5. Epidemiology
¤ Retroperitoneal sarcomas (RPS) are
rare tumors
¤ Incidence - 0.5 to 1 new cases per
100.000
¤ 53–56% of patients are female
¤ Median age at diagnosis is 59–61 years
¤ Only 15% of all sarcomas are located in
the retroperitoneum
¤ Management can be challenging due to
various presentation patterns, multiple
organ involvement, and a high local and
distant recurrence
8. Diagnosis
¤ Non specific
¤ Depends on the anatomic site
involved
¤ Grows as a mass, compressive
symptoms and sense of
abdominal discomfort
¤ Most frequently diagnosed
incidentally
¤ Symptoms are abdominal pain
and discomfort, back pain, bowel
obstruction, urinary and
gynecological symptoms
9. Imaging
¤ Correct imaging modality:
¤ stage the disease
¤ establish the best therapeutic pathway
¤ evaluate the surgical resectability
Contrast enhanced computed tomography (CT)
chest and abdomen- diagnosis of retroperitoneal masses
and disease staging
¤ Unable to provide the correct histopathological subtype,
except for well-differentiated liposarcoma (WDLS) and
angiomyolipoma
10. Imaging
Magnetic resonance imaging (MRI) doubt on muscles,
bones, foramina, and neurovascular structures involvement
¤ essential to assess pelvic masses extent and evaluate the
indication for radiotherapy and its treatment volume
¤ If surgery involves the removal of a kidney, a functional
examination of the contralateral is considered
FDG PET-CT is not used routinely, as it is not able to
distinguish benign and malignant retroperitoneal tumors
¤ extremely heterogeneous tumors FDG PET/CT may be used to
help guide biopsy which can be targeted to the most FDG avid
component
15. Biopsy
Image-guided percutaneous core needle biopsy (CNB,
14–16 gauge)
¤ Always be performed unless images are pathognomonic of
WDLS or the procedure is dangerous
¤ safest retroperitoneal route is preferred, but the transperitoneal
route can be considered
¤ risk of needle tract seeding 0.37–2%
¤ safe procedure that does not impact the local recurrence and
overall survival (OS) rates
¤ 98% of specificity and 85% of positive predictive value in
identifying high-grade RPS
Surgical Biopsy - laparoscopy or laparotomy should be avoided
18. Histopathology
¤ Over 75 histologic types of soft-tissue
sarcoma can occur in the retroperitoneum
¤ Immunohistochemical staining and can be
further confirmed by molecular biology
¤ FISH or RT-PCR to detect sarcoma-specific
gene mutations
¤ Most frequent histologic types are
liposarcoma (about 56.8%), leiomyosarcoma
(LMS, 24.7%) and undifferentiated sarcoma
(8.6%)
Mdm2 +
De differentiated tumor
22. Prognostic Factors
Affecting OS
o age, gender, tumour size, number of organs resected,
invasion of adjacent structures, radicality of the surgical
resection, multifocality, histopathological subtype and grade
Affecting LR
o Gender, size of the tumour, histologic grade, completeness
of surgical resection margins, adjacent organ involvement,
specialization of the surgeon, piecemeal resection and
perioperative radiotherapy
Affecting DM
o histology grade, subtype and adjacent organ involvement
Histologic type is a
significant
independent
prognostic
factor of disease-
specific death (DSD),
local recurrence (LR)
and distant
metastases (DM)
23. Surgical Management
• Surgery remains the only curative treatment
• En-bloc resection of the tumor with the removal of all the structures involved
• Extended surgery with a free-tumor margin offers the best results in terms of LR rates
• Contraindications to surgery:
• Bilateral renal involvement,
• Superior mesenteric artery,
• Celiac tripod, and
• portal vein infiltration
• spinal cord involvement
• Careful preoperative evaluation using MRI and CT scan images - plan the margins of the resection and
anticipate the structures and organs involved in the excision
24. Surgical Management
• Histopathologic organ invasion is considered a predicting factor of OS
• Liposarcomas, especially if well-differentiated, do not generally have clear margins and the fatty
tissue is not distinguishable from the retroperitoneal fat
• In these cases, more extensive resections may be indicated
• LMS and SFT have more defined margins, and therefore if adjacent organs are not infiltrated, they
could be
spared
