Soft tissue sarcomas and rare soft tissue tumours – Brief information

Author:  Maria Yiallouros, Editor:  Maria Yiallouros, Reviewer:  PD Dr. med. Monika Sparber-Sauer, English Translation:  Dr. med. Gesche Riabowol (nee Tallen), Last modification: 2024/04/16 https://dx.doi.org/10.1591/poh.patinfo.weichteiltumor.kurz.20101215

General information on the disease

The term soft tissue tumours includes a variety of very different diseases that all share having developed due to a malignant transformation (degeneration) of immature precursor cells of soft tissue‎s.

Soft tissues, however, include different tissue types such as muscles, fatty and connective tissues as well as blood vessels and tissue of the peripheral nervous system‎. Therefore, different types of soft tissue tumours exist. They differ with regard to their histological‎ structure and the type of cell‎s they arise from, and they also have different frequencies and biological behaviour. This means, for example, that they present with different growth rates and spread patterns (metastasis), or respond to treatment, such as chemotherapy‎, differently.

Soft tissue tumours can be benign, malignant or medium grade (intermediate) malignant. Usually, malignant soft tissue tumours are called soft tissue sarcomas; the term “soft tissue tumour” is rather neutral and refers to any type of tumour behaviour. “Soft tissue tumours“ and "soft tissue sarcomas“ summarize at least 150 different histological tumour types (entities).

Most soft tissue sarcomas are highly malignant; they grow and spread rapidly and, hence, are lethal within a few weeks or months, if not treated appropriately. The majority of the less frequent soft tissue tumours, however, is of intermediate malignancy or partially even benign. The growth pattern of these tumours varies; they can do both, spontaneously regress or locally grow very aggressively.

Incidence

Soft tissue tumours account for about 6 % of all malignant diseases in childhood and adolescence, thereby representing one of the most frequent solid tumour‎ types in this age group, following tumours of the central nervous system‎ (CNS tumours, brain tumours). According to the German Childhood Cancer Registry (Mainz), about 10 out of 1,000,000 (a total of approximately 125) children and adolescents between 0 and 17 years are diagnosed with a soft tissue tumour each year. More than half of these patients present with rhabdomyosarcoma‎, the most frequent soft tissue sarcoma in childhood and adolescence.

Soft tissue tumours are most frequent in children younger than five or six years of age. The average age at diagnosis is 8.5 years. Boys are slightly more affected than girls (gender ratio: 1.3 : 1). However, both age distribution and gender ratio differ very much depending on the type of soft tissue tumour.

The most frequent soft tissue sarcomas – that is to say, malignant soft tissue tumours – in children and adolecents under 18 years of age are:

• rhabdomyosarcoma (RMS): 61 %
• extraosseal tumours of the Ewing-group: 16 %
• synovial sarcoma (SySa): 7 %
• fibrosarcoma (FS): etwa 3 %
• leiomyosarcoma (LMS): etwa 2 %
• undifferenciated sarcomas (UDS): 2 %

All other soft tissue sarcomas are rather rare in childhood and adolescence.

Tumour types

There are multiple variants of soft tissue tumours, including more than 20 different types of soft tissue sarcomas.

As per currently valid clinical classification, soft tissue tumours are divided into three large groups:

• rhabdomyosarcomas (RMS)
• non-rhabdomyosarcoma soft tissue sarcomas (NRSTS)
• rare soft tissue tumours

Note: the „Cooperative Weichteilsarkom-Studiengruppe (CWS, German for „Cooperative Soft Tissue Sarcoma Study Group“) of the Society for Paediatric Oncology and Haematology (GPOH‎) differentiates within the CWS Guidance (status 2014) an additional group based on their clinical behaviour and treatment approach: the so-called rhabdomyosarcoma-like (RMS-like) soft tissue sarcomas. Two tumours assigned to this group (synovial sarcomas and undifferentiated sarcomas) are now included in the NRSTS group – both in Europe and the CWS Study Group.

According to the WHO‎, extraosseal tumours of the Ewing group (Ewing sarcomas originating from soft tissues) – which were previously also called “RMS-like” tumours – belong to the main group of Ewing sarcomas and are being treated as per therapy concepts of the Ewing group. Due to the identification of multiple (new) genetic markers, the classification of soft tissue tumours and sarcomas is currently in transition and hence, the term “RMS-like” is being abandoned.

