LITERATURE AND REVIEW OF SOFT TISSUE TUMOR BY HERRY SETYA YUDHA UTAMA

REVIEW of THE LITERATURE

Background

The large majority of soft tissue tumours are benign, with a very high cure rate after surgical excision. Malignant mesenchymal neoplasms amount to less than 1% of the overall human burden of malignant tumours but they are life threatening and may pose a significant diagnostic and therapeutic challenge since there are more than 50 histological subtypes of STS, which are often associ- ated with unique clinical, prognostic and therapeutic features. Over the past decade, our understanding of these neo plasms has increased significantly, both from a histopathological and genetic point of view. The close interaction of surgical pathologists, surgeons and oncologists has brought about a significant increase in disease-free survival for tumours which were previously almost invariably fatal, the overall 5-year survival rate for STS in the limbs now being in the order of 65-75%. Careful physical examination and radiographic evaluation to evaluate the size, depth and location of the mass, along with signs of neurovascular involvement are essential for designing the best ther- apeutic approach

Epidemiology

Benign mesenchymal tumours outnum-ber sarcomas by a factor of at least 100. annual clinical incidence (number of new patients consulting a doctor) of benign soft tissue tumours has been estimated as up to 3000/million population whereas the annual incidence of soft tissue sarcoma is around 30/million i.e. less than 1 percent of all malignant tumours. There are no data to indicate a change in the incidence of sarcoma nor are there significant geographic differences.

Etiology

The etiology of most benign and malignant soft tissue tumours is unknown. In rare cases, genetic and environmental factors, irradiation, viral infections and immune deficiency have been found associated with the development of usually malignant soft tissue tumours. There are also isolated reports of soft tissue sarcomas arising in scar tissue, at fracture sites and close to surgical implants. However, the large majority of soft tissue sarcomas seem to arise de novo, without an apparent causative factor. Some malignant mesenchymal neoplasms occur in the setting of familial cancer syndromes  Multistage tumourigenesis sequences with gradual accumulation of genetic alterations and increasing histological malignancy have not yet been clearly identified in soft tissue tumours.

1.      Chemical carcinogens

Several studies, many of them from Sweden, have reported an increased incidence of soft tissue sarcoma after exposure to phenoxyacetic herbicides, chlorophenols, and their contaminants (dioxin) in agricultural or forestry work . Other studies have not found this association. One explanation for different findings may be the use of herbicides with different dioxin contamina- tions

2.      Radiation

The reported incidence of post-irradiation sarcoma ranges from some few per thousand to nearly one percent. Most incidence estimates are based on breast cancer patients treated with radiation as adjuvant therapy . The risk increases with dose; most patients have received 50 Gy or more and the median time between exposure and tumour diagnosis is about 10 years, although there is some evidence that this latent interval is decreasing. More than half of the tumours have been classified as so- called malignant fibrous histiocytomamost often highly malignant. Patients with a germline mutation in the retinoblastomas gene (RB1) have a significantly elevated risk of developing post-irradia- tion sarcomas, usually osteosarcomas. Viral infection and immunodeficiency Human herpes virus 8 plays a key role in the development of Kaposi sarcoma and the clinical course is dependent on the immune status of the patient Epstein-Barr virus is associated with smooth muscle tumours in patients with immunodeficiency Stewart- Treves syndrome, development of angiosarcoma in chronic lymphoedema, particularly after radical mastectomy, has by some authors been attributed to regional acquired immunodeficiency.

3.      Genetic susceptibility

Several types of benign soft tissue tumour have been reported to occur on a familial or inherited basis. However these reports are rare and com- prise an insignificant number of tumours. The most common example is probably hereditary multiple lipomas (often angiolipomas) Desmoid tumours occur in patients with the familial Gardner syndrome (including adenoma- tous polyposis, osteomas and epidermalcysts) Neurofibromatosis (types 1 and 2) is associated with multiple benign nerve tumours (and sometimes also non- neural tumours). In around 2% of the patients with neurofibromatosis type1 malignant peripheral nerve sheath tumours develop in a benign nerve sheath tumour The Li-Fraumeni syndrome is a rare autosomal dominant disease caused by germline muta- tions in the TP53 tumour suppressor gene, which seems to be of importance for sarcomagenesis. Half of the patients have already developed malignant tumours at age 30, among them, in more than 30% of cases, soft tissue and bone sarcomas. The inherited, or bilateral form of retinoblastoma, with a germline muta- tion of the RB1 locus, may also be asso- ciated with sarcoma development