• Performed in dedicated high-volume centres by different surgical teams with specific expertise
• Cytoreductive surgery with HIPEC for abdominal multifocal sarcomatosis is associated with a high
toxicity rate and without conferring any survival advantage
25. Frontline Extended Surgery
• Since there are no defined anatomical compartments in the retroperitoneum, surgery for RPS will
always be a marginal resection
• Extended surgery includes the tumor and adjacent organs located at 1–2 cm from the tumor,
including
the colon anteriorly, kidney, and psoas muscle posteriorly, even if there is no macroscopic organ
invasion
• A. Gronchi and S. Bonvalot first described the concept of compartmental surgery
• Multi center study by S. Bonvalot showed that simple resection was associated with a threefold
higher rate of local recurrence than compartmental resection
• Decrease in local recurrence (LR) at 5 years of 48% vs. 28% in the extended surgery group
• Compartmental surgery can improve OS, especially in low- and intermediate-grade liposarcomas
26.
27.
28.
29. Histopathologic organ invasion (HOI)
• 25% of the resected organs without intraoperatively evidence of tumor invasion had HOI identified
pathologically
• In 2017, a study from Dana Farber/Brigham, HOI was an independent predictor of adverse
prognosis with a worse 5-year OS (34% vs. 62%, p = 0.04)
• Considered as a marker of biologic aggressiveness
• In sarcomas, HOI should not be just defined as the infiltration of visceral parenchyma, but also as
the tumor adherence to the organ
• For instance, in RP-LPS, detaching the tumor from an adherent organ will guarantee an R1
resection
• Compartmental surgery has been advocated by the masters of sarcoma surgery and recommended
by supporting guidelines
31. Radiotherapy
• Neoadjuvant radiotherapy (RT) for RPS has always been controversial and is
still under investigation
• Some of the advantages:
• tumor debulking
• increased chances of having a disease-free resection margin after
radical surgery
• eventual thickening of the tumor capsule leading to more radical surgery
• Concerns:
• damage caused to the bowel and nearby structures
• increased rate of postoperative complications
• Preoperative radiotherapy with selective augmentation on the margin at the
highest risk of local recurrence appeared to be a safe tool
• However, the survival benefit of neoadjuvant RT is still under investigation
32. Radiotherapy
• Multicentre, randomised, phase 3 trial comparing radiotherapy followed by surgery versus
surgery alone - STRASS-1 trial
• Higher rate of severe complications in the RT plus surgery group (24% versus 10%)
• No difference was noted between the groups regarding postoperative reoperation rate
(11%) and postoperative mortality rate (2%)
• No difference was noted in terms of abdominal recurrence-free survival (HR 1.01, 95% CI
0.71–1.44, p = 0.95) and OS (HR 1.16, 95% CI 0.65– 2.05, p = 0.62)
• Conclusion: Preoperative RT should not be considered as the standard of care treatment
for RPS
• Postoperative RT has been progressively abandoned due to the high morbidity rate, the
poor benefit on cancer control
34. Chemotherapy
• Advantages:
• Assess the tumour response
• Modulate the treatment
• reduce the possibility of micro-metastases
• Since soft-tissue sarcomas’ response is relatively poor (around 16–27% of metastatic patients are
responsive to doxorubicin therapy), the concern is to delay the radical surgery unnecessarily
• Prognosis is generally given by the probability of local recurrence, rather than by distant
metastases, a delay in surgery could negatively impact the prognosis
• Doxorubicin, alone or associated with ifosfamide, is the most used agent
35. Chemotherapy
• Although combined therapy does not improve the OS, improves the objective response
rate in patients with locally advanced, unresectable, or metastatic high grade soft-tissue
sarcoma (26% of patients in combined therapy versus 14% in doxorubicin alone)
• A prospective multicentre randomised trial (STRASS-2, NCT04031677) started in 2019 -
compare the outcomes of surgery with or without neoadjuvant chemotherapy in high-risk
RPS (high-grade liposarcoma and leiomyosarcoma)
• EORTC 62931 showed that chemotherapy after soft-tissue sarcoma resection does not
improve OS and DFS
36.