The following paragraphs will provide more information on the three groups of soft tissue sarcomas.

Rhabdomyosarcoma (RMS)

For a long time, rhabdomyosarcoma‎s (RMS) have been divided into two major groups based on their microscopic (histological) appearance: embryonal RMS (ERMS) and alveolar RMS (ARMS). Aside from their different histological‎ features, the two RMS types usually also show different characteristics regarding their growth pattern (localisation, extent, spread) as well as regarding age distribution and prognosis: embryonal RMS particularly affect children under 10 years of age and are mostly associated with a favourable outcome when compared to alveolar RMS, the incidence of which increases in children older than 10 years.

It is well-known by now that the course of the disease is mainly impacted by the molecular genetic‎ characteristics of the tumour cells. Hence, there are genetic alterations, so-called fusion genes, whose presence is associated with an unfavourable prognosis‎. This is, for example, the case for a typical fusion in the PAX-FOXO gene, which can be found in the majority of alveolar RMS (but not in embryonal RMS); the affected ARMS are also called fusion-positive RMS, whereas RMS lacking this specific PAX-FOXO gene fusion are called fusion-negative. However, in the meantime, additional alterations have been identified that can cause high malignancy in fusion-negative RMS, too.

Important to know: today, RMS are not primarily assessed based on their histological features, but rather on the presence or lack of genetic alterations. Genetic characterization of the tumours therefore plays a major role when assessing the probability of survival and choosing the appropriate treatment approach.

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS)

The non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) represent a rather heterogenous group of soft tissue sarcomas, which differ regarding multiple aspects, such as their growth behaviour, sensitivity to chemotherapy (chemosensitivity) and outcomes.

For example, alveolar soft tissue sarcoma, epitheloid sarcoma, malignant peripheral nerve sheath tumour, fibrosarcoma and leiomyosarcoma all belong to the group of NRSTS. Since these tumours may develop in adults, too, they are also known as „adult type NRSTS“. NRSTS also include those tumours that were previously called “RMS-like soft tissue sarcomas” by the CWS Study Group), based on their chemosensitivity and thus treatment, which are similar to that of rhabdomyosarcoma: the synovial sarcomas and the undifferentiated sarcomas (see chapter “Tumour types”).

Rare tumours

The group of the "rare soft tissue tumours” includes tumour types with malignant, medium-grade (intermediate) malignant or benign biological behaviour. Due to their extreme rarity, they are summarized, despite of their different growth patterns and degrees of malignancies. Rare soft tissue tumours are myofibromatosis, desmoid-type fibromatosis (DTF), inflammatory myofibroblastic tumour (IMT), gastrointestinal stromal tumour (GIST) and many more. Based on the tumour type, there are individual treatment concepts for each of these rare diseases.

Localisation and spread

Soft tissue tumours may generally develop anywhere in the human body, since there is soft tissue everywhere. The tumours usually spread along certain anatomical structures, for example along muscle sheaths, ligaments or blood vessels. In the course of this, single cells may detach from the primary tumour‎ and spread to other body sites via the blood and/or lymph stream. They can settle there and start multiplying again; daughter tumours are developing (metastasis‎). Metastases of soft tissue sarcomas particularly occur in the lungs, in adjacent lymph nodes‎ and in the bones. Other organs can be affected as well.

Origin and growth behaviour of soft tissue tumours are strongly associated with the tumour type.

Rhabdomyosarcomas, for example, can generally develop in almost every organ, however, most frequently, they are found in the head-and-neck area, the urinary tract and reproductive organs as well as the extremities. Usually, fusion-positive alveolar rhabdomyosarcomas (ARMS) show a more aggressive behaviour compared to embryonal rhabdomyosarcomas (ERMS), meaning that they frequently grow and spread faster via the blood and/or lymph stream. Also, fusion-positive ARMS are associated with a higher risk of recurrent disease than most ERMS.

