Malignant neoplasms of bone and articular cartilage: osteosarcoma, Ewing sarcoma: clinical guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

aPTT – activated partial thromboplastin time

EFS – event-free survival

WHO – World Health Organization

GCT – giant cell tumor

G-CSF – granulocyte colony-stimulating factor

Malignant neoplasm – malignant neoplasm

IHC – immunohistochemistry

CE – contrast enhancement

LDH – lactate dehydrogenase

RT – radiotherapy

INR – international normalized ratio

MRI – magnetic resonance imaging

MSCT – multislice computed tomography

NS – nutritional support

CBC – complete blood count

OS – overall survival

OS – osteosarcoma

OFD – osteofibrous dysplasia

SPECT/CT – single-photon emission computed tomography combined with whole-body computed tomography

PN – parenteral nutrition

CCT – combination chemotherapy

PCR – polymerase chain reaction

PET/CT – positron emission tomography combined with computed tomography

SD – single dose

SFD – single focal dose

rhG-CSF – recombinant human granulocyte colony-stimulating factor

TD – total dose

TFD – total focal dose

ES – Ewing's sarcoma

HSCT – hematopoietic stem cell transplantation

TEE – total energy expenditure

US – ultrasound examination

CS – chondrosarcoma

CVC – central venous catheter

ALP – alkaline phosphatase

EDTA – ethylenediaminetetraacetic acid

ECG – electrocardiography

EOC – extraosseous tumor component

II – image intensifier

EN – enteral nutrition

EchoCG – echocardiography

EEG – electroencephalography

AP – chemotherapy regimen: doxorubicin**, cisplatin**

BuMel – conditioning regimen: busulfan**/melphalan**

CTV – clinical target volume

FISH – in situ fluorescence hybridization

GTV – gross tumor volume

IE – chemotherapy regimen: ifosfamide**, etoposide**

M – methotrexate**

PTV – planning target volume

TreoMel – conditioning regimen: treosulfan/melphalan**

¹⁸F-FDG – fludeoxyglucose [18F]

Terms and Definitions

Event-free survival (EFS) is defined as the time period from the date of diagnosis to an adverse event, which is understood as relapse, disease progression, development of a secondary malignancy, death from any cause, or the date of last patient follow-up.

Overall survival (OS) is defined as the time period from the date of diagnosis to patient death from any cause or to the date of last patient follow-up.

Disease progression – the appearance of any new tumor lesion during ongoing treatment or an increase of more than 25% in a previously existing measurable lesion.

Disease relapse – the appearance of any new tumor lesions in patients who have achieved disease remission.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Osteosarcoma (OS) – a primary malignant bone tumor that develops from primitive mesenchymal stem cells producing pathological osteoid [1]. OS is the most common primary malignant bone tumor among patients aged 10 to 18 years [2].

Undifferentiated small round cell sarcomas – a group of primary malignant bone neoplasms consisting of small blue round cells, characterized by typical genetic rearrangements [1].

Ewing sarcoma – a highly malignant tumor belonging to the group of undifferentiated small round cell sarcomas, characterized by the fusion of FET family genes (usually EWSR1) with one of the ETS family members [1].

EWSR1-non-ETS-rearranged round cell sarcoma – a highly malignant tumor belonging to the group of undifferentiated small round cell sarcomas, characterized by aberrations in EWSR1 or FUS genes with partners not related to the ETS gene family [1].

CIC-rearranged sarcoma – a highly malignant round cell undifferentiated sarcoma characterized by rearrangements of the CIC gene, in most cases CIC-DUX [1].

Sarcoma with BCOR gene genetic alteration – a highly malignant tumor also belonging to the group of undifferentiated small round cell sarcomas, characterized by a genetic alteration of the BCOR gene, its oncogenic activation, and overexpression [1].

Chondrosarcoma – a term defining a heterogeneous group of primary malignant bone tumors characterized by the formation of a cartilaginous matrix by tumor cells [1].