Clinical features

Benign soft tissue tumours outnumber sarcomas by at least 100 to 1, although it is almost impossible to derive accurate numbers in this regard. Most benign lesions are located in superficial (dermal or subcutaneous) soft tissue. By far the most frequent benign lesion is lipoma, which often goes untreated. Some benign lesions have distinct clinical fea- tures but most do not. Some non-metas- tasizing lesions, such as desmoid-type fibromatosis or intramuscular haeman- gioma, require wide excision compara- ble to a sarcoma, otherwise local recur- rence is very frequent. Since excisional biopsy or ‘shelling out’ of a sarcoma is inappropriate and often may cause diffi- culties in further patient management, then it is generally advisable to obtain a  diagnostic biopsy (prior to definitive treatment) for all soft tissue masses>5 cm (unless a very obvious subcutaneous lipoma) and for all subfascial or deep-seated masses, almost irrespec- tive of size. Most soft tissue sarcomas of the extrem- ities and trunk wall present as painless, accidentally observed tumours, which do not influence function or general health despite the often large tumour volume. The seemingly innocent presentation and the rarity of soft tissue sarcomas often lead to misinterpretation as benign con- ditions. Epidemiological data regarding size and depth distribution for benign and malignant soft tissue tumours in Sweden have been used to formulate simple guidelines for the suspicion of a sarcoma: superficial soft tissue lesions that are larger than 5 cm and all deep- seated (irrespective of size) have such a high risk (around 10 percent) of being a sarcoma that such patients should ideally be referred to a special- ized tumour centre before surgery for optimal treatment

Diagnosis

Magnetic resonance imaging (MRI) is the modality of choice for detecting, characterizing, and staging soft tissue tumours due to its ability to distinguish tumour tis- sue from adjacent muscle and fat, as wel as to define relationships to key neu- rovascular bundles. Additionally, it aids in guiding biopsy, planning surgery, eval- uating response to chemotherapy, restaging, and in the long-term follow-up for local recurrence. Although MR imag- ing may not always reliably predict the histological diagnosis of a mass or its potential biologic activity, several condi- tions can be reliably diagnosed based on their characteristic pathological and signal pattern, location of mass, relation- ship to adjacent structures, multiplicity, and clinical history. MR imaging accu- rately defines tumour size, relationship to muscle compartments, fascial planes, and bone and neurovascular structures in multiple planes; it provides information on haemorrhage, necrosis, oedema, cys- tic and myxoid degeneration, and fibro- sis. MR imaging provides better tissue dis- crimination between normal and abnor- mal tissues than any other imaging modality. Most masses show a long T1 and long T2. However, there are a group of lesions that show a short T1 and short T2. Masses with relatively high signal intensity on T1 are lipoma, well-differenti- ated liposarcoma, haemangioma, suba- cute haemorrhage, and some examples of Ewing sarcoma/peripheral PNET. Clumps or streaks of high signal within the low signal intensity mass on T1- weighted sequences might be encoun- tered in haemangioma, myxoid liposar- coma, infiltrative intramuscular lipoma, and lipomatosis of nerve. Tumours that may have a low signal on T2 include dif- fuse-type giant cell tumour, clear-cell sar- coma and fibromatosis. Soft tissue mass- es that do not demonstrate tumour-spe- cific features on MR imaging should be considered indeterminate and biopsy should always be obtained to exclude malignancy.

MRI-guided biopsy. Radiologists should be cautious when asked to perform biop- sies of indeterminate soft tissue tumours. Caution has to be exercised in three respects: Selection of an appropriatepathway, coordination with the treating surgeon, and participation of a patholo- gist comfortable with interpreting percu- taneous biopsies. The radiologist should undertake biopsies only at the request o the treating surgeon and not necessarily at the request of the patient's initial physi- cian. In collaboration with the treating surgeon, the needle tract (which needs to be excised with the tumour) can beestablished and the patient well served. Spiral CT is preferable for examining sar- comas of the chest and abdomen, since air / tissue interface and motion artefacts often degrade MRI quality. A baseline chest CT scan at the time of diagnosis for evidence of lung metastasis is important, particularly for sarcomas >5 cm, for accurate staging of patients. Early stud- ies suggest that positron emission tomography (PET) has clinical potential by determining biological activity of soft tissue masses . The technique is selectively used for distin- guishing benign tumours from high grade sarcomas, pretreatment grading of sarcomas, and evaluation of local recurrence. Its role, vis-à-vis, MR imag- ing which remains the mainstay, is yet to be defined.