37. Targeted therapy
• Pazopanib, a multiple TKI that targets VEGFR and PDGFR, is approved as a second line
agent for advanced STS
• But not considered to be an appropriate neoadjuvant agent for any of the common RPS
histologies
• greatest efficacy in LMS and solitary fibrous tumors
• initial phase II study of pazopanib for STS, all but 26% of patients with adipocytic
tumors/LPS experienced tumor progression at 12 weeks
• phase III trial excluding LPS showed that pazopanib improved PFS in these patients by 3
months
• may provide an alternative for LMS, SFT, or synovial sarcoma patients who have
contraindications to doxorubicin/epirubicin
38. Immunotherapy
• Currently no established role for immunotherapy in the neoadjuvant setting
• Anti-PD-1 therapy pembrolizumab in patients with metastatic STS treated with multiple previous
lines of therapy (SARC028) - 40% objective response (OR) in UPS, a 20% OR in LPS, and no response
in LMS
• Alliance A091401 studied nivolumab alone or with ipilimumab - even lower response rates (5%
and 16%, respectively in LMS and UPS)
• Certain subtypes are consistently immunologically responsive (‘hot’)
• UPS had a higher immune fraction of M2 macrophages and greater PD-L1 expression than RMS
Active trials:
• French phase II trial (TORNADO) - effect of neoadjuvant chemotherapy and retifanlimab
• A phase II trial exploring neoadjuvant nivolumab +/- ipilimumab for resectable retroperitoneal DD-LPS
39. Multimodality Neoadjuvant Therapy
TRASTS trial : three cycles of neoadjuvant trabectidin and 45 Gy RT
• Phase I demonstrated a good safety profile and anti-tumor activity
• Phase II - 91.5% of patients completed their preoperative trabectedin, and all patients
completed RT and underwent surgery
• Dramatic improvement in residual tumor burden at the time of surgery, with over half having
less than 10% residual tumor volume
Overexpression of MDM2 protein - most commonly recognized abnormality in LPS
• PI-103, a dual phosphatidylinositol 3-kinase (PIK3) and mammalian target of rapamycin
(mTOR) inhibitor
• significant reduction in growth when combined with either cisplatin or doxorubicin
chemotherapy
40. Metastatic disease
• Primary surgery can be performed in selected cases to reduce the local disease burden or
practice
a complete local radicalisation, reduce symptoms, and facilitate any resection surgery on possible
recurrences
• Surgery on liver or lung metastases - selected patients with good performance status and a
high life
expectancy
• Favourable tumour biology, low-volume disease, DFS time greater than 12 months, and
response or prolonged stability to systemic chemotherapy
• Metachronous lung metastases (DFS ≥ 1 year) can be resected if R0 status can be achieved
• Synchronous lung metastases should be treated with chemotherapy, reserving surgery for
resectable residual lung lesions
41. Metastatic disease
• Extrapulmonary metastases can be treated with chemotherapy first followed by surgery
• Large-volume liver metastatic disease, arterial embolisation or chemoembolization can be
considered
• Incomplete resections do not have any benefit on survival
• RT could be an option for palliation of pain or symptoms of spinal compression
• Chemotherapy is usually the first approach in synchronous metastatic disease or non-resectable
disease
• Anthracycline-based chemotherapy (doxorubicin or epirubicin) is the first-line treatment
• Combined therapy with dacarbazine is preferred for LMS and SFT
• Phase 3 ANNOUNCE trial - no difference in OS with the addition of olaratumab to doxorubicin
45. Recurrent disease
• Worse prognosis
• Percutaneous core biopsy in order to confirm the actual relapse and possibly target the therapy
• In unifocal locoregional recurrence, a curative resection can be considered when complete excision
can be guaranteed
• Recurrent multifocal abdominal disease, radical excision of the disease is unlikely, and surgery
should be performed with palliative intent