Giant cell tumor (GCT) – an osteolytic neoplasm of the skeletal bones classified as a tumor with intermediate biological potential and characterized by locally aggressive growth, a high rate of local recurrences, and a low metastatic potential [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The pathogenesis and etiology of malignant bone tumors currently remain unknown. These diseases are multifactorial and lack specific driver mutations. Genetic rearrangements between the EWS and ETS gene families are involved in the pathogenesis of Ewing sarcoma [1, 3]. Most cases of osteosarcoma are sporadic. Less commonly, the development of OS is associated with the presence of a hereditary cancer predisposition syndrome in the patient, which include Li-Fraumeni syndrome (TP53 gene mutation), hereditary retinoblastoma (RB1 gene mutation), Rothmund-Thomson syndrome type 2 (RecQ4 gene mutation), Werner syndrome (WRN gene mutation), Bloom syndrome (BLM gene mutation), and Diamond-Blackfan anemia [4]. The only reliably studied exogenous risk factor for the development of osteosarcoma is ionizing radiation [5].

1.3 Epidemiology of the Disease or Condition

Primary malignant bone tumors account for about 0.2% of all malignant neoplasms [6]. Among patients under 18 years of age, malignant bone tumors rank 8th, with a peak incidence in the second decade of life. Bone malignancies account for up to 0.5% of patients under 5 years of age, 5% in the 5 to 9 age group, and 14% in the 10 to 18 age group. The overall incidence is 4.4 cases per 1 million pediatric population. The male-to-female ratio is 1.4:1 [2, 7, 8].

Osteosarcoma is the most common primary malignant bone tumor among children and adolescents, accounting for up to 56% of all bone malignancies in children [2]. The primary focus is typically located in the metaepiphyses of long tubular bones – most frequently the femur, tibia, and humerus. Bones of the skull and pelvis are less frequently affected [7, 8]. The incidence of osteosarcoma is 4.8 cases per 1 million pediatric population [8].

Ewing sarcoma and other tumors included in the group of undifferentiated small round cell sarcomas rank second in the structure of malignant bone neoplasms among patients under 18 years of age. They account for up to 34% of all cases [2, 7, 8]. Unlike osteosarcoma, Ewing sarcoma predominantly affects the bones of the axial skeleton, namely the pelvic bones, vertebrae, ribs, and skull bones (45%); less frequently, the process involves the diaphyses of the long tubular bones of the upper and lower extremities (14% and 29%, respectively) [8]. The incidence of Ewing sarcoma is 2.9 cases per 1 million pediatric population [8].

Chondrosarcoma, which is the most common primary malignant bone tumor in the adult population, ranks third among patients under 18 years of age, trailing osteosarcoma and Ewing sarcoma [8, 9]. The overall incidence of chondrosarcoma is 0.5 cases per 1 million pediatric population [8]. Primary (arising de novo) and secondary chondrosarcomas are distinguished, the latter resulting from the malignant transformation of benign cartilage-forming lesions, such as enchondroma or osteochondroma (osteocartilaginous exostosis). The malignant transformation of enchondromas in Ollier disease (enchondromatosis) and Maffucci syndrome (enchondromatosis associated with vascular lesions) reaches 45% and 57%, respectively [10, 11].

1.4 Features of Coding the Disease or Condition

D48.0 – Neoplasm of uncertain or unknown behavior of bones and articular cartilage

C40 – Malignant neoplasm of bone and articular cartilage of limbs:

C40.0 – Malignant neoplasm of scapula and long bones of upper limb

C40.1 – Malignant neoplasm of short bones of upper limb

C40.2 – Malignant neoplasm of long bones of lower limb

C40.3 – Malignant neoplasm of short bones of lower limb

C40.8 – Malignant neoplasm of bone and articular cartilage of limbs, overlapping lesion

C40.9 – Malignant neoplasm of bone and articular cartilage of limb, unspecified

C41 Malignant neoplasm of bone and articular cartilage of other and unspecified sites:

C41.0 – Malignant neoplasm of bones of skull and face

C41.1 – Malignant neoplasm of mandible

C41.2 – Malignant neoplasm of vertebral column

C41.3 – Malignant neoplasm of ribs, sternum and clavicle

C41.4 – Malignant neoplasm of pelvic bones, sacrum and coccyx

C41.8 – Malignant neoplasm of bone and articular cartilage of other and unspecified sites, overlapping lesion

C41.9 – Malignant neoplasm of bone and articular cartilage, unspecified

1.5 Classification of the disease or condition

Currently, bone tumors are classified in accordance with the 2020 WHO classification of bone tumors [1].

Osteogenic tumors:

Low-grade central osteosarcoma 9187/3

Osteosarcoma NOS 9180/3

Conventional osteosarcoma 9180/3

Telangiectatic osteosarcoma 9180/3

Small cell osteosarcoma 9180/3

Parosteal osteosarcoma 9192/3

Periosteal osteosarcoma 9193/3

High-grade surface osteosarcoma 9194/3

Secondary osteosarcoma 9184/3

Classification of undifferentiated small round cell sarcomas:

Ewing sarcoma 9364/3

Round cell sarcoma with EWSR1-non-ETS fusions 9366/3

CIC-rearranged sarcoma 9367/3

Sarcoma with BCOR genetic alterations 9368/3

Chondrogenic tumors:

Chondrosarcoma, grade 1 9222/3

Moderately differentiated chondrosarcoma (grade 2) 9220/3

Poorly differentiated chondrosarcoma (grade 3) 9220/3

Periosteal chondrosarcoma 9221/3

Clear cell chondrosarcoma 9242/3

Mesenchymal chondrosarcoma 9240/3

Dedifferentiated chondrosarcoma 9243/3

Vascular tumors

Epithelioid hemangioendothelioma 9133/3

Angiosarcoma 9120/3

Giant cell tumors

Tumor of intermediate biological potential:

Giant cell tumor of bone 9250/1

Malignant:

Malignant giant cell tumor 9250/3

Notochordal tumors

Chordoma 9370/3

Poorly differentiated chordoma 9370/3

Dedifferentiated chordoma 9372/3

Other mesenchymal bone tumors

Adamantinoma 9261/3

Leiomyosarcoma 8890/3

Undifferentiated (pleomorphic) sarcoma 8830/3

Staging of primary malignant bone tumors is performed in accordance with the AJCC 8th edition classification, based on the histological type of the tumor and its grade (G), size and location of the primary focus (T), presence or absence of regional lymph node involvement (N) or distant metastasis (M) [1,9,12,13].

Table 1.

T criterion (primary tumor located in the appendicular skeleton, ribs, skull bones)

Table 2.

T criterion (primary tumor located in the vertebra)

Table 3.

T criterion (primary tumor located in the pelvic bones, sacrum, coccyx)

Table 4.

N criterion (regional lymph node involvement)

Table 5.

M criterion (distant metastases)

Table 6.

G criterion (tumor grade)

Table 7.

TNMG staging criteria for determining the stage of the disease

Not applicable for tumors with a primary site in the pelvic bones or vertebrae

1.6 Clinical presentation of the disease or condition

The clinical presentation of malignant bone tumors depends on the anatomical location and size of the primary lesion, the degree of invasion and compression of adjacent organs and tissues, as well as the anatomical location of metastases. In extremely rare cases, the disease is asymptomatic and may be an incidental finding during routine health checks or examinations for another condition.

Typically, the leading symptom is pain in the projection of the mass, which over time may be accompanied by swelling and impaired movement in the adjacent joint if the mass is located in the bones of the extremities. In 10–15% of cases, patients present with a pathological fracture at the site of the mass.

In cases of cranial bone involvement, in addition to pain in the projection of the mass, exophthalmos and nasal breathing impairment may occur. When the mass is located in the thoracic region, shortness of breath, breathing difficulties, and cough may develop.