Extraossear tumours of the Ewing group – which, according to their naming, grow outside any body tissue – mostly develop in the area of the trunc and extremities. Synovial sarcomas occur most frequently close to joints in the extremities as well as in the head-and-neck area. All these tumour types tend to metastasize early. About 20 % of patients with a soft tissue sarcoma present with distant metastases already at the time of diagnosis.

Causes

The causes for the development of soft tissue tumours are not completely understood as of today. The assumption is that they originate from precursor cells of the connective tissue (soft tissue). In medical jargon, these cells are called „mesenchymal stem cells‎“. The malignant transformation is most certainly initiated by genetic‎ and/or chromosomal aberrations in these cells.

Different genetic and chromosomal aberrations have already been identified in the malignantly transformed cells, however, these happen to be quite heterogenous, do vary depending on the type of soft tissue tumour and are not regularly found in all tumours after all. Overall, multiple genetic alterations are most certainly responsible for the development of a soft tissue tumour. According to current research, most patients do not have any hereditary predisposition.

However, there are families presenting with high incidences of rhabdomyosarcoma in multiple generations. Also, children present with rhabdomyosarcoma more frequently in families with a frequent history of carcinoma‎. These observations indicate that those patients have a genetic predisposition to develop this disease, a so-called cancer predisposition syndrome‎ (CPS). These are complex diseases which are characterized by various kinds of developmental abnormalities and an elevated inherited risk to develop cancer. Cancer predisposition syndromes that are known to play a role in the development of a soft tissue tumour are, for example, neurofibromatosis‎, the Beckwith-Wiedemann syndrome‎, the Li-Fraumeni syndrome‎, the Gorlin-Goltz syndrome‎ and the Werner`s syndrome‎.

Also, there are indications that certain external factors increase the risk to develop soft tissue tumour. These include radiation exposure‎ of the unborn (for example by X-rays‎ or radiation therapy‎ received by the mother), alcohol or other parental drug abuse prior to or during pregnancy, respectively, as well as early radiotherapy of the child. Associations with viral infection‎s have been reported as well. Hence, HIV‎-positive, thus immunosuppressed children have an increased risk of developing leiomyosarcoma following an infection with the Epstein-Barr virus‎ (EBV).

For most patients with soft tissue tumour, no risk factors have been identified yet.

Symptoms

The symptoms of patients with soft tissue tumour depend on the site and the extent of the tumour and are therefore quite diverse. To name only a few of the frequent, representative symptoms here:

• Soft tissue tumours developing close to the surface often cause a continuously increasing swelling and/or pain. Both are not infrequently wrongly referred to as, for example, exercise-induced trauma. Also, they may cause a dysfunction of the affected organ, such as limited range of motion in arms and legs.
• A soft tissue tumour of the orbita may initially present with a painless bulging of the eye anteriorly out of the orbit (exophthalmus‎) and a swelling of the eyelid; later it usually causes pain because of the increased local pressure. Vision impairment is also possible.
• Soft tissue tumours of the nose are often associated with a long history of congestion or sniffle at the timepoint of diagnosis.
• In case the skull base is involved, cranial nerve impairments may occur, which present as facial nerve palsy or double vision.
• Tumours of the urinary tract and reproductive organs may present with general malaise, constipation and/or impaired urination, vaginal bleeds, blood in the urine and pain, however, usually once the tumour is already quite large

As for other parts of the body, soft tissue tumours are often getting noticed only because of their palpable or visible tumour mass, for example during a routine physical exam at the paediatrician or by imaging‎ diagnostics such as an ultrasound‎. They often do not cause any complaints, meaning that the patients feel good.

Children and adolescents with complaints as described above do, of course, not always necessarily have soft tissue tumour or any other malignant tumour. Nevertheless, it is strongly recommended to have the cause of such symptom‎s be evaluated by an experienced paediatrician.

Good to know: in case of suspected soft tissue tumour, the paediatrician should refer the patient to a treatment centre that is specialized on cancer in children and adolescents (paediatric oncology / haematology program). Initial diagnostic tests (imaging procedures or biopsy, respectively) that are done elsewhere often turn out insufficient and, thus, may negatively impact appropriate treatment and also the patient’s prognosis (chance of cure).

