usmle文件克氏外科学19版chapter

1、 CHAPTER 33SOFT TISSUE SARCOMASSamuel SingerMost cases of soft tissue sarcoma are thought to be sporadic and their cause is unknown. In rare cases, genetic factors, envi- ronmental factors, prior radiation therapy, viral infections, and immunodeficiency have been associated with the development of s

2、arcoma. In addition, sarcomas have been reported to arise in scar tissue, fracture sites, or anatomic regions associated with prior soft tissue trauma. Genetic syndromes such as neurofibro- matosis, familial adenomatous polyposis, and the Li-Fraumeni syndrome have all been shown to be associated wit

3、h the develop- ment of soft tissue sarcoma. Desmoid tumors occur in patients with familial adenomatous polyposis, a disorder caused by the germline adenomatous polyposis coli (APC) gene mutation. Malignant peripheral nerve sheath tumors develop in a benign nerve sheath in approximately 2% of patient

4、s with neurofibro- matosis. The Li-Fraumeni syndrome is a rare, highly penetrant, familial cancer phenotype usually associated with germline mutations in the p53 tumor suppressor gene.2 Of patients with this syndrome, 80% develop cancer by age 45 and soft tissue or bone sarcomas of diverse histology

5、 arise as the index tumor in 36% of patients. Heritable retinoblastoma gene (RB1) muta- tions are associated with an increased risk of bone and soft tissue sarcoma. For example, patients with RB1 mutations have a 36% cumulative incidence over 50 years of developing sarcoma in previously irradiated t

6、issue.3 Most of the excess cancer risks in hereditary retinoblastoma survivors can be prevented by limiting exposures to DNA damaging agents such as radiotherapy, tobacco, and ultraviolet (UV) light,4 emphasizing the impor- tance of avoiding the use of radiation in sarcoma patients with a known germ

7、line mutation in RB1.A soft tissue sarcoma (STS) is one of the most commontypes of radiation-associated tumors in the general popula- tion.5 Although a clear dose-response relationship for radiation-associated malignancies is not established, it is gener- ally accepted that carcinomas arise in tissu

8、es exposed to lower doses, whereas sarcomas are induced in heavily radiated tissues (most patients have received 50 Gy or more) in or close to the radiation fields. The median interval between radiation expo- sure and the development of sarcoma is 10 years (range, 1.3 to 74 years) and this varies by

9、 histologic type, with the shortest latency observed in liposarcoma (median, 4.3 years; range, 3 to 17 years), and the longest in leiomyosarcoma (median,23.5 years; range, 7.0 to 74.0 years).6 Radiation-associated sarcomas are associated with inferior survival compared with sporadic soft tissue sarc

10、oma, even if one adjusts for known prognostic factors such as histologic type, size, age, margin status, and site.6Soft tissue sarcomas are rare and unusual neoplasms, accounting for approximately 1% of adult human cancers and 15% of pediatric malignancies. Sarcomas affect more than 10,600 patients/

11、year in the United States and approximately 4000 patients will die each year from inoperable forms of soft tissue sarcoma.1 Sarcomas continue to carry biologic and clinical inter- est and significance disproportionate to their clinical frequency because of their often clearly defined molecular genet

12、ics and the vast expansion of cytogenetic and molecular genetic information that has been discovered over the past 10 years. Soft tissue sar- comas may develop in any anatomic site and this feature, together with the more than 50 histologic types and subtypes, continues to pose a challenge in diagno

13、sis and management. Our understanding of the histology-specific natural history and of the most important clinicopathologic factors that predict outcome and response to therapy has improved our ability to select an optimal treatment plan for the patient diagnosed with soft tissue sarcoma. Most sarco

14、ma types remain resistant to conventional chemotherapy, which means that approximately 40% of newly diagnosed patients will eventually die of disease. Therefore, there exists an urgent unmet need for new therapies targeting the underlying genetic aberrations driving sarcomagen- esis. This chapter fo

15、cuses on the biology, epidemiology, molecu- lar genetics, histopathology, clinical features, and management of soft tissue sarcomas among adults (older than 16 years).DISTRIBUTION, AGE, AND CAUSESAlthough soft tissue sarcomas may occur in any anatomic site, 45% occur in the extremity, most commonly

16、in the thigh, fol- lowed in order of frequency by visceral (20%), retroperitoneal (15%), truncal or thoracic (10%), and other locations (10%). Soft tissue sarcomas become more common with increasing age, with the translocation-associated sarcomas having a median age of onset in the 1930s and the com

