Case PresentationGordon Callender M.D.

Surgical Resident

Retroperitoneal Sarcomas

Sarcomas• Heterogeneous group of rare tumors that arise predominantly from

the embryonic mesoderm.

• Expected incidence for 2004: 8,680 in the US (.63% of all cancers)

• Expected sarcoma related deaths: 3,660 (1.15% of all cancers)

• Soft tissue sarcomas can occur anywhere in the body, however:

1. Extremity (59%)2. Trunk (19%)3. Retroperitoneum (15%)4. Head & Neck (9%)

Cormier JN et al CA Cancer J Clin 2004; 54:94-109

General Characteristics• >50 histologic subtypes: Most common...

1. Malignant fibrous histiocytoma (28%)2. Liposarcoma (15%)3. Synovial (10%)4. Malignant peripheral nerve sheath tumors (6%)5. Rhabdomyosarcoma is the most common in pediatric patients.

• Most exhibit similar clinical behavior, and staging is defined by depth, grade, and size of the tumor.

• Dominant pattern of metastasis is hematogenous. Lymph node involvement is rare (<5% of cases) except for certain histologic subtypes (epithelioid, synovial, rhabdomyosarcoma, clear-cell, angiosarcoma.)

breast, cervix, ovary, testes, or lymphatic sys-tem.5,6 However, the risk of sarcoma appearsto be commensurate with the dose of radiation.Regardless, the median latency period is ap-proximately 10 years. Other risk factors includeoccupational exposure to certain chemicals, in-cluding herbicides such as phenoxyacetic acidsand wood preservatives containing chlorophe-nols.7,8 Chronic lymphedema following axil-lary dissection is another risk factor; thesubsequent lymphangiosarcoma is known asStewart-Treves syndrome. Lymphangiosar-coma has also been seen after filarial infectionsand in the setting of congenital or heritablelymphedema, in which case the lower extrem-ities are usually the site of the tumor.9

Genetics

Specific inherited genetic alterations are asso-ciated with an increased risk of both bone and softtissue sarcomas. The oncogenes (ie, genes that caninduce malignant transformation and tend todrive cells toward proliferation) that have beenimplicated in the development of soft tissue sar-comas include MDM2, N-myc, c-erbB2, andmembers of the ras family. Amplification of thesegenes in several subtypes of soft tissue sarcomashas been shown to correlate with an adverseoutcome.10 Cytogenetic analysis of soft tissue tu-mors has also identified distinct chromosomal

translocations that code for oncoproteins associ-ated with certain histologic subtypes. The bestcharacterized gene rearrangements have beenfound in Ewing’s sarcoma (EWS–FLI-1 fusion),clear-cell sarcoma (EWS–ATF1 fusion), myxoidliposarcoma (TLS–CHOP fusion), alveolar rhab-domyosarcoma (PAX3–FHKR fusion), desmo-plastic small round-cell tumor (EWS–WT1fusion), and synovial sarcoma (SSX–SYT fu-sion).11

Tumor suppressor genes play a critical rolein cell growth inhibition and can suppress thegrowth of cancer cells. However, these genescan be inactivated by hereditary or sporadicmechanisms. Two such genes that are particu-larly relevant to soft tissue tumors are the ret-inoblastoma (Rb) gene and the p53 tumorsuppressor gene. Mutations or deletions in theRb gene can lead to the development of reti-noblastomas and sarcomas of the soft tissue andbone. In addition, although mutations in thep53 tumor suppressor gene are the most com-mon mutations in human solid tumors, theyhave also been observed in 30% to 60% of softtissue sarcomas.12,13 There is also a high inci-dence of soft tissue sarcomas in patients withgermline mutations in the tumor suppressorgene p53 (ie, the Li-Fraumeni syndrome).