Diagnosis

If the doctor thinks that the young patient’s history and physical exam are suspicious of a soft tissue tumour, the child should immediately be referred to a hospital with a childhood cancer program (paediatric oncology unit), where further diagnostics can be initiated and performed by childhood cancer professionals. Very close collaboration between various specialists (such as paediatric oncologist‎s, paediatric surgeons, paediatric radiologist‎s, to name a few) is required both to find out whether the patient really suffers from a soft tissue tumour and, if so, to determine the tumour type and the extension of the disease. Knowing these details is absolutely essential for optimal treatment planning and prognosis‎. Diagnostic management follows the European guidelines as well as the trial recommendations of the CWS Study Group, the Society of Paediatric Oncology and Haematology (GPOH‎), and the "European pediatric Soft tissue Sarcoma Study Group“ (EpSSG), the latter of which is the merger of the European study groups.

Diagnostic imaging

Apart from comprehensive medical history taking (anamnesis‎) and physical examination‎, imaging‎ procedures – preferably a magnetic resonance imaging‎ (MRI) with and without contrast agent‎ – play a major role in soft tissue tumour diagnostics. First of all, they serve to assess or rule out a tumour. Also, the localization, size and volume of a tumour as well as its demarcation with regard to adjacent tissue (such as organs, blood vessels and nerves) or any tumour-induced changes of the bone system can be diagnosed by such imaging techniques very well.

Tissue extraction (biopsy) to confirm diagnosis

For final confirmation of the diagnosis, tumour tissue is required to be removed (biopsy), even if the tumour may be benign (as is the case with a lipoma‎ or haemangioma‎, for example). The biopsy‎ should only be performed by doctors who are specialized in surgery of sarcomas.

The obtained samples are subsequently analysed histological‎ly, immunohistochemical‎ly and genetic‎ally by specialists, with molecular genetic‎ tests becoming more and more important. The analyses serve to confirm the diagnosis of a soft tissue tumour and, once confirmed, to determine the subtype. For this, a very comprehensive characterization of soft tissue tumours will be available soon, which will make individualized (meaning tailored) therapies for single patients possible. Hence, analysis and research on tumour tissue is crucial.

Since the disease is overall rare, the obtained tissue samples should not only be studied by the local pathologist‎, but should also be sent to a reference centre for paediatric pathology – such as the reference pathologist of the CWS Study Group of the GPOH‎ in Bonn. Such a centre receives tissue samples of a certain tumours from all over Germany and therefore provides special experience with the assessment. The diagnosis is further confirmed by an additional molecular genetic analysis promoting superior tumour characterization, thereby providing relevant directions for the treatment.

Note: for molecular genetic analysis, fresh frozen tumour tissue is implicitly required. Therefore, it is crucial that the biopsy is taken in a centre that is specialized in paediatric oncology, where both the expertise and the facilities to process the tumour samples are adequately given. Remaining samples will be stored in the tumour bank and may be used for research aiming at treatment optimisation of these tumours.

Tests to assess spread of disease (staging)

Once the diagnosis of "soft tissue sarcoma" or "(intermediate) malignant soft tissue tumour" has been confirmed, further tests are required to find out if and to which extent the cancer has spread and which organs are involved. Since especially soft tissue sarcomas predominantly develop metastases in the lungs [see metastasis‎], a chest X-ray examination‎ as well as a computed tomography‎ (CT) of the chest are indispensable. In addition, a magnetic resonance imaging‎ (MRI) is performed to assess or, respectively, rule out metastases in the abdominal and pelvic region or the brain.

For all high-grade malignant soft tissue sarcomas (G3 sarcomas), a bone marrow puncture‎ is done to rule out bone marrow‎ involvement. Depending on the disease and treatment situation, additional tests to diagnose and/or further assess metastases may be done, such as an ultrasound‎ or a lumbar puncture‎ (to analyze the cerebrospinal fluid‎ when dealing with skull base or spinal tumours), a total body MRI and/or a positron emission tomography‎ (PET).

The positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) is meanwhile increasingly used – combined with MRI (PET-MRI) or CT (PET-CT) – for children and adolescents with suspected metastases. Its advantage is that, aside from bone, it can also detect soft tissue metastases. So far, PET has not been established in every treatment centre, and its benefits for soft tissue sarcomas are still being examined.

