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DERMATOFIBROSARCOMA OF DARIER

-
FERRAND
DERMATOFIBROSARCOMA PROTUBERANS

CHRISTIAN DUMONTIER MD, PHD
PROFESSOR OF PLASTIC SURGERY
CLINIQUE LES EAUX CLAIRES, GUADELOUPE, FWI
WWW.DIUCHIRURGIEMAIN.ORG
DEFINITION

Source: Orphanet

▸ Le dermatofibrosarcome de Darier-Ferrand (DFS) est un sarcome
infiltrant rare du tissu mou, généralement de bas grade de
malignité, prenant naissance dans le derme de la peau et
associé à une translocation chromosomique spécifique t(17 ;22).

▸ Dermatofibrosarcoma protuberans (DFSP) is a relatively
uncommon soft tissue neoplasm of intermediate- to low-grade
malignancy. Metastasis rarely occurs. DFSP is a cutaneous
malignancy that arises from the dermis and invades deeper
tissue (eg, fat, fascia, muscle, bone). DFSP is a locally aggressive
tumor with a high recurrence rate.
Source: emedicine
HISTORICAL

▸ First description in 1890 by Taylor,

▸ Named after Jean Darier and Marcel Ferrand who describe
the lesion in 1924,

▸ Named dermatofibrosarcoma protuberans (DFSP) in 1925
by Hoffman.

▸ Classified as a fibrous histiocytoma (Stout, 1967).

Darier J, Ferrand M. Dermatofibromes progressifs et récidivants ou fibrosarcomes de la peau. Ann Dermatol Syph. 1924;
5:545 - 62.
Hoffmann E. Uber das Knollentreinbende Fibrosarkom der Haut (Dermatofibrosarcoma protuberans). Dermatol Z. 1925;
43:1.
Taylor RW. Sarcomatous Tumors ressembling in some respects Keloïd. J Cutan Genitourin Dis. 1890; 8:384 - 387
Stout, A. P. and Lattes, R. (1967) Atlas of Tumor Pathology, Second Series, Fascicle I, Tumors of the Soft Tissues. Washington,
United States Armed Forces Institute (of Pathology), 35-37.
EPIDEMIOLOGY
▸ Prevalence is estimated to be 1 / 10 000.

▸ Less than 0.1% of all malignant neoplasms and approximately 1% of
all soft tissue sarcomas. DFSP is the most common type of cutaneous
sarcoma.

▸ Incidence of DFSP has been estimated to be 0.8-5 case per million
population per year.

▸ In France, from a population-based cancer registry from 1982-2002 ,
incidence was 3 cases per million population

▸ DFSP most commonly occurs on the trunk (42-72%), followed by the
proximal extremities (16-30%). DFSP rarely occurs above the neck
(10-16%) - Case reports in fingers

▸ Usually occurs in adults aged 20-50 years (extremes newborns - 80 y)
RACE & SEX
▸ Almost equal sexual distribution or a slight male predominance (57%
vs 43%) although this varies from study to study

▸ No racial predilection seems to exist in previous reports. However,
Criscione and Weinstock found:

▸ The incidence among African Americans (6.5 cases per million
population) was almost double the incidence among American
whites (3.9 cases per million population).

▸ Annual incidence increases by 43% (3.1 to 4.4 per million per year)
only in whites.

▸ Women had higher rates of incidence than men

▸ Relative 5-year survival was 99.2% (95% confidence interval
98.3-100%).

Criscione VD, Weinstock MA. Descriptive epidemiology of dermatofibrosarcoma protuberans in the United States,
1973 to 2002. J Am Acad Dermatol. 2007 Jun;56(6):968-73.
VARIATIONS & RACE

▸ An uncommon pigmented variant
of DFSP, accounting for 1% of all
DFSP cases, is called the Bednar
tumor. 2 examples of Bednar tumor, from
emedicine

▸ Annual incidence of Bednar tumor
among blacks is 7.5 times higher
than that of white patients.

Simon MP, Pedeutour F, Sirvent N, et al. Deregulation of the platelet-derived growth factor B-chain gene via fusion with
collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997 Jan. 15(1):
95-8.
CAUSES

▸ The cause of DFSP is unknown.

▸ Chromosomal aberrations may contribute to the
pathogenesis of DFSP; however, no evidence of hereditary
or familial predisposition exists.