INITIAL ASSESSMENT

Clinical Presentation

Soft tissue sarcomas most commonly presentas an asymptomatic mass. The size at presenta-tion usually depends on the location of thetumor. Tumors in the distal extremities areoften small when discovered, whereas tumorsin the proximal extremities and retroperito-neum can become quite large before they areapparent. Soft tissue sarcomas grow in a cen-trifugal fashion and compress surrounding nor-mal structures, but rarely does impingement onbone or neurovascular bundles produce pain,edema, and swelling. Similarly, retroperitonealsoft tissue sarcomas are almost always observedas a large asymptomatic mass. Infrequently, pa-tients may initially exhibit obstructive gastro-intestinal symptoms or neurologic symptoms

TABLE 1 Histologic Subtypes of Soft TissueSarcoma

Histologic Subtypes n %

Malignant Fibrous Histiocytoma 349 28Liposarcoma 188 15Leiomyosarcoma 148 12Unclassified Sarcoma 140 11Synovial Sarcoma 125 10Malignant Peripheral Nerve Sheath Tumor 72 6Rhabdomyosarcoma 60 5Fibrosarcoma 38 3Ewing’s Sarcoma 25 2Angiosarcoma 25 2Osteosarcoma 14 1Epithelioid Sarcoma 14 1Chondrosarcoma 13 1Clear cell Sarcoma 12 1Alveolar Soft Part Sarcoma 7 1Malignant Hemangiopericytoma 5 0.4

Modified from Coindre et al.1

CA Cancer J Clin 2004;54:94–109

Volume 54 Y Number 2 Y March/April 2004 95

General Characteristics• Risk factors:

1. External beam RT• 8x-50x increase chance of developing sarcomas in pt. treated for

breast, cervical, ovarian, or testicular cancer (latency of 10 years).

2. Exposure to herbicides (phenoxyacetic acid) and wood preservatives (with chlorophenols).

3. Chronic lymphedema following ALND: may develop lymphangiosarcoma of the involved extremity (Stewart-Treves syndrome).

Histology of Retroperitoneal Sarcomas

• Most frequently encountered are liposarcoma (~20%) and leiomyosarcoma (~20%) followed by fibrosarcoma, schwannoma, and malignant fibrous histiocytoma in adults.

• Tumor grading:

• atypia

• number of mitotic figures

• presence of necrosis

Extrarenal Rhabdoid Tumor

• Described in 1978.

• Initially found after a review of Wilms tumors.1

• A rare, highly aggressive malignancy seen almost exclusively in infancy or early childhood.2

1. Beckwith JB et al. Histopathology and prognosis of Wilms’ tumor from the first National Wilms’ Tumor Study. Cancer 1978; 41:1937-1948.2. Lowe L et al. Radiographics 2000; 20: 1585-1603

• Two general types of malignant rhabdoid tumor:1

• intrinsic renal disease.

• extrarenal disease:

• most common: CNS

• other locations: retroperitoneum, paravertebral, esophagus, liver, musculoskeletal, bladder, heart, lungs, orbit, breast, placenta.2,3

• One case report involved the mesentery.4

• Considered a very rare tumor with extremely poor prognosis. 18-month survival rate of ~20%. 5

1. Sajedi M. et al. J Ped Hem Onc. May 2002;24(4) 316-20.2. Chang et al. Journal of Urology. 171(2):820-821, Feb 2004.3. Ng W et al. J Clin Pathol 2003;56:713-714.4. Ohgaki M, et al. Surg Today. 2003; 33(7):556-9.5. Chung C et al. AJR 1995;164: 697-700.

1596 Novem ber- D ecem ber 2000 RG ! Volum e 20 • Num ber 6

14. 15.

Figures 14, 15. (14) Rhabdoid tumor. Photograph of a gross specimen shows a round, lobulated mass with a non-

specific appearance. A small amount of normal kidney (K) is noted at the edge of the specimen. (Reprinted, with

permission, from reference 7.) (15) Rhabdoid tumor in an 8-month-old boy with hematuria. CT scan shows a left

renal mass with heterogeneous enhancement (arrow). (Courtesy of T im Booth, MD, Children’s Medical Center,

Dallas, T ex.)

Imaging demonstrates a large, centrally lo-

cated, heterogeneous soft-tissue mass involving

the renal hilum with indistinct margins (Fig 15).

Although the appearance may closely resemble

that of Wilms tumor, several features can suggest

the diagnosis: subcapsular fluid collections, tu-

mor lobules separated by dark areas of necrosis

or hemorrhage, and linear calcifications outlining

tumor lobules. Vascular and local invasion is

common (10,15,16).