17、plex sarcoma types having a median age of onset in the 1950s or 1960s.768distribution, age, and causes molecular genetics evaluationhistologic grading and prognostic factors for outcomestagingmanagement summary Soft tiSSue SarcomaS Chapter 33 769Several studies have reported an increased incidence o

18、f soft tissue sarcoma after relatively high level occupational expo- sure to phenoxyacetic herbicides, chlorophenols, and dioxins. However, more recent case-control studies have not confirmed this association and have shown no positive correlation between dioxin concentrations and soft tissue sarcom

19、a risk. In fact, sarcoma risk was highest among those having the lowest dioxin level.7,8MOLECULAR GENETICSpatients to achieve statistical significance, as demonstrated in several studies of mixed adult soft tissue sarcoma. Its high preva- lence in this class of sarcomas may account for its limited a

20、bility to define distinct clinical prognostic subsets in these tumors.In addition to serving as specific and powerful diagnostic markers, fusion genes resulting from translocations encode chi- meric proteins that are important determinants of tumor biology, acting as abnormal transcription factors t

21、hat alter the transcrip- tion of a number of downstream genes and pathways. The struc- tures of these chimeric proteins play a prominent role in the pathogenesis of sarcoma; this has been shown by the impact of relatively minor cytogenetic variability, as a result of variant molecular breakpoints, o

22、n tumor phenotype and clinical behav- ior.16,17 Although the diagnostic significance of sarcoma genomic aberrations has been known for more than 20 years, these same aberrations have only recently become useful as potential thera- peutic targets. For example, the identification of the COL1A1- PDGFB1

23、 gene fusion leading to constitutive expression of the platelet-derived growth factor (and its receptor, presumably through an autocrine or paracrine loop) in dermatofibrosarcoma protuberans (DFSP) has paved the way for targeted therapy with imatinib in patients with advanced disease.18,19 The recen

24、t discovery that angiosarcomas show distinct upregulation of vascular-specific receptor tyrosine kinases, including TIE1, KDR, SNRK, TEK, and FLT1, by expression profiling and that 10% of patients harbor KDR mutations with evidence for ligand-dependent kinase activation provides a basis for treating

25、 angiosarcoma patients with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors.20 In a multicenter phase II trial of sorafenib, a small-molecule B-raf and VEGFR inhibitor, in a cohort of patients with metastatic or recurrent sarcoma, only patients with angiosarcoma showed

26、 a significant response to therapy, with 5 of 37 patients (14%) having a partial response.21EVALUATIONClinical Evaluation and DiagnosisBenign soft tissue tumors outnumber sarcomas by at least 100 to 1, with most benign lesions located superficially to the fascia. The most frequent benign lesion is a

27、 lipoma, which frequently goes untreated. Because excisional biopsy may often cause dif- ficulties with further patient management, it is generally recom- mended to obtain a diagnostic biopsy prior to definitive treatment for all soft tissue masses larger than 5 cm, unless an obvious subcutaneous li

28、poma, and for all subfascial or deep- seated masses, almost irrespective of size.Patients with extremity sarcoma usually present with a painless mass, often with no functional impact, although pain is noted at presentation in up to 33% of patients. Delay in diagnosis is common, with the most common

29、differential diag- nosis for extremity and trunk lesions being a hematoma or a pulled muscle. Physical examination should include assessment of the size of the mass, its depth in relation to superficial fascia, and its relationship to neurovascular and bony structures. Gen- erally, in an adult, any

30、soft tissue mass that is symptomatic or enlarging, any superficial mass that is larger than 5 cm, and all deep-seated masses irrespective of size should be sampled. Biopsy technique is important. For most soft tissue masses, an open incisional biopsy or core needle biopsy is usually preferred. Ideal

31、ly, the initial diagnostic procedure should be performed atKnowledge of tomic alterations in soft tissue sarcoma islimited to only the most recurrent alterations. These alterationssegregate sarcoma into two major groups. The first group con- sists of sarcoma types with near-diploid, simple karyotype

32、s that bear few chromosomal rearrangements but have pathognomonic alterations, such as the translocations in myxoid round cell liposarcoma (MRC) t(12;16)(q13;p11), t(12;22)(q13;q12) and synovial sarcomas (SSs) t(X;18)(p11;q11), APC/-catenin mutations in desmoid tumors, and activating mutations in KI