Tests before treatment begins

Before treatment begins, further tests are needed in order to assess the condition of different organs. Therefore, the doctors will recommend an electrocardiography‎ (ECG) as well as an ultrasound of the heart (echocardiography‎), an electroencephalography‎ (EEC), a hearing test (audiometry‎), special diagnostics for determining kidney and lung functions as well as various blood tests. Any changes occurring during the course of treatment can be assessed and managed better based on the results of those initial tests, which thus help to keep the risk of certain treatment-related side effects as low as possible.

Good to know: Not all the tests listed above need to be done for every patient. Contrariwise, the patient’s individual situation may require additional diagnostic procedures that have not been mentioned in this chapter. Therefore, you should always ask your doctor, based on the information above, which test your child needs and why.

Treatment planning

After the diagnosis has been confirmed and the spread of the disease has been assessed, therapy is planned. In order to design a highly individual, risk-adapted treatment regimen for the patient, certain individual factors influencing the patient’s prognosis‎ (called risk factors or prognostic factors‎) are being considered before and during treatment (risk-adapted treatment strategy).

Important prognostic factors are, for example, the type, the localisation, size and spread of the tumour. In addition, the patient’s age has an impact on treatment planning.

• The type of the tumour (meaning its fine tissue features (histology‎) and genetic‎ characteristics) impacts, amongst other factors, how fast the tumour grows and how the disease will respond to chemotherapy‎ or another kind of systemic‎ therapy (such as “new agent therapies”): there are, for example, chemosensitive and chemoinsensitive soft tissue sarcomas. The tumour type also impacts the risk of metastasis‎ and the probability of relapse. Experts accordingly differentiate between soft tissue sarcomas with favourable and with unfavourable histology or genetics, respectively (see also chapter “Tumour types”).
• The site, size and extent of the tumour (including potential lymph node involvement and metastases) determine the options of surgical tumour removal and radiation therapy‎ (radiotherapy).
• The patient’s age is also considered for the decision with regard to systemic and/or radiotherapy. Hence, younger patients usually tolerate chemotherapy better than older children. For children under the age of three years (in particular under one year), radiotherapy is only rarely given, but still an option in individual cases.

All these factors are included in treatment planning in order to achieve the best outcome possible for each patient, while keeping the risks of side effects and long-term sequelae as low as possible.

Patients with rhabdomyosarcoma are –– depending on whether their prognosis has been considered to be favourable or less favourable – assigned to different risk groups during therapy planning (low-risk group, standard-risk group, high-risk group), thus being treated according to different treatment plans. In Germany and other European countries, the differentiation according to risk groups with associated treatment plans is carried out according to the recommendations of the „European pediatric Soft tissue Sarcoma Study Group“ (EpSSG) and the „Cooperative Weichteilsarkom Studiengruppe“ (CWS Study Group).

Treatment

Treatment of children and adolescents with soft tissue tumour should take place in a children's hospital with a paediatric oncology program. Only such a childhood cancer centre provides highly experienced and qualified staff (doctors, nurses and many more), since they are specialised and focussed on the diagnostics and treatment of children and teenagers with cancer according to the most advanced treatment concepts. The doctors in these centres collaborate closely with each other. Together, they treat their patients according to treatment plans (protocols) that are continuously optimised.

The goal of treatment is to eliminate the cancer while keeping the risk of side effects and late sequelae as low as possible.

Treatment methods

Treatment options for children and adolescents with soft tissue sarcomas or rare soft tissue tumours include surgery, radiotherapy, systemic therapy (such as chemotherapy or a so-called “new agent” therapy) or a combination of those, respectively.

Individual treatment (meaning which types of therapy to be applied and in which order) depends in particular on the microscopical and molecular genetic‎ tumour type, the localisation of the tumour, as well as on the patient’s age. Treatment is also adapted to the extent of the tumour as well as to its surgical accessibility and sensitivity to chemotherapy (see chapter „Treatment planning“ above). Since the treatment of soft tissue tumours can be associated with side effects, supportive treatment measures (supportive therapy‎) are also applied to prevent and/or treat these side effects. Here your will find further information on supportive care as well as on recommendations for home, the latter of which may be helpful during or after chemo- and radiotherapy.