Biopsy

Given the prognostic and therapeutic importance of accurate diagnosis, a biopsy is necessary (and appropriate) to establish malignancy, to assess histolog- ical grade, and to determine the specific histological type of sarcoma, if possible. A treatment plan can then be designed that is tailored to a lesion’s predicted pat- tern of local growth, risk of metastasis, and likely sites of distant spread. A large enough sample from a viable area of sar- coma is usually required for definitive diagnosis and accurate grading. Most limb masses are generally best sampled through a longitudinally oriented incision, so that the entire biopsy tract can be completely excised at the time of defini- tive resection. An incisional biopsy with minimal extension into adjacent tissue planes is the ideal approach for most extremity masses. Excisional biopsy should be avoided, particularly for lesions greater than 2 cm in size, since such an approach will make definitive re- excision more extensive due to the con- tamination of surrounding tissue planes. For deep-seated lesions, a core biopsy approach may be used to establish a diagnosis, however, the limited tissue obtained with this technique may make definitive grading and prognostication difficult. Fine needle aspiration (FNA) cytology is generally best limited to those centres with a high case volume and with a well-integrated multidisciplinary team, since careful clinicoradiologic correlation and considerable experience are required in order to make accurate diag- noses. A particular problem with needle biopsies and FNA is the inevitability of limited sampling, which impacts not only diagnostic accuracy but also the possi- bility of triaging tissue for ancillary diag- nostic techniques such as cytogenetics and electron microscopy. Terminology regarding biological potential As part of this new WHO classification of Soft Tissue Tumours, the Working Group wished to address the problems which have existed regarding definition of a lesion’s biological potential, particularly with regard to the current ambiguity of such terms as ‘intermediate malignancy’ or ‘borderline malignant potential.’ With this goal in mind, it is recommended to divide soft tissue tumours into the follow- ing four categories: benign, intermediate (locally aggressive), intermediate (rarely metastasizing) and malignant. Definitions of these categories are as follows:

a)      Benign

Most benign soft tissue tumours do not recur locally. Those that do recur do so in a non-destructive fashion and are almost always readily cured by complete local excision. Exceedingly rarely (almost cer- tainly <1/50,000 cases, and probably much less than that), a morphologically benign lesion may give rise to distant metastases. This is entirely unpre- dictable on the basis of conventional his- tological examination and, to date has been best documented in cutaneous benign fibrous histiocytoma. Intermediate (locally aggressive) Soft tissue tumours in this category often recur locally and are associated with an infiltrative and locally destructive growth pattern. Lesions in this category do not have any evident potential to metastasize but typically require wide excision with a margin of normaltissue in order to ensure local control. The prototypical lesion in this category is desmoid fibro- matosis. Intermediate (rarely metastasizing) Soft tissue tumours in this category are often locally aggressive (see above) but, in addition, show the well-documented ability to give rise to distant metastase Modified from Trojani et al. PNET: primitive neuroectodermal tumour *A high power field (HPF) measures 0.1734 mm2 in occasional cases. The risk of such metastases appears to be <2% and is not reliably predictable on the basis of histomorphology. Metastasis in such lesions is usually to lymph node or lung. Prototypical examples in this category include plexiform fibrohistiocytic tumour and so-called angiomatoid fibrous histiocytoma.

