Dermatofibrosarcoma protuberans (overview)C44.-

Rare, exclusively skin, fibroblastic, intermediate, locally aggressive growing, rarely metastatic tumor of the skin connective tissue. DFSP is the most common sarcoma of the skin.

• Stage I: only primary tumor present
• Stage II: locoregional recurrences
• Stage III: Remote metastasis.

Rare; accounts for < 0.1% of all malignant neoplasms. Incidence: 0.8-5/1,000,000 population/year. Panethnic incidence. A larger population-based study in the US showed an increased incidence in African Americans and in women (Kreicher KL et al 2016).

The etiology is unclear in detail. Chromosomal translocation mutations ("ring chromosomes") resulting from a fusion of chromosomal regions 17q22 and 22q13 have been described. These are the gene loci that also encode the alpha chain ofcollagen-A1 (COL1A1) and the beta chain of platelet derived growth factor (see below growth factors), a functional growth factor. The now fused COL1A1-PDGFß gene is outsourced from the other genes as a "ring chromosome". As a consequence, excessive amounts of functional growth factor PDGF-beta are produced under the influence of transcription factors, driving the tumor to grow autocrine via PDGF receptor stimulation. This dysfunction is highly characteristic for DFSP (detection in >90%) and at the same time key for molecular targeted therapy with imatinib (Gleevec) type tyrosine kinase inhibitors.

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).

1-10 cm large, very coarse, usually skin-colored to brownish-livid, bumpy, plate-like spreading, promontory-like conglomerate nodule consisting of a nodular and an underlying plate-like portion. An "iceberg phenomenon" is typical (only a portion of the tumor protrudes above the level of the skin, only with careful palpation can one gauge the actual size below the surface).

Growth occurs in two stages: first formation of a rough cutaneous-subcutaneous plate-like induration (stage 1); then transition to a "tumor stage" with formation of variously sized, very firm nodules (stage 2).

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

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%)

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.

• 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:
• Fibrosarcoma
• malignant schwannoma ( neurofibrosarcoma)
• Fibroxanthoma, atypical
• Dermatofibroma
• Dermatomyofibroma
• plaqueform neurofibroma
• undifferentiated pleomorphic sarcoma (formerly malignant fibrous histiocytoma)
• Leiomyosarcoma
• spindle-cell malignant melanoma (see below melanoma, malignant).

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!

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).

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.

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.

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