Chemotherapy

Chemotherapy includes treatment with agents (so-called cytostatic agents or cytostatics‎), which inhibit cell growth, thereby contributing to eliminating the tumour and potentially existent metastases. In order to eliminate as many of the cancer cells as possible (even those that cannot be detected by diagnostic imaging techniques such as magnetic resonance imaging‎), a combination of cell and, thus, tumour growth inhibiting agents that have proven to be efficient in treating soft tissue sarcomas/tumours are used.

Frequently-used agents for rhabdomyosarcomas are, for example, actinomycin D (also known as dactinomycin), vincristine, cyclophosphamide, ifosfamide and doxorubicin (= adriamycin), in case of insufficient treatment response or in high-risk patients other agents, too. The combination of agents as well as their dosages and the duration of treatment vary depending on treatment or risk group. The cytostatic agents are given in multiple chemotherapy‎ cycles with treatment pauses in between, which serve the patient’s recovery.

Local therapy

In addition to chemotherapy, local tumour control is provided by surgery‎ and sometimes radiation therapy‎. Surgical tumour removal may be performed both prior and after chemotherapy (primary or late resection, respectively), a potentially necessary radiotherapy either prior or after surgery (pre- or postoperative radiation). The CWS study centre and the CWS reference experts will help the local caregiver team with decision-making regarding the treatment approaches for individual patients. For certain patient groups with rhabdomyosarcoma, the optimal treatment design will be evaluated in the framework of a new study (FaR-RMS).

Surgery

Surgery aims at complete tumour removal. Hence, it is frequently scheduled later in the treatment plan, in fact, after the tumour volume has been decreased by chemotherapy (experts call this „late resection“). This particularly applies to soft tissue sarcomas that are known to be very responsive to chemotherapy, which hence allows to expect tumour shrinkage. These tumours include rhabdomyosarcomas and some other tumours behaving like RMS (therefore previously also called ”RMS-like soft tissue sarcomas“).

Surgery as the first treatment choice (primary tumour resection) is usually per-formed only when, based on diagnostic imaging results, total gross tumour resection is possible without damaging healthy tissue. This is limited to very small tumours with favourable location. For patients with tumours less responsive to chemotherapy, primary surgery may also be an option as long as it is doable.

Surgery is carefully planned in the local treatment centre by representatives of all participating disciplines (paediatric oncologist‎s, surgeons, radiotherapists, radiologist‎s). The CWS study centre and the CWS reference expert group are standing by for advice. Since soft tissue sarcomas are rare, surgical treatments should only be performed in a centre with long-standing sarcoma experience.

Radiotherapy

Radiotherapy is done using energy-rich, electromagnetic‎ radiation, given through the skin to the tumour region. Radiation causes DNA‎ damage in tumour cells, thereby leading to cell death.

Radiotherapy is a very efficient treatment method for patients with eventually remaining soft tissue tumour tissue following surgery. It is a particularly favourable approach when surgery is not an option, for example for patients with rabdomyosarcoma in the head and neck area. Also, patients with a site-associated high risk of tumour spread (for example patients with rhabdomyosarcoma close to the meninges‎ or inside the orbita) should receive radiation therapy‎. Patients with rhabdomyosarcoma (RMS) or a non-RMS-like soft tissue sarcoma (NRSTS) whose tumour could be resected completely by primary surgery do not require radiotherapy.

The radiation dose is calculated based on the tumour type, its localisation and extent, its response to chemotherapy as well as its surgical resectability. Conventional treatment uses total radiation doses of about 40-50 gray‎ (Gy), given in single daily doses of 1.8-2 Gy. For individual cases, modern radiation techniques such as the so-called intensity-modulated radiotherapy (imrt) may be favourable. For certain tumour sites or age groups, proton therapy is increasingly used.

New therapy options – "new agent“ therapies

The term “new-agent“ therapy summarizes new types of systemic‎ therapies (system therapies). These include targeted treatments with new agents that work in a different way compared to chemotherapy. There is already a variety of promising medications, however, their use within the childhood population is mostly still limited to individual treatment settings.