▸ In 10-20% of patients, trauma at the site seems to be
incriminated. Surgical and burn scars and sites of
vaccinations have been reported as sites of DFSP.
ORIGIN
▸ The cellular origin of DFSP is not clear. Evidence supports the cellular origin
being fibroblastic, histiocytic, or neuroectodermal. DFSP manifests partial
features of each. Many suggest pluripotential progenitor cells, such as
undifferentiated mesenchymal cells, may be the origin of DFSP, because they
have the capacity to differentiate into all 3 cell types.

▸ Cultured DFSP tumor cells have increased growth in response to platelet-
derived growth factor (PDGF)–beta. Cytogenetic studies reveal specific
abnormalities in DFSP tumor cells, such as reciprocal translocations of
chromosomes 17 and 22, t(17;22), and supernumerary ring chromosomes
composed of interspersed sequences from bands 17(17q22) and 22(22q12).
These rearrangements fuse the collagen type I alpha 1 (COL1A1) and the
PDGF-beta chain (PDGFB, c-sis proto-oncogene) genes. The collagen
promoter drives COL1A1 and PDGFB fusion protein production. The fusion
protein is then processed into functional PDGF-B and subsequently interacts
with the PDGF receptor on the cell surface of DFSP tumor cells. The activation
of the PDGF receptor tyrosine kinase triggers the proliferation of DFSP tumor
cells.
NATURAL HISTORY & EVOLUTION
▸ DFSP is a very slowly growing
tumor.

▸ Diagnosis is often delayed for
months to years.

▸ DFSP may start as a small
Source, emedicine
asymptomatic papule or
nonindurated patch. The tumor
may gradually enlarge into a lumpy
nodule, or it may evolve into an
atrophic and/or sclerotic plaque.
Accelerated growth, ulceration,
and hemorrhage may be observed
when DFSP grows.
CLINICAL PRESENTATION
▸ DFSP usually presents as a
large, indurated plaque several
centimeters in diameter. DFSP
is composed of firm, irregular
nodules varying in color from
flesh to reddish brown.
Telangiectasia may be
Source, Dr Abimelec, Paris
apparent on the surface or at
the periphery.

▸ Sometimes, DFSP may present
as a morphealike, atrophic,
sclerotic, violaceous plaque
without nodularity that may
ulcerate as it slowly increases
in size.
CLINICAL PRESENTATION

Source, Dr Abimelec, Paris
CLINICAL PRESENTATION

DFSP of the abdomen presenting as an atrophic
plaque with foci of modularity (source, emedicine)
Source, Demiri et al. JPRAS
CLINICAL PRESENTATION

▸ The tumor is mobile upon palpation; however,
fixation to deeper structures such as fascia,
muscle, and bone may occur in the later stage.
CLINICAL PRESENTATION

Late presentation in an albinos African lady with multiple previous surgery
IMAGING TECHNIQUES

▸ No imaging studies are used
unless metastatic disease is
suspected (Chest X-ray, CT-scan,
…), US may be helpful for
monitoring local DFSP or
regional lymph node metastasis.

▸ Dermoscopy may help to
identify suspected DFSP.

▸ MRI may be helpful for defining
the approximate tumor margins
OTHER TESTS (SOURCE E-MEDICINE)

▸ Cytogenetic testing of DFSP is not established as a standard
workup, reverse transcriptase polymerase chain reaction (RT-
PCR) and fluorescence in situ hybridization (FISH) are suggested
as screening tools for the presence of COL1A1-PDGFB fusion
gene prior to initiation of oral imatinib molecular-targeted
therapy. DFSP tumors lacking the classic t(17,22) translocation
mutation seem to respond poorly to imatinib.

▸ DFSP-FS (fibrosarcomatous variant) is a variant of DFSP that
exhibits more aggressive behavior than DFSP, with lower
recurrence-free survival and greater metastatic potential. As a
result of the similar clinical presentation, it is necessary to have
histopathological differentiation to determine prognosis.
PROCEDURES
▸ Skin biopsy is essential or biopsy under US control.
HISTOLOGIC FINDINGS
Source, emedicine

▸ Slender tumor cells with large, spindle-
shaped nuclei are embedded fairly
uniformly in the collagen stroma,
parallel to the skin surface.

▸ Mitotic figures are sparse.

