Soft tissue sarcoma in children
I. Rhabdomyosarcoma
Rhabdomyosarcoma is the most common type of soft tissue malignant tumor in children and is extremely malignant, accounting for 10% of solid malignant tumors in children. 70% of cases are under 10 years old, with peak incidence between 2 and 5 years old, accounting for 1/3 of all cases, and there are also neonatal cases, with equal incidence in both sexes.
1.Pathological classification
Rhabdomyosarcoma originates from mesenchymal tissues, and its original tissue is rhabdomyoblast, which can occur in various parts of the body, with head and neck and genitourinary organs being the most prevalent. Among them, orbital and temporal areas, bladder, prostate, paratesticular tissue, vagina and uterus are the most common, followed by extremities, trunk, retroperitoneum, and rare sites such as bile duct, lung, gallbladder, kidney, and greater omentum. Yao Yuan, Department of Radiotherapy, North Hospital of the Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine
There are four types according to the World Health Organization classification: in children mostly embryonic type and glandular alveolar type, which together are called pediatric type; polymorphic type, which is adult type; and the mixture of both is called mixed type.
(1) Embryonic type: 50-80% of children under 5 years of age are mainly of this type. About 75% of head and neck and genitourinary tumors are of this type. It has the best prognosis.
(2) Glandular alveolar type: It accounts for about 20% and is a common type above 6 years old. It is common in the trunk, limbs and perineum and has the worst prognosis.
(3) Polymorphic type: only 1%, mostly in the limbs and trunk, with a poor prognosis.
(4) Mixed type: Most of them are a mixture of embryonic type and glandular follicle type, with a poor prognosis.
Transverse myosarcoma mostly invades the surrounding tissues and organs directly and is mainly hematogenous, but also lymphatic metastasis. Lung and central nervous system are the most common, followed by lymph nodes, bone, liver and bone marrow.
2.Clinical stage
Stage I
The tumor is limited, completely resected, and the regional lymph nodes are not invaded.
Ia
Tumor is limited to the primary muscle and organs
Ib
Tumor infiltrates beyond the primary muscles and organs, such as through the fascial layer
Stage II
Tumor confined, completely resected under the naked eye
IIa
Resection of the primary tumor under the naked eye with microscopic residuals and no regional lymph node metastasis
IIb
Tumor confined, completely resected, with regional lymph node metastasis
IIc
Resection of primary tumor under the naked eye, with microscopic residue and regional lymph node metastasis
Stage III
Incomplete resection or biopsy with subsarcoid residue
Stage IV
distant metastasis at the time of diagnosis
Clinical manifestations: mainly present as a painless mass with progressive enlargement and poorly defined borders.
Diagnosis: There is no specific biological marker to detect rhabdomyosarcoma, and the diagnosis is only confirmed by histology.
3.Treatment principle
The current view is comprehensive treatment. The modern concept of rhabdomyosarcoma treatment: a combination of surgery and radiotherapy to control the primary tumor with nutritional support, and chemotherapy to eliminate micro metastases. As a result of this updated view, survival rates have improved from 20% in the past to nearly 70% currently.
Stage I tumors are mainly treated with radical surgery without postoperative radiotherapy, and VAC regimens are given for 2 years.
Stage II tumors are treated with surgery plus radiotherapy to the tumor bed, and VAC regimen for 2 years.
Stage III and IV tumors are treated with surgery plus tumor bed radiotherapy and shock dose VAC regimen or shock dose VADRC-VAC regimen for 2 years.
Surgical resection is required within a certain distance of normal tissues surrounding the tumor, and extensive radical resection of the primary tumor should be pursued as long as it does not cause severe disfigurement and functional impairment. The scope of resection is determined by the pathological type, growth site, infiltration range and metastasis of the tumor. As far as possible, the tumor should be extensively resected while preserving the limbs and functions, with a view to achieving clinical stage I and II in surgery. If the tumor is too large to be removed, radiotherapy (30Gy) and chemotherapy can be used first to shrink the tumor and then postpone the surgery. Surgery is performed about 3 weeks after radiotherapy.
