresectable DFSP. Imatinib interrupts the growth stimulation induced by PDGF (see etiology below). Therapy with imatinib can also be used for tumor reduction in extensive, difficult to operate tumors (70% of cases respond therapeutically).

Progression/forecast
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In general, the DFSP has an excellent prognosis with a 10-year survival rate of up to 99% for lege artis surgery.

Cave: Local recurrence rate of 50-80% with insufficient surgical safety margin.

Lymph node metastases can occur, but are rare. Distant metastases are usually only seen after a long period of existence and with frequent recurrences (< 0.5% of cases).

Recurrences are also described after radiotherapy.

Aftercare
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Clinical follow-up examinations (and sonography in the scar area if necessary) in the first year at 3-monthly intervals, then at 6-monthly intervals and after 3 years at annual intervals. Tumour aftercare for a total of 5 years.

Note(s)
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If the uniform storiform cell pattern of Dermatofibrosarcoma protuberans is interrupted by sections with high cell density, nuclear polymorphism and mitosis rate, a sarcomatous degeneration (CD34 negativity) with the danger of metastasis is present.

The rare fibrosarcomatous dermatofibrosarcoma protuberans has a greater tendency to metastasis than the non-fibrosarcomatous DFSP. Hence the larger safety margin of 3.0-5.0 cm.

Literature
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  1. Ah-Weng A et al (2002) Dermatofibrosarcoma protuberans treated by micrographic surgery. Br J Cancer 87: 1386-1389
  2. Bednar B (1957) Storiform neurofibromas of the skin, pigmented and non pigmented. Cancer 10: 368-376
  3. Bernard J et al (2013) Dermoscopy of dermatofibrosarcoma protuberans: a study of 15 cases. Br J Dermatol 169:85-90.
  4. Breuninger H et al (2004) Dermatofibrosarcoma protuberans - an update. J Dtsch Dermatol Ges 2: 661-667
  5. Cribier B et al (2001) Stromelysin 3 expression: a useful marker for the differential diagnosis dermatofibroma versus dermatofibrosarcoma protuberans. J Am Acad Dermatol 46: 408-413
  6. D'Andrea F et al (2001) Dermatofibrosarcoma protuberans: experience with 14 cases. J Eur Acad Dermatol Venereol 15: 427-429
  7. Darier F, Ferrand M (1924) Dermato-fibromes progressifs et récidivantes ou fibro-sarcomes de la peau Annales de dermatologie et de syphilographie (Paris) 5: 45-62
  8. Güngör S et al (2014) Atrophic dermatofibrosarcoma portuberans. Are there specific recognition features in dermoscopy? JDDG 12: 425-428
  9. Hoffmann E (1925) On the tuberous fibrosarcoma of the skin (dermatofibrosarcoma protuberans). Dermatol Z 43: 1-28
  10. Hill H (2006) Fibrohistiocytic skin tumors. J Dtsch Dermatol Ges 4: 544-555
  11. Kilian KJ et al (2013) Recurrence of a fibrosarcomatous dermatofibrosarcoma protuberans. Dermatologist 64: 512-515
  12. Kreicher KL et al (2016) Incidence and Survival of Primary Dermatofibrosarcoma Protuberans in the UnitedStates
    . Dermatol Surgery 42 Suppl 1:S24-31.
  13. Monnier D et al (2006) Dermatofibrosarcoma protuberans: a population-based registry descriptive study of 66 consecutive cases diagnosed between 1982 and 2002 J Eur Acad Dermatol Venereol 20: 1237-1242
  14. Oliveira-Soares R et al (2002) Dermatofibrosarcoma protuberans: a clinicopathological study of 20 cases. J Eur Acad Dermatol Venereol 16: 441-446
  15. Saeki H et al (2003) Dermatofibrosarcoma protuberans with COL1A1 (exon 18) -PDGFB (exon 2) fusion transcript. Br J Dermatol 148: 1028-1031
  16. Ugurel S et al (2008) Short guideline dermatofibrosarcoma protuberans. JDDG 6 (Suppl1) S19-S20
  17. Vogt T et al (2012) Malignant connective tissue tumor sarcomas. Act Dermatol 38: 248-264
  18. Weinstein JM et al (2003) Congenital dermatofibrosarcoma protuberans: variability in presentation. Arch Dermatol 139: 207-211
  19. Young CR 3rd, Albertini MJ (2003) Atrophic dermatofibrosarcoma protuberans: case report, review, and proposed molecular mechanisms. J Am Acad Dermatol 49: 761-764
  20. Zeng Yue-Ping et al (2016) A subclavicular dark red spot with spontaneous hemorrhage in a 24-year-old woman. JDDG 14:315-317

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Last updated on: 23.07.2021