University of Groningen

Soft tissue sarcoma at the turn of the millenniumNijhuis, Paulus Henricus Antonius

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Chapter 1

Introduction and aim of the thesis

10 Introduction and aim of the thesis Chapter 1

Introduction

Soft tissue sarcomas (STS) can be defined as malignant tumors arising from the non-epithelial extra-skeletal tissue of the body, exclusive of the reticulo-endothelial systemand glia. Embryologically, these tumors are derived principally from mesoderm, exceptsome, which derive from the neuroectoderm [1]. The pathogenesis of most STS remainsunknown. Genetic factors (neurofibromatosis I and II, retinoblastoma, Li-Fraumeni syn-drome, Gardner�s syndrome), environmental factors (exposure to environmental car-cinogens as dioxin and some herbicides, and trauma, injury or ionizing radiation in thepast), and immunological factors (immunosuppression after transplant surgery) havebeen identified as etiological factors in STS development [1-11]. As in most other malig-nancies, it is very unlikely that only one of these various factors is causing the disease;a multifactorial etiology seems obvious.

STS are rare tumors, accounting for approximately 1% of all malignant tumors diag-nosed annually (8100 patients in the United States and 422 in the Netherlands) [12,13].There is a slight male preponderance and the incidence is increasing with age [14,15,16].As prognosis varies between the different histological types and even between subtypes,an adequate histopathological classification is crucial. The most recent classification ofsoft tissue tumors is the World Health Organization histological classification (1994),dividing these tumors into 15 categories [17].

Figure 1 presents the distribution of STS according to anatomical site in patients olderthan 16 years who were treated at the Memorial Sloan-Kettering Cancer Center (MSKCC)from 1982-1990. It should be mentioned that patients with visceral and genitourinarySTS were included in that series. Figure 2 shows the distribution according to histo-pathology in the MSKCC series. In accordance with other reports, the most commonhistopathogical types were liposarcoma (LPS), malignant fibrous histiocytoma (MFH),and leiomyosarcoma [15,18,19,20]. Approximately half of the STS occurred in the ex-tremities (Figure 1), where liposarcoma and MFH were most common [19]. In theretroperitoneum and visceral tissues, however, leiomyosarcoma predominated [19].

Figure 1.Distribution of soft tissue sarcomas according to histopathology (Brennan, Ann Surg 1991; 214: 328-336).

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Unfortunately, there are only relatively few studies on epidemiological aspects of STS,and most of them are center-based. In the northeastern part of Netherlands, all malig-nancies, sarcomas included, are registered by the cancer registry of the ComprehensiveCancer Center North-Netherlands (CCCN), which is population-based, thus having a majoradvantage of avoiding selection bias caused by referral pattern. Collecting and studyingdata from such a cancer registry may provide more insight into STS epidemiology.

During the last decennia, many prognostic clinical factors have been identified in STS[21-39]. One of the most potent factors determining outcome seems to be the histo-pathological (sub)type of the tumor, which may become indiscernible if prognosticallyfavorable tumor (sub)types are reviewed together with less favorable (sub)types, as inmost reports on STS. Liposarcoma, as a group, has a better prognosis than epithelioidsarcoma [21-28], which in turn has a better prognosis than synovial sarcoma [29]. Buteven in the group of liposarcomas prognosis largely differs between the varioushistopathological subtypes [21-24].Besides histological (sub)type, other prognostic characteristics, as age at presentation,gender, tumor size, anatomical site, tumor depth, surgical margin, tumor grade, tumornecrosis, and vascular invasion have been reported [30-39], and the most important oneshave been embedded in the new staging system of the American Joint Committee onCancer (AJCC) (Table 1) [40]. As liposarcoma is one of the most common STS in whichseveral histopathological subtypes can be distinguished, this tumor is particularly suit-able to study prognostic characteristics.In recent years, the interest in the genetic etiology of malignancies has been increasingrapidly, and significant progress has been made in identifying chromosomal abnormali-ties in solid tumors. In several STS, characteristic cytogenetic alterations have been found,which often have diagnostic relevance [1,41-45]. As in other solid neoplasms, as well as insome hematological malignancies, it seems likely that some of these alterations haveprognostic importance in STS, although, at present, such a relation between (specific)cytogenetic alterations and prognosis and survival in STS could not be demonstratedunequivocally [46,47].

Figure 2.Distribution of soft tissue sarcomas according to anatomical site(Brennan, Ann Surg 1991; 214: 328-336).