Chemotherapy is necessary in all cases, and chemotherapy drugs and methods can be selected according to different clinical stages.
4.Radiotherapy
The effective radiation therapy dose should not be less than 40Gy, 40-45Gy for under 3 years old; 45-50Gy for 3-6 years old; 50-55Gy for over 6 years old, but 14-18Gy for whole lung irradiation and 30Gy for abdominal irradiation. 20-25cGy per day, 5d per week, 4-5 weeks. The irradiation field should include the tumor bed and the surrounding 1-5 cm of normal tissue, and attention should be paid to the protection of surrounding important structures. No lymph node metastasis is generally not irradiated for prophylaxis.
Other soft tissue tumors
Soft tissue sarcomas other than rhabdomyosarcoma are rare in children and adolescents, and if they occur, they have a better prognosis than adults. They have a better prognosis than adults.
1.Fibrosarcoma
Fibrosarcoma is rare and most common in pediatric and children before the age of 5 years. Most tumors occur in the distal part of the trunk and extremities. The differential diagnosis includes fibroblastic hyperplasia in pediatrics and children and fibrosarcoma in juveniles. Histologically, fibrosarcoma consists of mesenchymal spindle cells arranged in a “herringbone” shape, with abundant cells and marked filopodia. The five-year survival rate is 83-92% in children and pediatric patients, while the prognosis in older children is close to 60% in adults.
Management of fibrosarcoma in pediatric and children is extensive local excision, which often yields excellent results, but amputation is still necessary for large and extensive primary tumors. Chemotherapy and radiation have no definite efficacy.
2.Neurofibrosarcoma
Neurofibrosarcoma (malignant nerve sheath tumor) is a tumor that originates from the nerve sheath. In children, this tumor often coexists with neurofibromatosis, with the latter eventually developing into neurofibrosarcoma in 5-16% of cases. The disease is most commonly seen in the extremities, followed by the intra-abdominal and trunk regions. Localized lesions can be surgically removed and postoperative chemotherapy can give a better prognosis.
3.Smooth muscle sarcoma
Smooth muscle sarcoma in children is very rare. The frequent sites are retroperitoneum, blood vessels, peripheral soft tissues and gastrointestinal tract. The main differences between smooth muscle sarcoma and smooth muscle tumor are the abundance of tumor cells, atypia, mitosis, necrosis, mucinous changes, glassy changes, calcification and ulceration. The typical cells of this tumor are long prismatic, with abundant cytoplasm and a central nucleolus with blunt, “cigar smoke-like” terminals, and many nuclear divisions.
The standard management is extensive local excision. Smooth muscle sarcoma of the viscera has a worse prognosis than other parts of the body.
4.Liposarcoma
Liposarcoma in children is also a rare pediatric tumor. Compared to adults, most liposarcomas in children originate in the thigh, with other sites including the neck, chest, axilla, knee, and retroperitoneum. Histologically, liposarcomas appear mucinous. The cells are well differentiated and round in shape. It is important to distinguish liposarcoma from adipoblastosis, which is a benign nodular disease that does not infiltrate.
Management is extensive local excision, as this tumor occurs only as a local diffuse infiltrate and does not metastasize. The prognosis of this rare tumor is generally excellent.
5. Angioepithelial cell tumor
Hemangiopericytoma usually occurs in the soft tissues of the lower extremities, retroperitoneum or the epithelium around the blood vessels of the head and neck, and often metastasizes to the lungs and stomach. The clinical presentation of hemangioepithelial cell tumors in children is the same as that of adults. Management includes local surgical excision, radiation therapy and chemotherapy. There are generic chemotherapeutic agents including: vincristine, cyclophosphamide, actinomycin D, adriamycin, methotrexate and other alkylating compounds.
6.Vesicular soft tissue sarcoma
Vesicle-like soft tissue sarcoma is one of the rare malignant tumors in children, mostly occurring in the skeletal muscles of the extremities and predominantly in juvenile females. Ultrastructural studies have shown that the tumor histologically originates from neurons. Patients may present without any clinical complaints of discomfort or pain.