Example: an already licensed targeted therapy for soft tissue tumours is the use of the NTRK-inhibitor‎ Larotrectinib for patients with a so-called NTRK-positive infantile fibrosarcoma (a non-rhabdomyosarcoma-like soft tissue sarcoma, NRSTS). These patients have a NTRK gene fusion (NTRK is the abbreviation for neurotrophic tyrosine receptor kinase), which can be inhibited by Larotrectinib. The agent is the treatment of choice for metastatic disease and is even an option for tumours that are not surgically resectable. However, since data regarding length of treatment, development of resistance‎ and long-term sequelae are still limited, the use of these agents versus the option of chemotherapy requires careful consideration. Children with this disease have been treated with chemotherapy and surgery for many years and show excellent prognosis.

Good to know: future studies using these kinds of agents are being planned. The treatment of children according to such studies should definitely be given preference over any individualized treatment regimen. Only in this way can valid data be acquired that will serve to optimise future therapies.

Treatment of patients with rhabdomyosarcoma (RMS)

In Germany and other European countries, patients with rhabdomyosarcoma (RMS) are treated according to recommendations of the “European pediatric Soft tissue Sarcoma Study Group” (EpSSG) and the “Cooperative Weichteil-sarkom-Studiengruppe” (CWS).

Depending on the patient’s risk factors, rhabdomyosarcoma are divided into four different risk groups: one low-risk group, one standard-risk group and two high-risk groups. The upcoming European treatment guideline (ERN-Guidance) is considering a joint “very high risk-group” (VHR) for high-risk patients – such as patients with alveolar rhabdomyosarcoma with lymph node involvement (lymph node positive ARMS) or patients with metastasized RMS disease.

Treatment for the different risk groups is as follows:

• Low-risk group: for the low-risk group, treatment consists of total gross tumour resection and a chemotherapy with the agents vincristine and actinomycin D (dactinomycin) for about 22 weeks.
• Standard-risk group: in the standard-risk group, surgery and chemotherapy are also done; the latter includes, aside from vincristine and actinomycin D, additionally ifosfamide, and most patients also receive radiotherapy (time of therapy about 25 weeks). .
• High-risk groups: in both high-risk groups, surgical tumour removal is planned either prior to chemotherapy or later, depending on the site and extent of the tumour. All patients in these groups receive radiotherapy. Chemotherapy includes ifosfamide, vincristine, actinomycin D, and sometimes doxorubicin (adriamycin) and takes about 25 weeks. As mentioned above, RMS patients with metastases will be included in the one high-risk group according to the ERN Guidance in the future.

Treatment of patients with non-RMS soft tissue sarcoma (NRSTS)

The wide variety of tumours in the group of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) is not only mirrored by their growth pattern, malignancy, operability and chemosensitivity; it also impacts the type of treatment to be considered for the individual patient:

There are NRSTS that are about as chemosensitive as rhabdomyosarcomas, for example the synovial sarcomas and the undifferentiated sarcomas. Patients with these tumour types (also called “RMS-like soft tissue sarcomas” in the past) are treated quite similarly to high-risk patients with RMS (see chapter „Treatment of patients with rhabdomyosarcoma“). The treatment takes about 25 weeks, depending on the therapy group.

A large group of the rare NRSTS, the so-called „adult-type“ NRSTS (named that way because they also appear in adults) are often not chemosensitive. New treatment options are currently tested for patients with these tumours, mainly in the framework of new trials (see chapter “New agent therapy” above). Some other of these rare NRSTS are rather benign; treatment in this case involves mainly a so-called extended resection, which is defined by surgical removal of the tumour with a certain safety distance, meaning removal of adjacent tissue surrounding the tumour. For some patients with NRSTS, the type of treatment also depends on the size of the tumour and the success of surgery.

Important to know: the treatment spectrum for this inhomogenous disease group is quite large, and new treatment options are being tested. Your caregiver team will explain to you, which therapy options exist for you/your child.

Treatment of patients with rare soft tissue tumours

Treatment of patients with a rare (frequently intermediate malignant or benign) soft tissue tumour mainly depends on its growth pattern. For tumours growing locally very aggressively (this can be the case for both benign and intermediate malignant tumours), surgery aiming at tumour removal is not always the first choice of treatment. For most of these tumours, the doctors will wait and see whether growth is ongoing, since spontaneous tumour regression is possible as well. If this does not happen or if the localisation of the tumour jeopardizes adjacent organs, a low-dose chemotherapy, depending on the tumor type, is indicated. By now, even newer, so-called targeted therapies (that consider the individual genetic alterations) are an option as well.