• Synchronous abdominal and distant recurrences, considered for systemic therapy rather than for
surgery
• Efficacy of postoperative adjuvant therapies in fully resected recurrent disease has not been proven
46. Follow-up
• Patients at high/intermediate risk of recurrence
• CT scan of the lung and abdomen and MRI abdomen every 3–4 months for the first 2–3 years,
then every 6 months for the next 3 years and once a year afterwards
• Low risk of recurrence
• Every 4–6 months for the first 3–5 years, then once a year
• 5-year follow-up period seems insufficient as approximately 9% of local recurrences and 6% of
distant recurrences occur later
• Follow-up period should be at least 10 years or even indefinite
48. RPS is best managed by an experienced multidisciplinary team in a specialized reference center
Standard method for staging is contrast tomography (CT) scan of the chest/abdomen/ pelvis with IV
contrast
Magnetic resonance imaging (MRI) is an option for patients with IV CT contrast allergy or other
contraindication, pelvic tumors and for assessing the extent of tumor to specific sites (i.e., vertebral
foramina, sciatic notch) that is not clear on the CT scan
Functional assessment of the contralateral kidney typically is necessary when planning nephrectomy
Bone scan, head CT, brain MRI, and positron emission tomography (PET) scanning usually are NOT
required
Image-guided percutaneous coaxial core needle biopsy (14 or 16 gauge) is strongly recommended
unless the imaging is pathognomonic or and no preoperative treatment is planned
Fine-needle aspiration should be avoided
Staging and Preop assessment
49. Laparotomy and open biopsy of suspected RPS should be avoided
Laparoscopic biopsy of suspected RPS carries the same risks as open biopsy
During any other abdominal procedure an RP mass is detected, it is recommended that nothing
further be done to assess or explore the mass at that time. The patient should undergo subsequent
dedicated imaging
Complete gross resection is the cornerstone of management
surgery should be aimed at achieving macroscopically complete resection
best achieved by resecting the tumor en bloc with adherent structures even if not overtly
infiltrated
Grossly incomplete resection of RPS is of questionable benefit and potentially harmful
Liposarcoma (LPS) is the most common histologic subtype of RPS. Complete resection of all RP fatty
tissue at risk for harboring tumor is ideal
Approach should be imaging based, deliberate, and not ‘‘exploratory,’’ avoiding dissection in marginal
tumor planes
Surgical approach
50. Preoperative RT should not be considered as the standard of care treatment for RPS
Intraoperative radiation therapy (IORT, with electron beam) is of no study-proven value
Postoperative/adjuvant external beam radiation after complete gross resection is of no study-proven value
and is associated with significant short- and long-term toxicities
Brachytherapy is of no study-proven value
Postoperative/adjuvant chemotherapy after complete gross resection is of no study-proven value
Risk of recurrence after grossly complete resection of RPS does not plateau, even after 15 to 20 years.
Patients should be followed indefinitely
The median time to recurrence of high-grade RPS is less than 5 years after definitive treatment
Follow-up assessment should include clinical evaluation and cross-sectional imaging
Interval between follow-up evaluations should be 3-6 monthly initially followed by annually after 5 years
Every effort should be made to enter eligible patients into international collaborative prospective trials or
registries
Adj / Neo-adj therapies and followup
51. Case capsule
• 50yr old gentleman
• Chronic abdominal pain and
abdominal swelling x 1 yr
• 25cm x 15cm intra-abdominal mass
on imaging
• Core bx – neurofibroma
• Intra-op: two retroperitoneal mass,
one near DJ flexure, another beneath
sigmoid mesentery
• Final HPE - MPNST
Good morning respected director sir, faculty members, seniors, colleagues and juniors
The topic for discussion is ….