Rhabdoid tumor has the worst prognosis of all

renal tumors. It is highly aggressive and metasta-

sizes early, with most patients presenting with ad-

vanced disease. Eighty percent develop metasta-

ses, most commonly to the lungs and less often

to the liver, abdomen, brain, lymph nodes, or

skeleton. Survival is poor, with an 18-month sur-

vival rate of only 20% (3,16).

Angiom yolipom a

Angiomyolipoma is an uncommon tumor that

consists of a disordered arrangement of vascular,

smooth muscle, and fatty elements. Its histologic

composition suggests a hamartoma, but it is cur-

rently believed to represent a benign neoplasm

(17,18). T hese tumors most often occur sporadi-

cally. H owever, they may occur in 40%–80% of

patients with tuberous sclerosis (19). Angiomyo-

lipoma is also associated with neurofibromatosis

and von H ippel–Lindau syndrome. T he mean

age at presentation is 41 years, with a 4:1 female

predominance. In children, angiomyolipomas are

rare in the absence of tuberous sclerosis. Eighty

percent of children with tuberous sclerosis may

be expected to develop lesions by the age of 10

years (17). Angiomyolipomas are more often bi-

lateral, multifocal, and larger than in patients

with tuberous sclerosis.

Symptoms are related to intratumoral bleeding

from aneurysms that develop due to the abun-

dant abnormal, elastin-poor vascularity of the tu-

mor. Lesions smaller than 4 cm in diameter are

typically asymptomatic; those larger than 4 cm in

diameter are more likely to spontaneously hemor-

rhage, leading to flank or abdominal pain, hema-

turia, or even severe life-threatening hemorrhage

(10,18). Severe retroperitoneal hemorrhage has

been termed W underlich syndrome (20).

T he imaging appearance of angiomyolipoma

varies considerably based on the amount and

type of histologic elements present. CT scans

and MR images are diagnostic when fat is found

within the mass (Fig 16). US demonstrates

highly echogenic nonshadowing foci, which cor-

relate with the fatty elements. Angiography can

demonstrate the characteristic dilated tortuous

vessels with aneurysm formation, although some

• Typically occur in infancy, but median patient age ranges from 3 weeks to 50 years of life.

• Death occurs on average 6 months after diagnosis, although a handful of case reports of patients living for years after diagnosis. One was of a patient with bladder involvement s/p partial cystectomy and chemotherapy who lived for 9 years.

• 5 year survival rates are not available.

1. Parham D et al. Am J Surg Pathol 1994; 18:1010-1029.2. Chang J et al. J Urol 2004; 171(2):820-821

Pathological/Immunohistochemistry Features

of Rhabdoid Tumors• Histologically characterized by sheets of large polygonal

cells with prominent nucleoli & cytoplasmic inclusions of hyaline material. They lack myogenous characteristics unlike rhabdomyosarcomas.

• Positive for cytokeratin, +/- epithelial membrane antigen (EMA), vimentin, and CAM5.2. 1,2

• Similarity has been found between rhabdoid tumor and epithelioid sarcomas histologically.3

1. Zhou Y et al. Arch Pathol Lab Med. Sept 1999. 123. 853-4.2. Ohgaki M, et al. Surg Today. 2003; 33(7):556-9.3. Guillou L Am J Surg Pathol. 1997;21:130-146.

Genetics of Rhabdoid Tumors

• Genetically appears to be a chromosomal translocation of 11 and 22 (t(11;22)(p15.5;q11.23).

• This abnormality is located in close proximity to genes involved in Beckwith-Wiedermann syndrome, rhabdomyosarcoma and Wilms’ tumor.

Newsham I et al. Genomics. 1994 Feb;19(3):433-40

Clinical Presentation of Retroperitoneal Sarcomas

• Often present with mild non-specific symptoms, or lack there of due to their location, unless they become large and cause obstruction.

• Most frequent symptoms are abdominal pain, discomfort, or a non-tender palpable mass. Neurological signs, or ascites are less often seen.

• Local invasion of retroperitoneal structures have been described in the literature.

• Some patients may have moderate fever, mild leukocytosis: secondary to central necrosis of large tumors.