The primary management is complete resection of the primary lesion and postoperative radiotherapy plus alkylating compound chemotherapy. The long-term prognosis is poor, with a two-year survival rate of 80% and five- and ten-year survival rates of 50% and 45%, respectively. Lung, bone, brain, and lymph nodes are the common sites of metastasis.
Pediatric osteosarcoma
Pediatric osteosarcoma is a malignant tumor originating from bone tissue, which used to be called osteogenic sarcoma or osteogenic sarcoma because the tumor cells can directly produce tumor-like bone tissue; the incidence is highest in children during the period of vigorous bone growth and development or in adolescents with long growth and development. The age of occurrence is 10-15 years old, and boys have two times more than girls. It is most common in the long bone epiphysis of the limbs, with the lower end of femur being the most common, accounting for more than 50%; the upper tibia and upper humerus are the next most common, accounting for 10-20%; occasionally, it is found in the pelvis, spine and ribs. Among the malignant bone tumors in children, osteosarcoma is the most common, accounting for 6-8% of the malignant solid tumors in children.
1.Pathology
The pathology of osteosarcoma can be divided into four types: type I is mainly bone like tissue; type II has both bone like tissue and bone tissue; type III has no bone like tissue and bone tissue, only collagen fibers; type IV is rare and its main components are chondrocytes and poorly differentiated tumor cells with variable morphology. It is valuable to consider the pathological findings and clinical association. The rate of tumor growth, pathways of metastasis and survival time of the child cannot be estimated by pathological findings alone. The nucleus division is a marker to measure the speed of tumor growth, but it is not useful to estimate the prognosis.
2.Clinical manifestations
The first symptom is local pain and persistent, especially at night. The first symptom is local pain and persistent, especially at night, followed by local swelling or lump with hard texture, increased skin temperature, angry veins, mild pressure pain and occasional vascular murmur. The adjacent joints are not swollen and movement is not restricted. However, in the advanced stage, movement is limited in the semi-flexed position. Pathological fractures may occur, and in 10% of cases, metastases to the proximal lymph nodes occur. The muscles gradually atrophy and limp. Systemic symptoms appear early, including loss of appetite, weakness, anemia, and emaciation, and cachexia in the late stage. Children with lung metastasis have cough and hemoptysis.
3.Diagnosis
X-ray examination of the primary lesion site, off to the side of the long bone epiphysis, shows limited or extensive bone destruction with blurred borders, non-inflated but penetrated cortex, and the presence of periosteal reaction; there may be soft tissue shadows with irregular calcification. The deep bone type shows destruction and disappearance of bone trabeculae and cortical penetration; soft tissue shadows may be present, and periosteal reaction is manifested as Codman’s triangle, with fewer and fainter needle-like shadows, sometimes with cortical expansion on one side. The osteogenic type shows extensive dense shadows without trabecular structures and no boundaries, which can invade into soft tissues; periosteal reaction is obvious and needle shadows are prominent; in grade I, the lesion is located in the bone marrow cavity and there may be a small amount of periosteal reaction; in grade II, the cortex is penetrated and periosteal reaction is obvious; in grade III, there are shadows in soft tissues outside the bone; CT examination and radionuclide bone scan can show the extent of the tumor, and lung radiographs can identify metastases. Serum alkaline phosphatase is increased in half of the cases.
The diagnosis of bone tumor should be made by combining clinical, X-ray and pathological methods to improve the correct rate. Pediatric bone tumors have obvious characteristics in terms of age, category and site of onset, and typical X-ray signs. Therefore, it is easy to get the correct diagnosis before treatment. However, when early X-ray diagnosis is difficult, it should be followed up continuously in a short period of time. Anyone who is suspected of malignant tumor on X-ray should have a biopsy in time to make a clear diagnosis.
