retroperitoneal sarcoma - evaluation and management

1. Evaluation and
Management of
Retroperitoneal
Sarcoma
Dr Mohammad Masoom Parwez
M.Ch Resident
Surgical Oncology, SCI

2. Anatomy of
the retro-
peritoneum

4. Outline
Epidemiology
Clinical features
Imaging
Biopsy
Management
Recurrent disease
Metastatic disease

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

6. AJCC 8TH Edition, Ch 44 soft tissue sarcoma in retroperitoneum

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

12. Liposarcoma

13. Leiomyosarcoma

14. Solitary fibrous tumor

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

16. Staging

17. FNCLCC Grading

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

19. Histopathology

20. NCCN
Guidelines

21. NCCN
Guidelines

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

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

30. NCCN
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

33. Radiotherapy

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

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

42. NCCN
Guidelines

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

47. Summary
A Consensus approach

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

52. References

53. THANK YOU FOR
YOUR TIME