Herman K, Surg Onc 7(1999): 77-81.

Diagnosis• History & Physical

• CBC, Electrolytes, LDH?

• Radiology:

• CT Scan: may differentiate between lymphoma, or GU tumors.

• MRI: can be useful in identifying invasion of nearby organs or major vascular structures including the aorta, IVC.

• FNA biopsy or open biopsy for tissue diagnosis

Treatment• Patients with resectable disease should undergo laparotomy.

• Goal of a curative operation is a complete resection of tumor with adjacent or infiltrated organs and structures. En bloc resections with contiguous organs is seen in up to 83%.1

• Most advocate attaining control of large vessels prior to excising the mass.

• Overall resectability rates have appeared to improve during the 1990s (50-95%) compared to historical rates of 38-74%.

• A case report has described a laparoscopic resection of a primary RS tumor. 2

1. Jaques D et al, Ann Surg 1990;212:51-92. Horiguchi A et al. J Urol 1998;159:1296-7.

Survival DataTable 2Survival data from combined series, collected by Storm [8]

Group ofpatients

Number ofpatients

5-yearsurvival rate

10-yearsurvival rate

All 410 34% 18%Complete

resection240 54% 45%

Incompleteresection

228 17% 8%

Partial resection 59 26% 12%Biopsy only 54 9% 0%GI 49 74% 42%GII,GIII 80 24% 11%

Table 3Tumour grading and survival in retroperitoneal sarcoma studies

Author/year Number ofpatients

5-year survivalGrade I

5-year survivalGrade II, III

Zorig [6] 1992 51 69% 16%Singer [22] 1995 83 92% 46%Karakousis [10]

199687 88% 48%

Herman [19]1998

70 62% (GI,II) 30% (GIII)

information on the microscopical margin of resectedspecimens in some data. The issue of radicallity of sur-gery in RS is a very complicated one. Terms such as totalresection, radical excision, complete surgery, whole extir-pation do not mean the same in di!erent centres, becauseof the di$culty assessing all histological margins andstating whether the complete tumour was resected withadequate margins of free tissues. Even in well-knowncancer centres [16] surgeons assess &&a complete grossresection that there was no visible tumour left at the endof the surgery'' and &&the pathologic microscopic marginswere not well characterised in a signi"cant portion ofthese tumours because of the size and location of thesetumours, and therefore were not considered further''.Some authors [6] adopted the classi"cation of types ofresection (R0,R1,R2), based on the histological margin,from other cancer studies. However, this scheme may notbe readily applicable to RS tumours which are often over15 cm in diameter. Dissemination of RS is not very fre-quent and it is well documented [30] that only one thirdof patients developed distant metastases (mostly in thelung or liver), local recurrence being the usual cause offailure. Until systemic treatment provides more bene"tfor such patients, resections of distant metastases seemsto be the best manner of prolonging survival. Some dataindicate disease-free survival of at least 3-years, followingsecondary excision of tumours from scapula and adrenalgland [31].

The overall and disease-free survival rates mostly de-pend on tumour grading. High-grade or intermediate-grades were associated with a 3-fold [19] to 6-fold [22]independent increase of risk of death compared withlow-grade histology (Table 3). The completeness of theexcision, type of histology and other factors seem to playan additional role, however some authors showed thatmacroscopic, non-radical surgery and positive marginwere of signi"cant and independent value [22].

Sometimes is di$cult to understand why in di!erentcentres with high resectability rate (more than 80%)5 years prognosis after resection is more (63%) [10] orless (36%) [16] favourable. Moreover, a few authors did

not con"rm survival bene"t in patients after total resec-tion, compared with patients after subtotal resection[19, 31]. Data from our institution showed DNA ploidyand grading to be the only two independent prognosticvariables which in#uenced the prognosis [19]. Amongother assessed factors, only Zorig [6] found the presenceof lymph node metastases of independent prognosticvalue.