Chapter 1 Introduction and aim of the thesis

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Advances in technology have resulted in an important progress in diagnostic tools inSTS. The introduction of the computer tomography scan (CT-scan) caused a major break-through in radiodiagnostics because, for the first time, it was possible to visualize thesoft tissues directly using X-rays [48]. Notwithstanding its possibilities, this techniquealso had its shortcomings (the use of X-rays, direct images limited to only two plains,only information on anatomy and not on metabolism). The development of the mag-netic resonance imaging (MRI) and the currently available spiral CT-scan overcame thefirst two shortcomings of the CT-scan [49,50], but still could not cope with the third one.The positron emission tomography scan (PET-scan) and the single photon emission to-mography (SPECT) made it possible to study the metabolism of tumors [51,52].As with all new technology-driven instruments, these challenging techniques can easilybe used inappropriately, resulting in significant health-care costs [53]. Therefore, thedevelopment of specific diagnostic guidelines is important, especially in rare tumors, asclinical and histopathological presentation widely varies, the experience in individualhospitals is limited, and treatment often is very complex, including many modalities.

In February 1983, a cooperative group for rare tumors, consisting of specialists in surgi-cal oncology, medical oncology, radiotherapeutic oncology and pathology from varioushospitals in the CCCN-region, recognized this problem and developed regional guide-

Introduction and aim of the thesis Chapter 1

Table 1. The American Joint Committee on Cancer (AJCC) soft tissue sarcoma stagingsystem.*

Primary Tumor (T)

TX Primary tumor cannot be assessedT0 No evidence of primary tumorT1 Tumor 5 cm or less in greatest dimension

T1a superficial tumorT1b deep tumor

T2 Tumor more than 5 cm in greatestdimension

T2a superficial tumorT2b deep tumor

Regional Lymph Nodes (N)

NX Regional lymph nodes cannot beassessed

N0 No regional lymph node metastasisN1 Regional lymph node metastasis

Distant metastasis (M)

MX Distant metastasis cannot be assessedM0 No distant metastasis

Histopathologic grade

GX Grade cannot be assessedG1 Well differentiatedG2 Moderately differentiatedG3 Poorly differentiatedG4 Undifferentiated

Stage grouping

Stage IA G1-2, T1a-1b, N0, M0Stage IB G1-2, T2a, N0, M0Stage IIA G1-2, T2b, N0, M0Stage IIB G3-4, T1a-1b, N0, M0Stage IIC G3-4, T2a, N0, M0Stage III G3-4, T2b, N0, M0Stage IV Any G, any T, N1, M0

Any G, any T, N0, M1

* Fleming ID, Cooper JS, Henson DE, et al, Eds.Chapter 22. Soft Tissue Sarcoma. In: AJCC Can-cer Staging Manual. 5th Ed. Philadelphia,Lippincott-Raven Publishers. 1997:149-156

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lines for the diagnosis and treatment of soft tissue tumors [54]. A few years later, theDutch Sarcoma Group initiated national guidelines for STS diagnosis and treatment[55]. Although compliance with such guidelines is important for various reasons (e.g.appropriateness of practice, health-care savings, and better outcome and survival [53,56-58]), and despite an increase in medical practice guideline development and dissemina-tion, compliance with such guidelines has often been surprisingly low. In malignantdisorders, reports on the adherence to such guidelines are very limited, whereas in softtissue tumors, nothing has been published on this item. Nevertheless, such informationseems very valuable for future guideline development and introduction.

Treatment of STS has changed dramatically during the second half of the last century.Prior to the 1950s and 1960s, most surgeons dealing with STS performed local resec-tions or shell-out procedures, which were associated with an unacceptable high localrecurrence rate of 60-95% [59-63]. In the same period, Bowden and Booher reportedlimb-saving techniques with a low local recurrence risk [64]. In the same year, 1958, thegroup of Stener published the same surgical principles and results [65,66]. Both groupsmight be considered true pioneers in modern STS treatment, because both recognizedthe infiltrative manner of sarcoma growth, explaining the high local recurrence rate aftershell-out procedures. Later, this high local recurrence rate was further explained byEnneking�s theory of sarcoma tumor growth pattern [67]. STS grow in a centrifugal fash-ion, resulting in the formation of an edematous pseudocapsule of compressed, normaltissue and a reactive zone of proliferating mesenchymal cells and neovascularization.Further tumor growth causes a continuous extent of microscopic tumor pseudopodsinto this pseudocapsule, where they form microscopic and macroscopic nodules (satel-lites). Especially in high-grade lesions, such satellites can also be found in surrounding�normal� tissue, far beyond the pseudocapsule (skip metastases). In extremities, wheremost of the STS are located, the tumor extends longitudinally, within the compartment,bounded by fibrous barriers (muscle fascia and aponeurosis, deep fascia and intermus-cular septae). Crossing these barriers is a late phenomenon, and is associated with high-grade lesions [67,68].