Before we jump into the sarcoma proper, let us have a brief idea of the anatomy
Schematic representation of the retroperitoneal perinephric compartments. ARF anteriorrenal fascia, PRF posterior renal fascia, TF transversalis fascia, APS anterior pararenal space, PPSposterior pararenal space, PS pararenal space, V vena cava, A abdominal aorta, D duodenum, ACascending colon, DC descending colon, P pancreas, PC peritoneal cavity
Diagram representation of the common subtypes of sarcoma within the retroperitoneum:DDLPS dedifferentiated liposarcoma; WDLPS well-differentiated liposarcoma, LMS leiomyosarcoma;US undifferentiated sarcoma; SFT solitary fibrous tumor, MPNST malignant peripheral nerve sheath,FS fibrosarcoma
WDLS is constituted by well-differentiated hypodense fat, whereas the angiomyolipoma presents vascular structures in the fatty tissue.
large left retroperitoneal mass, which is of predominantly fatty attenuation - well-differentiated liposarcoma
large fatty right retroperitoneal mass with areas of soft tissue density (arrow) and coarse calcification (arrowhead) - dedifferentiated liposarcoma
enhancing retroperitoneal soft tissue mass with central necrosis (arrow) – Pleomorphic liposarcoma
a An 85-yearold man who presented with abdominal pain. CT shows a large heterogeneous left sided retroperitoneal mass (arrow) withcentral low attenuation in keeping with necrosis
b) Large heterogeneous in the right abdomen, which is displacing the overlying liver
c) large mass within the IVC (arrow).
contrast-enhanced CT shows a left sided large heterogeneous retroperitoneal mass (arrow) showing enhancement with central necrotic area, which is displacing andcompressing the adjacent kidney causing mild hydronephrosis (arrowhead).
same patient shows the large mass causing distortion of the left kidney and left renal vessels
systemic therapy if high risk for metastatic disease or if downstaging is needed to facilitate resection
intensity-modulated RT (IMRT) would be preferred to optimize sparing of nearby critical structures.
Dedifferentiated liposarcoma in a 44-year-old woman.
a CECT scan of right retroperitoneal mass.
b Tumor at laparotomy.
c Surgical field after tumor removal.
d Surgical specimen.The tumor is covered by the rightkidney and colon (and psoas muscle inthe back, not shown)
* planned per sample size calculation. ** 1st sensitivity analysis conducted such that local progression on radiotherapy was not regarded as a primary endpoint event for those who had macroscopically complete resection; 2nd sensitivity analysis conducted such that neither local progression nor becoming medically unfit on radiotherapy were regarded as primary endpoint events for those who had macroscopically complete resection. 3DCRT—3D conformal radiotherapy, IMRT—intensity-modulated radiotherapy, ARFS—abdominal recurrence-free survival, DMFS—distant metastasis-free survival, ARFI—abdominal recurrence-free interval, OS—overall survival, QoL—quality of life, ITT—intention to treat, LMS—leiomyosarcoma, LPS—liposarcoma, ADM—doxorubicin, DTIC—dacarbazine, DFS—disease-free survival, LRFS—local recurrence-free survival
Retifanlimab is a humanized PD-L1 inhibitor that has orphan drug status for Merkel cell carcinoma and anal carcinoma
Olaratumab – monoclonal antibody against PDGFRA, FDA approved in 2016, removed from market in 2019
most active systemic therapy regimen in an unselected patient population is AIM (doxorubicin/ifosfamide/mesna) in terms of response rate. Judson I, et al. LancetOncol 2014;15:415-423.r Resection of resectable metastatic disease should always be considered if primary tumor can be controlled