8. Conclusion

Surgery remains the main modality in the therapy ofRS. While cases of laparoscopic resection of these tu-mours have already been reported [32], and even port-site recurrence after such a procedure [33], traditional,open surgical techniques are the best way to treat pa-tients. There are still some unresolved problems in RSsuch as the actual value of di!erent prognostic factors,histopathological assessment and the role of non-surgicaltreatment. Following other authors [8], we would like tostress that because of the rarity of RS only the arrange-ment of an international retroperitoneal sarcoma registryand co-operative intergroup studies can be helpful inevaluating the treatment and application of innovativemultimodal therapies to these neoplasms.

References

[1] Mettlin C, Priore R, Rao U. Results of the national soft-tissue sarcomas registry. Journal of Surgical Oncology 1982;19:224}227.

[2] Arlen M, Marcove RC. Retroperitoneal sarcomas. In: Arlen M,Marcove RC, editors. Surgical management of soft tissue sarcomas.Philadelphia, WB Saunders, 1987:220.

[3] Braash JW, Mon AB. Primary retroperitoneal tumors. SurgicalClinics of North America 1967;47:663}78.

[4] Dalton RR, Donohue JH, Mucha PJr, van Heerdan JA, ReimanHM, Chen S. Management of retroperitoneal sarcomas. Surgery1989;106:725}33.

[5] Storm FK, Eilber FR, Mirra J. Retroperitoneal sarcomas: a re-appraisal of treatment. Journal of Surgical Oncology 1981;17:1}7.

80 K. Herman, T. Kusy / Surgical Oncology 7 (1999) 77}81

Table 2Survival data from combined series, collected by Storm [8]

Group ofpatients

Number ofpatients

5-yearsurvival rate

10-yearsurvival rate

All 410 34% 18%Complete

resection240 54% 45%

Incompleteresection

228 17% 8%

Partial resection 59 26% 12%Biopsy only 54 9% 0%GI 49 74% 42%GII,GIII 80 24% 11%

Table 3Tumour grading and survival in retroperitoneal sarcoma studies

Author/year Number ofpatients

5-year survivalGrade I

5-year survivalGrade II, III

Zorig [6] 1992 51 69% 16%Singer [22] 1995 83 92% 46%Karakousis [10]

199687 88% 48%

Herman [19]1998

70 62% (GI,II) 30% (GIII)

information on the microscopical margin of resectedspecimens in some data. The issue of radicallity of sur-gery in RS is a very complicated one. Terms such as totalresection, radical excision, complete surgery, whole extir-pation do not mean the same in di!erent centres, becauseof the di$culty assessing all histological margins andstating whether the complete tumour was resected withadequate margins of free tissues. Even in well-knowncancer centres [16] surgeons assess &&a complete grossresection that there was no visible tumour left at the endof the surgery'' and &&the pathologic microscopic marginswere not well characterised in a signi"cant portion ofthese tumours because of the size and location of thesetumours, and therefore were not considered further''.Some authors [6] adopted the classi"cation of types ofresection (R0,R1,R2), based on the histological margin,from other cancer studies. However, this scheme may notbe readily applicable to RS tumours which are often over15 cm in diameter. Dissemination of RS is not very fre-quent and it is well documented [30] that only one thirdof patients developed distant metastases (mostly in thelung or liver), local recurrence being the usual cause offailure. Until systemic treatment provides more bene"tfor such patients, resections of distant metastases seemsto be the best manner of prolonging survival. Some dataindicate disease-free survival of at least 3-years, followingsecondary excision of tumours from scapula and adrenalgland [31].

The overall and disease-free survival rates mostly de-pend on tumour grading. High-grade or intermediate-grades were associated with a 3-fold [19] to 6-fold [22]independent increase of risk of death compared withlow-grade histology (Table 3). The completeness of theexcision, type of histology and other factors seem to playan additional role, however some authors showed thatmacroscopic, non-radical surgery and positive marginwere of signi"cant and independent value [22].

Sometimes is di$cult to understand why in di!erentcentres with high resectability rate (more than 80%)5 years prognosis after resection is more (63%) [10] orless (36%) [16] favourable. Moreover, a few authors did

not con"rm survival bene"t in patients after total resec-tion, compared with patients after subtotal resection[19, 31]. Data from our institution showed DNA ploidyand grading to be the only two independent prognosticvariables which in#uenced the prognosis [19]. Amongother assessed factors, only Zorig [6] found the presenceof lymph node metastases of independent prognosticvalue.