▸ The more characteristic findings are
seen in the nodular type. These include
the high cellularity and irregular, short,
intersecting bands of tumor cells
forming a storiform pattern. Also typical
are cells radiating from a central hub of
fibrous tissue forming a cartwheel
pattern. The degree of cellular atypia is
higher in nodular lesions than in plaque
lesions.
HISTOLOGIC FINDINGS
Source, emedicine
▸ Occasionally, DFSP may show focal
fibrosarcomatous changes with a
characteristic herringbone pattern.
The cellular atypia is then even
more prominent with
hyperchromatic nuclei and more
mitotic figures.

Source, Demiri et al. JPRAS
HISTOLOGIC FINDINGS

▸ Immunohistochemistry studies
Source, emedicine
have shown moderate-to-strong
staining of human progenitor cell
antigen CD34 in tumor cells. In
dermatofibroma, tumor cells are
positive for factor XIIIa and are
rarely positive for CD34.
Additionally, immunostaining
using CD34 as a marker is helpful
in identifying tumor cells at the
surgical margins, particularly when
treating recurrent DFSP in which
tumor cell fascicles are often
interspersed with the scar tissue.
[
HISTOLOGIC FINDINGS

▸ In the pigmented variant of DFSP, also known as Bednar
tumor, the melanin-containing dendritic cells are scattered
between the neoplastic spindle-shaped cells.

▸ In the juvenile form (giant cell fibroblastoma), cleftlike
pseudovascular spaces are lined by multinucleated cells.
The intervening tumor may have loose hypocellular areas
and areas that resemble mature DFSP.
SURGICAL CARE

▸ Surgical excision remains the mainstay of treatment for DFSP.

▸ Mohs micrographic surgery has been increasingly accepted
as the treatment of choice, while others advocate wide local
excision. Mohs surgery requires less tissue removal and
allows complete margin assessment. However, large tumor
can be a challenge for this very time-consuming procedure.

▸ Studies have demonstrated a low recurrence rate after
surgery for DFSP if a multidisciplinary approach and careful
pathology margin assessment are used.

DuBay D, Cimmino V, Lowe L, Johnson TM, Sondak VK. Low recurrence rate after surgery for dermatofibrosarcoma
protuberans: a multidisciplinary approach from a single institution. Cancer. 2004 Mar 1. 100(5):1008-16.
Farma JM, Ammori JB, Zager JS, et al. Dermatofibrosarcoma protuberans: how wide should we resect?. Ann Surg Oncol.
2010 Aug. 17(8):2112-8
SURGICAL CARE

▸ DFSP is characterized by its aggressive local invasion. The tumor invades local
tissue by extending tentaclelike projections underneath healthy skin,
rendering complete removal of the tumor very difficult. this accounts in part
for the high recurrence rate after standard surgical excision.

▸ Excision of 2-3 cm or more of the margins beyond clinically identifiable tumor
border, down to and including the fascia, is recommended

▸ Despite wide local excisions, an average recurrence rate of 15.7% is still
observed among 1201 body cases and 51.8% is observed among 193 head
and neck cases, as reported in the literature since 1951.

▸ A superior cure rate (an overall average recurrence rate of 1.3% among 463
cases reported) and tissue conservation are seen when Mohs micrographic
surgery is used; thus, Mohs micrographic surgery is now considered the
treatment of choice, particularly when a lesion is located in the head and neck
region.
Clinical practice guidelines in Oncology: DFSP v. 1.2012
Reconstruction using Integra®
SURGERY AND ADJUVANT TREATMENTS

▸ In his series of 244 patients with DFSP, tumor depth was
the only factor associated with disease-free survival in the
primary setting, underscoring the importance to excise the
deep fascia to remove any infltrating tumor cells (Fields).

▸ So confirmation of negative margins should precede any
reconstruction that requires extensive undermining or
tissue movement. If concern exists that the surgical
margins are not completely clear, tissue rearrangement
should be avoided and split- thickness skin grafting
considered to monitor for recurrence.
JNCCN–Journal of the National Comprehensive Cancer Network, March 2012; 10(3)

Fields RC, Hameed M, Qin LX, et al. Dermatofbrosarcoma protuberans (DFSP): predictors of recurrence and the use of
systemic therapy. Ann Surg Oncol 2011;18:328–336.
MEDICAL CARE: CHEMOTHERAPY

▸ DFSP is characterized by a translocation between chromosomes 17 and 22
(t(17:22)) resulting in the overexpression of platelet-derived growth factor
receptor (PDGFR) β. These findings suggest that targeting PDGFRs may lead
to the development of new therapeutic options for DFSP.