4.Treatment principle
Early comprehensive treatment is based on chemotherapy and surgery. Chemotherapy as preoperative and postoperative adjuvant therapy for osteogenic sarcoma is a major advancement that can significantly improve survival rates and make its role and status no longer objectionable, and every case should receive chemotherapy. High-dose methotrexate (MTX) with calcium formyl tetrahydrofolate depot has been shown to be effective, as have adriamycin, cisplatin, and cyclophosphamide, but a combination is appropriate. Preoperative chemotherapy has been reported in the literature to be useful in killing microscopic metastases existing in the body at the time of consultation, as well as in shrinking the tumor and facilitating surgery. The effect of the drugs can be observed to provide a basis for whether to apply the same drugs after surgery. With early diagnosis, careful preoperative staging, careful surgery plus preoperative and postoperative chemotherapy, the prognosis will be greatly improved. In recent years, the five-year cure rate has improved significantly.
Radical surgery should be performed to treat osteosarcoma. Extensive local excision with limb preservation can be performed in cases where available. A conservative (limb-preserving) radical resection can achieve the same survival outcomes as an aggressive radical procedure. Postoperative necrosis of the soft tissue (plus wound) is the most common complication of limb-preserving surgery, and aggressive use of transfer or free flap techniques at the time of surgery has resulted in a significant reduction in complications. In addition, biopsies should be performed before amputation to further confirm the clinical and x-ray diagnosis. Both radiotherapy and chemotherapy are important adjuvant treatments. It is appropriate to divide radiotherapy into several phases: 1) 10-20 Gy for a total of 5-6 days before biopsy, with the last day being the date of performing the biopsy. Subsequently, 60 Gy is given before and after amputation. 2) Chemotherapy includes the selection of high-dose methotrexate (MTX), formyl tetrahydrofolate, adriamycin, scramblomycin, and vincristine applied as a combination agent.
Postoperative chemotherapy is based on tumor pathological examination results. If more than 90% of tumor cells are necrotic, it means that the preoperative protocol can be continued, if less than 60% of cancer cells are necrotic, it is appropriate to develop a protocol with other drugs instead. The duration of continuous chemotherapy is 8 to 12 months.
(1) Radiation therapy technique
Implementation of radiation therapy requires well-fixed body position and meticulous treatment plan design. To reduce distal limb edema and constrictive fibrosis, it is important to use individually tailored monolithic metal blocks or multileaf collimator field shaping, as well as to protect the limb with a certain skin zone band (1.5-2.0 cm wide if possible) to be irradiated.
Designing a treatment plan based on CT or MRI imaging data as well as the appropriate use of electron beams can improve the effectiveness of treatment. We always recommend the use of high-energy particle beam irradiation because bone tumors are generally considered to be less sensitive to radiation. The site of the lesion often requires a sharp-edged beam collimator to avoid serious side effects (e.g., lesions at the skull base).
For osteosarcoma, a variety of radiotherapy treatments have been clinically investigated.
1) Using a combination of arterial infusion chemotherapy plus radiation (46Gy, 2-3Gy/dose), a clinical trial performed in combination with multiple treatment centers showed a local control rate of 98.5% in the entire group of 66 patients, 60 of whom were first treated with limb-preserving surgery.
(2) The local control rate was 81% in 21 patients treated with accelerated hypofractionated irradiation with or without chemotherapy palliation, and a local control rate of 92% was reported in 13 patients treated radically with a combination approach.
(3) Intraoperative radiotherapy (IORT) of 50-60 Gy with or without preoperative chemotherapy can achieve similar local control rates.
(4) For pulmonary metastatic lesions, experimental observation of radiotherapy alone or combined chemotherapy has been ongoing.
(2) Prognosis
Prognosis is related to tissue type, primary site, tumor size at diagnosis, and metastatic status. The prognosis of fibroblast type is better than the other two types, and the distal bone is better than the proximal bone. The survival rate of the original single-agent low-dose chemotherapy is only 20%, but now the 2-year survival rate of preoperative and postoperative high-dose combination chemotherapy has reached 70%-90%.
(3) Treatment complications
The side effects of radiotherapy on bone are directly related to the irradiation dose and volume, and negatively related to the age of the patient at the time of treatment. Clinically significant developmental abnormalities can be seen in infants and children as early as 6 months and 1 year after treatment, respectively. The scoliosis caused by radiation to the vertebral body is not too pronounced and is often compensated by the tilt of the pelvis. The irradiated bone is more susceptible to infection, fracture and necrosis due to changes in small blood vessels caused by radiation.