8. Conclusion

Surgery remains the main modality in the therapy ofRS. While cases of laparoscopic resection of these tu-mours have already been reported [32], and even port-site recurrence after such a procedure [33], traditional,open surgical techniques are the best way to treat pa-tients. There are still some unresolved problems in RSsuch as the actual value of di!erent prognostic factors,histopathological assessment and the role of non-surgicaltreatment. Following other authors [8], we would like tostress that because of the rarity of RS only the arrange-ment of an international retroperitoneal sarcoma registryand co-operative intergroup studies can be helpful inevaluating the treatment and application of innovativemultimodal therapies to these neoplasms.

References

[1] Mettlin C, Priore R, Rao U. Results of the national soft-tissue sarcomas registry. Journal of Surgical Oncology 1982;19:224}227.

[2] Arlen M, Marcove RC. Retroperitoneal sarcomas. In: Arlen M,Marcove RC, editors. Surgical management of soft tissue sarcomas.Philadelphia, WB Saunders, 1987:220.

[3] Braash JW, Mon AB. Primary retroperitoneal tumors. SurgicalClinics of North America 1967;47:663}78.

[4] Dalton RR, Donohue JH, Mucha PJr, van Heerdan JA, ReimanHM, Chen S. Management of retroperitoneal sarcomas. Surgery1989;106:725}33.

[5] Storm FK, Eilber FR, Mirra J. Retroperitoneal sarcomas: a re-appraisal of treatment. Journal of Surgical Oncology 1981;17:1}7.

80 K. Herman, T. Kusy / Surgical Oncology 7 (1999) 77}81

Local recurrence rates after a complete resection has been described as 40% after 2 years, 72% after 5 years, and 91% after 10 years

Prognostic Factors• Unresectable primary tumor

• Positive gross margins

• High grade histology

• Dr. Brennan’s experience:Median survival: 103 months vs 18 months (gross negative vs incomplete resection). (MSKCC Ann Surg 1998).

• Local relapse is the most common cause of cancer related death

• Studies have also found improved survival from radical resections vs. incomplete resections +/- chemotherapy or RT.

Malerba M et al World J. Surg. 23,670-675, 1999

Chemotherapy

• Overall discouraging.

• Most studies have demonstrated no difference in survival.

• May be useful in combined modality therapy.

• One study examined the use of autologous peripheral blood stem cell transplantation (PBCST) + high dose chemotherapy using ICE protocol (ifosfamide, carboplatin and etoposide) for patients with recurrent refractory sarcomas. The data suggested a possible delay in relapse of disease.

• Hyperthermic intraperitoneal intraoperative chemotherapy following debulking surgery for abdominal sarcomatosis has been performed using doxorubicin and cisplatin (Phase I) has been performed and suggested an therapeutic potential in improving locoregional control.

Anticancer Res. 2002 Sep-Oct;22(5):2939-44.Cancer 2004. 100(9) 1943-50.

Radiation Therapy• Less effective than treating sarcomas of the extremity.

• May be due to limitation of toxic effects (ex. radiation enteritis or delayed wound healing > 50 Gy) or selection bias, in that more aggressive tumors are referred to RT.

• Some evidence that local control may be achieved with intraoperative brachytherapy vs. external beam RT. However no improvement in survival was demonstrated.

McGinn C. Surgical Oncology 9 (2000) 61-65

Surveillance & Recurrence

• Recurrence patterns are related to the histopathology:1

• Liposarcomas tend to recur with local disease (rarely have distant mets.)

• All other types of retroperitoneal sarcomas are more likely to recur with distant metastasis.

• Some authors2 have recommended follow-up CT scans every 6 months and surgical resection when feasible.

1. Gronchi A et al, Cancer. 2004 Jun1;100(11):2448-55.2. Eillber FC et al, Curr Treat Options Oncol. 2000 Aug;1(3):274-8.

Summary• Retroperitoneal sarcomas represent aggressive tumors

that often present late.

• Surgery remains the main modality of therapy. When feasible, contiguous organs should be excised in addition to the primary tumor.

• At present little evidence of effective chemotherapy or radiotherapy to treat these tumors.