33、T or PDGFRA in gastrointestinal stromal tumors (GISTs).9-11 Dis- covery of these last mutations has led to the clinical deployment of imatinib for the treatment of GIST,12 providing a m for genotype-directed therapies in molecularly defined sarcoma sub- types. Conversely, the second group consists o

34、f sarcomas with complex karyotypes, including dedifferentiated and pleomor- phic liposarcomas, leiomyosarcomas, pleomorphic malignant fibrous histiocytoma, and myxofibrosarcomas. Sarcomas in this group have no known characteristic mutations or fusion genes, although abnormalities are frequently obse

35、rved in the Rb, p53, and specific growth factor signaling pathways. Thus, a significant subset of soft tissue sarcoma is characterized by recurrent and specific chromosomal aberrations that can be diagnostically and, occasionally, prognostically useful (Table 33-1). The fusion gene translocations in

36、clude 13 different gene fusions involving the EWS gene or EWS family members (TLS, TAF2N) found in five different sarcomas and 11 other types of fusions in eight other sarcoma types.If conventional cytogenetics is not available, molecular genetic techniques (e.g., reverse transcription polymerase ch

37、ain reaction and fluorescence in situ hybridization) are useful as diagnostic adjuncts. In addition, investigation of molecular changes of genes at the sites of chromosomal alterations has led to the identification of novel genes and the characterization of their mechanisms of deregulation. The tumo

38、r suppressor genes best studied in sarcoma are p53, RB1, and NF1. Inactivation of these genes is involved in the tumorigenesis of several sarcomas. The major mechanisms of p53 pathway inactivation in sarcomas include p53 point mutations, homozygous deletion of CDKN2A, which encodes both p14ARF and p

39、16, and MDM2 amplifi- cation. In sarcomas with specific reciprocal translocations, p53 pathway alteration is a rare event but, when present, is a strong prognostic factor, associated with significantly decreased survival in synovial sarcoma,13 myxoid liposarcoma,14 and Ewings sarcomaperipheral neuro

40、ectodermal tumor (PNET).15 Decreased survival and poor response to chemotherapy in Ewings sarcomaPNET was associated with deletion of CDKN2A, representing a type of p53 pathway alteration through loss of the CDKN2A alternative product p14ARF.15 In contrast, in sarcomas with nonspecific genetic alter

41、ations and complex karyotypes, p53 pathway alteration is more common and has weaker prognostic value, often requiring large numbers ofSECTION V SurGicaL oNcoLoGY770SeCtION V SurGicaL oNcoLoGYthe center at which the patient will be treated. This facilitates proper placement of the biopsy site (or inc

42、ision) and also avoids the complications and diagnostic difficulties that can arise if such biopsy samples are handled infrequently. Limb masses are generally best sampled through a longitudinal incision so that the entire biopsy tract can be excised at the time of definitive resection. The incision

43、 should be centered over the mass in its most superficial location. No tissue flap should be raised, and meticulous hemostasis should be ensured to prevent cellular dissemination by hematoma. Excisional biopsy is recommended only for small cutaneous or subcutaneous tumors, usually smallerthan 5 cm,

44、in which a wide reexcision (if required) is usually straightforward. Fine-needle aspiration biopsy has a limited role in diagnosing extremity soft tissue tumors but may be of value in the documentation of recurrence. An analysis of 164 soft tissue masses for the value of core needle biopsy has sugge

45、sted that 83% of specimens obtained at initial biopsy are adequate for diagnosis. Of the adequate biopsy specimens, 95% correlated with the final resection diagnosis for malignancy, 88% for histologic grade, and 75% for histologic subtype. Core needle biopsy can be then advocated as the first step i

46、n the diagnostic armamentarium. The high diagnostic accuracy, easetable 33-1 Cytogenetic and Molecular abnormalities in SarcomasGeNe rearraNGeMeNt OrFreQUeNCYhIStOLOGIC tYpeCYtOGeNetIC eVeNtMOLeCULar aBNOrMaLItY(%)DIaGNOStICSynovial sarcomat(X;18)(p11;q11)>90YesSYT-SSX1 fusion66YesSYT-SSX2 fusion

47、33YesSYT-SSX4 fusion<1Yesmyxoid, round cell liposarcomat(12;16)(q13;p11)TLS-CHOP fusion>90Yest(12;22)(q13;q12)EWS-CHOP fusion<5Yesewings sarcomat(11;22)(q24;q12)EWS-FLI1 fusion>80Yes t(21;22)(q22;q12)EWS-ERG fusion10-15Yest(7;22)(p22;q12)EWS-ETV1 fusion<2Yest(17;22)(q12;q12)EWS-E1AF f