b)     Malignant

In addition to the potential for locally destructive growth and recurrence, malignant soft tissue tumours (known as soft tissue sarcomas) have significant risk of distant metastasis, ranging in most instances from 20% to almost 100%, depending upon histological type and grade. Some (but not all) histologically low grade sarcomas have a metastatic risk of only 2-10%, but such lesions may advance in grade in alocal recurrence, and thereby acquire a higher risk of dis- tant spread (e.g., myxofibrosarcoma and leiomyosarcoma).It is important to note, that in this new classification scheme, the intermediate categories do not correspond to histo- logically determined intermediate grade in a soft tissue sarcoma (see below), nor do they correspond to the ICD-O/1 cate- gory described as uncertain whether benign or malignant. The locally aggres- sive subset with no metastatic potential, as defined above, are generally given ICD-O/1 codes , while the rarely metasta- sizing lesions are given ICD-O/3 codes. Histological grading of soft tissue sarcomas The histological type of sarcomas doesnot always provide sufficient information for predicting the clinical course and therefore for planning therapy. Grading, based on histological parameters only, evaluates the degree of malignancy and mainly the probability of distant metastasis. Staging, based on both clinical and histological parameters, provides infor- mation on the extent of the tumour. The concept of grading in STS was first properly introduced by Russell et al in 1977 and was the most important factor of their clinico-pathological classi- fication. Several grading systems, based on various histological parameters, have been published and proved to correlate with prognosis The two most important parame- ters seem to be the mitotic index and the extent of tumour necrosis A three-grade system is recom- mended, retaining an intermediate histo- logical grade (grade 2) of malignancy. Grade particularly indicates the probabil- ity of distant metastasis and overall sur- vival but is of poor value for predicting local recurrence which is mainly related to the quality of surgical margins. Moreover, the initial response to chemotherapy has been reported to be better in patients with a high grade tumour than in patients with a low grade one The two most widely used systems are the NCI (United States National Cancer nstitute) system  and the FNCLCC (French Fédération Nationale des Centres de Lutte Contre le Cancer) system According to the methodology defined in 1984 and refined in 1999  the NCI system uses a combination of histo- logical type, cellularity, pleomorphism and mitotic rate for attributing grade 1 or 3. All the other types of sarcomas were classified as either grade 2 or grade 3 depending on the amount of tumour necrosis, with 15% necrosis as thethreshold for separation of grade 2 and grade 3 lesions.he FNCLCC system is based on a score obtained by evaluating three parameters selected after multivariate analysis of several histological features: tumour dif- ferentiation, mitotic rate and amount of tumour necrosis . A score is attrib- uted independently to each parameter and the grade is obtained byadding the three attributed scores. Tumour differenti- ation is highly dependent on histologicaltype and subtype . The repro- ducibility of this system was tested by 15 pathologists: the crude proportion in agreement was 75% for tumour grade but only 61% for histological type Guillou et al performed a compar- ative study of the NCI and FNCLCC sys-tems on a subgroup of 410 patients. In univariate analysis both systems were of good prognostic value, although grade discrepancies were observed in 34% of the cases. In the NCI system, there were more grade 2 tumours, and use of the FNCLCC resulted in a better correlation with overall and metastasis-free survival. Because of some limitations and pitfalls of grading, some rules must be respect- ed in order to get the highest perform- ance and reproducibility of the system: >Grading should be used only for untreated primary soft tissue sarcomas. >Grading should be performed on rep- resentative and well processed material. >Grading is not a substitute for a histological diagnosis and does not dif- ferentiate benign and malignant lesions, and, before grading a soft tissue lesion, one must be sure that one is dealing with a true sarcoma and not a pseu- dosarcoma. >Grading is not applicable to all types of soft tissue sarcoma. Because of the over- all rarity of STS, grade is used on the whole group of sarcomas consid- ered as a single entity, but the significance of the histological parameters used in grading systems differs for vari- ous sarcomas. Therefore, grade is of no prognostic value for some histological types, such as MPNST and its use is not recommended for angiosar- coma, extraskeletal myxoid chondrosar-coma, alveolar soft part sarcoma, clear cell sarcoma and epithelioid sarcoma . In a recent study , it was shown that the FNCLCC grading was the most important predictive factor for metastasis for pleomorphic sarco- mas, unclassified sarcomas and syn- ovial sarcomas and the second and third independent factor for leiomyosar- comas and liposarcomas. Parameters of grading must be carefully evaluated and, particularly, mitosis counting should be done rigorously. Staging Staging of soft tissue sarcomas is based on both histological and clinical informa- tion. The major staging system used for STS was developed by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) and appears to be clinically use- ful and of prognostic value. This TNM system incorporates histological grade as well as tumour size and depth, region- al lymph node involvement and distantmetastasis. It accommodates 2, 3, 4- tiered grading systems.

Treatment
In general, treatment for soft tissue tumors depends on the stage of the tumor. Tumor stage based on the size and extent of the tumor. Treatment options for soft tissue tumors include surgery, radiation therapy, and chemotherapy.
• Therapy Surgery (Surgical Therapy).
Surgery is the most common treatment for soft tissue tumors. If possible, the doctor will remove the cancer and a safe margin of healthy tissue around it. It is important to obtain tumor-free margins to reduce the likelihood of local recurrence and provide the best for the eradication of the tumor. Depending on the size and location of the tumor, may, rarely, be required to remove all or part of an arm or leg.
• Radiation therapy
Radiation therapy can be used for both operations shrink tumors before or after surgery to kill any cancer cells that might remain. In some cases, it can be used to treat tumors that can not be removed surgically. In some studies, radiation therapy has been found to improve the local level, but no one has an effect on the whole of life.
• Chemotherapy
Chemotherapy can be used with radiation therapy, either before or after surgery to try to hide in the tumor or kill any remaining cancer cells. The use of chemotherapy to prevent the spread of soft tissue tumors has not been proven to be more effective. If the cancer has spread to other areas of the body, chemotherapy may be used for Shrink tumors and reduce pain and anxiety they cause, but it is not possible to eradicate the disease.

Prognosis

Prognosis depends on:
• Size of tumor
• Location of the tumor
• Depth of tumor
• The degree of malignancy
• cell necrosis (assessed at histopathologic examination)

5 Years Survival Rate
Stage I: Low Grade 85-90%
Stage II: High Grade 70 -80%
Stage III: Hugh Grade 45-55%
Stage IV: Any Grade 0-20%

LITERATURE

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4. Staf Pengajar Bagian Ilmu Bedah Fakultas Kedokteran Universitas Indonesia.  2011. Kumpulan Kuliah Ilmu Bedah. Jakarta.
5. Utama HSY. 2012. Soft Tissue Tumor Diagnosis and Management. Available online at http://www.dokterbedahherryyudha.com/2012/07/soft-tissue-tumor-diagnosis-and.html (diakses 10 Mei 2013).