Based on these new insights, en-block resections of the entire compartment containingthe tumor or amputations were recommended, resulting not only in a drop of local re-currence rate to 5-30%, but also in a high amputation rate of 40-50% [60,61,68-70].Although these so-called �compartment resections� were widely adopted, the division ofsurgical oncology of the Groningen University Hospital performed only wide local resec-tions followed by external beam radiotherapy (EBRT) or amputation of the affected limb.

Modern STS management started at the end of the seventies and the beginning of theeighties. Suit and Lindberg were the first to demonstrate the importance of adjuvantradiotherapy in STS therapy [71,72]. Their results formed the basis of the famous Na-tional Cancer Institute (NCI) trial by Steven Rosenberg et al., a study that became one ofthe cornerstones in today�s state of the art STS treatment [70]. For the first time, a pro-spective randomized study showed that adequately performed local resection followedby high dose radiotherapy formed a reliable limb-saving treatment, comparable to am-putation with regard to local recurrence, disease-free and overall survival rates.

Chapter 1 Introduction and aim of the thesis

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Unfortunately, the optimal treatment for locally advanced extremity sarcomas remainedan unsolved problem. One of the most promising approaches at that time was a multi-modality therapy, consisting of preoperative (intraarterial) chemotherapy, immediatelyfollowed by EBRT, and surgical resection. This technique was initiated by Morton andEilber [73], and later further developed by Eilber and co-workers at the UCLA School ofMedicine [74,75]. The sequence of the various therapies was based on the premise thatpreoperative treatment of micrometastases at the periphery of the tumor with intact bloodsupply would enable the surgeon to perform a local surgical procedure. In three sequentialtrials, Eilber et al. showed a high limb salvage rate of 95%, with a low local recurrencerate of approximately 10% [75]. In the early eighties, this treatment strategy was adoptedby the Groningen Sarcoma Working Party, which added postoperative EBRT to thetreatment protocol in case of a marginal resection or involvement of the surgical margin[76]. The multimodality treatment, as initiated by Morton and Eilber, has been associatedwith a substantial short-term morbidity, especially wound complications [75]. Althoughthere has been a growing awareness of potential long-term side-effects of intensified(multimodality) cancer treatment protocols, only very few reports have dealt with thelong-term complications and functional outcome after this intensive STS treatment [75,77-79].

Another way to decrease the number of amputations in locally advanced extremity STShas been hyperthermic isolated limb perfusion (HILP) with cytostatics agents. Severaldrugs have been used (melphalan, the standard drug for HILP in melanoma, doxorubicin,cisplatinum, and other agents), without improvement of local control or disease-freesurvival when compared to the other therapies, as intravenous or intraarterial adriamycinin combination with neoadjuvant radiotherapy followed by local resection [75,80-83].It was not until the early nineties, that significant progress was made by the addition oftumor necrosis factor-alpha (TNF-α) to melphalan in HILP for locally advanced extrem-ity STS [84]. This resulted in a high response rate and high limb salvage rates with anacceptable toxicity level [85]. In the early nineties, the Groningen Sarcoma Working Partychanged the treatment of locally advanced extremity STS in HILP with TNF-α, melphalan,with or without interferon-gamma (IFN-γ), with good results [85]. In 1998, this sarcomagroup published the results of a study on adjuvant EBRT (60-70 Gy) after HILP withmelphalan, TNF-α, and IFN-γ and delayed tumor resection of locally advanced extremitySTS with histopathological viable tumor after resection [86]. It was demonstrated thatthis was feasible and that the addition of EBRT increased local tumor control withoutincreasing treatment morbidity. Recently, Ham et al. highlighted several aspects of mod-ern surgical sarcoma treatment at the Groningen University Hospital [87].

Since the mid eighties, the cancer registry of the CCCN has registered all STS in theCCCN-region, and the Groningen Sarcoma Working Party discusses all sarcomas re-ferred to the Groningen University Hospital. In recent years, many aspects of these tumorshave been studied and reported by this sarcoma group, resulting in several theses [88-90]. Still a variety of questions remain unanswered. The goal of the present thesis is toget more insight into several aspects of this uncommon malignancy.

Introduction and aim of the thesis Chapter 1

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Chapter 1 Introduction and aim of the thesis

Aim of the thesis

1. To provide more insight into epidemiological aspects of STS, based on a population-basedsurvey.

2. To study the impact of the histopathological heterogeneity on prognosis in one of the mostcommon STS, liposarcoma.

3. To evaluate the necessity of long-term follow-up, especially in case of intensive, multimodalitytreatment protocols, in order to determine long-term effects, which might interfere with theprimary goal of such therapies.

4. To investigate the adherence to (diagnostic) STS guidelines, and to evaluate the role ofcentralization in the diagnostic management of these rare tumors.

5. To look into the (near) future of STS treatment, and to evaluate the prognostic importanceof cytogenetic changes in these tumors.

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Introduction and aim of the thesis Chapter 1