Treatment of RMS patients with metastases or relapse

According to the current CWS Guidance and the upcoming European ERN Guidance, patients with metastatic disease [see metastasis‎] of rhabdomyosarcoma receive chemotherapy. Local treatment (radiotherapy, surgery) plays an important role.

According to the current CWS Guidance and the upcoming European ERN Guidance, patients with metastatic disease of rhabdomyosarcoma receive chemotherapy. Local treatment (radiotherapy, surgery) plays an important role. These are either given as pills (orally) or intravenous‎ly once a week, so that treatment can almost exclusively be done on an outpatient basis. Total duration of therapy takes about one year; the upcoming trial FaR-RMS is testing the efficacy of an extended maintenance to up to 24 months. In general, an oral-only maintenance therapy as per CWS Guidance with the agents trofosfamide and etoposide (in short: O-TIE) is an option, too; in this case, treatment will take about a year or even longer in individual situations.

Patients with a particularly unfavourable prognosis can participate in so-called experimental trials. Your caregiver team will inform you whether one of those experimental treatment approaches is an option for your child. For patients whose disease does not respond to chemotherapy or with a recurrent disease, treatment is based on the frontline therapy. Usually, different and partially new agents are given that are not necessarily part of the standard treatment plans, but allow hope based on most recent research results.

Therapy optimising trials and registries

In the large paediatriac treatment centres, children and adolescents with a soft tissue tumour receive therapy according to standardised treatment plans (protocols). These protocols are designed by experts and aim at steadily improving the patients’ survival rates while also reducing the risk of therapy-related late effects. Therapy according to such treatment protocols is carried out within „therapy optimising trial‎s“. These are controlled clinical trials, which have been developed, are being monitored and adjusted to the most recent research by the Society of Paediatric Oncology and Haematology (“Gesellschaft für Pädiatrische Onkologie und Hämatologie“, GPOH‎‎).

For patients who are not being treated within a trial (such as the upcoming trial FaR-RMS), there is a registry („SoTiSaR / from 2024 SoTiSAR 2.0“) to collect all relevant patient data. These patients receive the currently recommended standard treatment, so far as per CWS Guidance (guidance of the CWS Study Centre), in the future as per European guidance (ERN Guidance) for patients with rhabdomyosarcoma. In addition, a randomized study („CWS-2007 HR“) had been available for certain patients until 30/06/2019. The opening of a new trial for patients with rhabdomyosarcoma or relapsed rhabdomyosarcoma (FaR-RMS) is considered to start in 2023/2024.

For further information on above-mentioned registries and guidelines, please see here. Details are available on the website of the CWS Study Group: https://www.klinikum-stuttgart.de/cws/home

Prognosis

Prognosis for children and adolescents with a soft tissue tumour depends on multiple factors. Most relevant are the type, localisation and size of the tumour, its spread, operability (resectability) and the patient’s age.

Over the past four decades, prognosis‎ for patients with soft tissue tumour has improved drastically due to standardised treatment based on therapy optimising trial‎s. At the end of the 70s, still only 30 to 40 % of all children survived, while the 10-year survival rate is now a bit over 70 % due to continuous treatment optimisation.

In favourable constellations, long-term survival can be observed in over 80 % of patients, while the chance of long-term cure decreases for patients with large, inoperable tumours at diagnosis. Similar, even more unfavourable outcomes have been reported for patients presenting with lymph node involvement and/or spread into other body sites at the time of diagnosis. For example, for patients with a metastasised RMS-like soft tissue sarcoma, the 5-year-survival rate is currently 30 %. Various studies aim at improving the prognosis for these patients as well.

Note: The above-mentioned numbers are statistical values. Therefore, they only provide information on the total cohort of patients with these types of tumour. They do not predict individual outcomes. Please ask the doctor, who is responsible for your child, for competent information on the individual prognosis

Brief information on soft tissue sarcomas and soft tissue tumours (504KB)
Author: Maria Yiallouros
glossary added 18/03/2024