48、usion<2Yest(2;22)(q33;q12)EWS-FEV fusion<2Yesinv(22)(q12q12)EWS-ZSG fusion<2Yesalveolar rhabdomyosarcomat(2;13)(q35;q14)PAX3-FKHR fusion>75Yest(1;13)(p36;q14)PAX7-FKHR fusion10-20Yesembryonal rhabdomyosarcomatrisomies 2q, 8, and 20>75Yes LoH at 11p15>75Yesextraskelmyxoid chondrosar

49、comat(9;22)(q22;q12)eWS-Nr4a3 fusion>75Yest(9;17)(q22;q11)taf2N-Nr4a3 fusion<10Yes t(9;15)(q22;q21)tcf12-Nr4a3 fusion<10Yesendometrial stromal tumort(7;17)(p15;q21)JaZf1-JJaZ130YesDermatofibrosarcoma protuberansrings derived from t(17;22)coL1a1-PDGfB1 fusion>75Yest(17;22)(q22;q13.1)COL1A

50、1-PDGFB1 fusion10YesDesmoplastic small round cell tumort(11;22)(p13;q12)EWS-WT1 fusion>75Yesclear cell sarcomat(12;22)(q13;q12)EWS-ATF1 fusion>75Yesinfantile fibrosarcomat(12;15)(p13;q25)etV6-NtrK3 fusion>75Yesalveolar soft part sarcomat(X;17)(p11;q25)aSPL-tfe3 fusion>90Yesinflammatory m

51、yofibroblastic tumor2p23 rearrangementALK fusion genes50YesGastrointestinal stromal tumormonosomies 14 and 22>75YesDeletion of 1p>25NoKIT or PDGFRA mutation>90YesDesmoid fibromatosistrisomies 8 and 2030YesDeletion of 5qAPC inactivation by mutation/10Yes deletion-Catenin mutations85YesWell-d

52、ifferentiated or dedifferentiated12q rings and giant markersMDM2 and CDK4 amplification>85Yes liposarcomaLeiomyosarcomacomplex*>90No Deletions of 1p>50NoRB1 point mutations, deletions?NoPleomorphic liposarcomacomplex*>90NoPleomorphic malignant fibrouscomplex*>90No histiocytoma and myx

53、ofibrosarcomamalignant peripheral nerve sheath tumorcomplex*90NoNF-1 mutation, loss, or>50No deletion*Complex karyotypes containing multiple numeric and structural chromosomal aberrations.Soft tiSSue SarcomaS Chapter 33 771of performance, low cost, and low complication rate make this technique at

54、tractive. If tissue is inadequate or there is any indeci- sion, repeat core biopsy under image guidance or an open, lin- early placed incisional biopsy is then indicated. Tumor histologic type and grade are correctly identified in most patients and can be used to define the optimal treatment plan an

55、d extent of surgery required for definitive therapy.Patients with intra-abdominal or retroperitoneal sarcomas often experience nonspecific abdominal discomfort and gastro- intestinal symptoms before diagnosis. The diagnosis is usually suspected on finding a soft tissue mass on abdominal computed tom

56、ography (CT) or magnetic resonance imaging (MRI). Fine- needle aspiration biopsy or CT-guided core biopsy has a limited role in the routine diagnostic evaluation of these patients. CT-guided core biopsy is indicated if abdominal lymphoma, germ cell tumor, or carcinoma is strongly suspected as part o

57、f the differential diagnosis. Preoperative percutaneous biopsy is also indicated for patients who present with distant metastasis or advanced local disease that on abdominal or pelvic imaging appears to be surgically difficult to remove completely without substantial morbidity. In most patients, exp

58、loratory laparotomy should be performed and the diagnosis made at operation, unless the patients tumor is clearly unresectable or the patient will be undergoing preoperative investigational treatment.Evaluation of Extent of DiseaseAll patients require a thorough history and physical examina- tion. M

59、RI examination is usually the preferred procedure for imaging extremity soft tissue masses. MRI enhances the contrast between tumor and adjacent structures and provides excellent three-dimensional definition of fascial planes. Also, it aids in guiding biopsies, planning surgery, evaluating response to therapy, and restaging and in the long-term follow-up for local rec