▸ Imatinib mesylate (Gleevec®, Glivec®), a protein tyrosine kinase inhibitor, has
shown clinical activity against localized and metastatic DFSP tumors
containing t(17:22). The recommended oral dose is 800 mg/d. A response
rate of approximately 65% has been achieved among DFSP patients treated
with imatinib

▸ Because tumors lacking the t(17;22) translocation may not respond to
imatinib molecular, analysis with cytogenetics may be useful before initiating
imatinib therapy. Chromosome translocation t(17,22) is detected in more than
90% of DFSP tumors.

▸ Imatinib mesylate has been approved by the FDA (19/10/2006) for the
treatment of unresectable, recurrent, and/or metastatic DFSP in adult patients.
MEDICAL CARE: RADIOTHERAPY

▸ Radiation has occasionally been used as a primary
therapeutic modality for DFSP, but it is more commonly
used as adjuvant therapy after surgery. Postoperative
radiation therapy or imatinib mesylate should be
considered for positive surgical margins if further resection
is not feasible (unresectable disease). If a negative margin
is achieved, no adjuvant treatment is necessary.

▸ The complete radiation therapy dose ranges from 50-70
Gy. Overall, the risk of severe complications from RT is low.
Close follow-up care after radiation therapy is warranted
because some DFSP tumors may become more
aggressive.
OTHER TREATMENT MODALITIES

▸ Some clinical trials are on the way (www.clinicaltrials.org)

▸ In France, Pr Celeste LEBBE (Hôpital St Louis, Paris) is
conducting a phase II study on Pazopanib
PROGNOSIS AND LONG-TERM OUTCOMES

▸ High local recurrence rate (up to 49% reported). Most recurrences occur within 3
years of the primary excision (mean 32 months)

▸ Patients should be seen every 6 months during this period and annually thereafter.

▸ The extent of surgical excision determines the prognosis for the patient.

▸ Age > 50 years is a risk factor associated with a poor clinical outcome.
OTHER PROGNOSTIC FACTORS

▸ Histologic: A high number of mitotic figures, increased cellularity,
DNA aneuploidy, TP53 gene overexpression, and the presence of
fibrosarcomatous changes within the tumor are poor prognostic
indicators.

▸ Genetic: Fibrosarcomatous variants of DFSP lacking a genetic
marker of translocation between chromosomes 17 and 22 may
not respond to imatinib. The loss of the t(17,22) cytogenetic
marker in the fibrosarcomatous progression DFSP variant may
represent progression of the malignancy.

▸ A small subset of DFSP patients presents with fibrosarcomatous
progression (< 5%-10%). This fibrosarcomatous progression DFSP
variant is more aggressive in nature, and the clinical outcome
usually is poor.
EXTENSION AND METASTASES

▸ DFSP rarely metastasizes. For the classic form of DFSP, the
risk is assumed to be only 0.5%. According to the
literature, the overall risk for the development of
metastatic disease is 5%, including 1% with regional lymph
node metastasis and 4% with distant metastasis.

▸ Regional lymph node involvement represents a sign of
poor prognosis; most patients die within 2 years. The lungs
are the most common site of distant metastasis that occurs
via hematogenous spread. Usually, metastatic disease is
preceded by multiple local recurrences.
SURVIVAL

▸ A total of 5249 cases were identified. Of these, 3.1% of patients died during an
average of 51.4 months of follow up.

▸ After adjusting for relevant factors, uninsured and/or Medicaid/Medicare
insurance, anaplastic histology, and positive postoperative margins predicted
mortality, while treatment at Integrated Network Cancer programs predicted

survival (P < .05).

▸ Higher odds of postoperative radiation therapy were directly associated with
larger tumors, anaplastic and poorly differentiated histology, and positive
postoperative margins and inversely associated with treatment at high volume
facilities, and non-head or neck tumors.

▸ Higher second surgery rates were associated with Hispanic ethnicity, while lower
rates were associated with female gender.

Trofymenko O, Bordeaux JS, Zeitouni NC. Survival in patients with primary Dermatofibrosarcoma Protuberans:
National Cancer Data Base analysis. J Am Dermatol 2017 (accepted)