When the tumor invades the spinal canal or compresses peripheral nerve trunks, neurological symptoms may develop, such as paresis, paralysis, and pelvic organ dysfunction.

Subsequently, the patient may develop general symptoms of intoxication, fever, and weight loss.

2. Diagnostics, medical indications and contraindications for diagnostic methods

All patients with suspected malignant bone tumors require discussion by a multidisciplinary team consisting of a radiologist, pathologist, orthopedic surgeon, and pediatric oncologist [1, 12, 14, 15]. Diagnostic measures necessary to assess the extent and nature of the primary lesion must be performed prior to the biopsy of the mass. An accurate histological diagnosis often cannot be established without correlation with the radiological findings [11, 16].

All children with suspected tumors should be referred to pediatric oncology centers (medical facilities of at least the secondary level) equipped with the necessary diagnostic equipment.

Criteria for establishing the diagnosis/condition: the diagnosis is established based on pathognomonic data:

1. anamnestic data

2. physical examination

3. laboratory tests

4. instrumental examination

5. histological examination

6. cytogenetic examination

2.1 Complaints and Anamnesis

• All patients with suspected or established bone malignancy are recommended to undergo a thorough collection of complaints and anamnesis, including family and oncological history, to assess the patient's condition and identify factors that may influence the choice of treatment tactics [9, 14, 16].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: taking the anamnesis should include a detailed family history, clarifying the oncological history—the presence of benign or malignant tumors in family members—as well as the personal history (presence of retinoblastoma or other past oncological diseases, injuries, surgical interventions, radiation therapy, or contact with ionizing radiation).

The identification of tumor cases in the family or in the patient's anamnesis requires medical genetic counseling to identify the underlying genetic mechanisms of predisposition.

When collecting complaints, it is necessary to pay attention to the duration and character of the pain syndrome persisting for more than 2 weeks, regardless of the presence or absence of a history of trauma. A thorough anamnesis is recommended in the presence of a fracture without preceding trauma or with trauma that should not have caused a fracture given the force applied.

2.2 Physical Examination

• All patients with suspected or established bone malignancy at the initial visit, at each visit to a pediatric oncologist, before each subsequent course of chemotherapy, when assessing the response to therapy during treatment, and during follow-up are recommended to undergo a physical examination by a physician, including palpation and auscultation [16].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: the initial examination of the patient is aimed at assessing the general status of the patient, the presence of intoxication syndrome, identifying the primary lesion, the potential presence of metastases, determining the scope of the initial examination, and the extent of surgical intervention aimed at tumor verification. When assessing the patient's general condition, it is also recommended to use rating scales (see Appendix G1, Appendix G2).

The initial examination should include:

• anthropometric measurements (weight, height, and body surface area) and assessment of nutritional status (percentiles);

• assessment of skin and mucous membranes;

• search for and identification of a palpable mass: determination of location, tumor characteristics, and degree of functional impairment;

• assessment of the musculoskeletal system (detection of pain syndrome, identification of extremity dysfunction);

• assessment of cardiovascular system function;

• assessment of pulmonary system function;

• abdominal palpation;

• assessment of the size of peripheral lymph nodes;

• characterization of pelvic organ function.

2.3 Laboratory Diagnostics

• All patients with suspected or established bone malignancy at the initial visit, at each visit to a pediatric oncologist, before each subsequent course of chemotherapy, when assessing the response to therapy during treatment, and during follow-up are recommended to undergo the following laboratory tests to clarify the patient's condition, plan therapeutic tactics, determine the need for their modification, and assess the need for supportive and concomitant care [15]:

  • complete blood count (CBC) with differential;

  • general clinical biochemistry blood test including the following parameters: blood lactate dehydrogenase (LDH) activity, blood alanine aminotransferase (ALT) activity, blood aspartate aminotransferase (AST) activity, total blood bilirubin level, blood alkaline phosphatase activity, total blood protein level, blood albumin level, blood creatinine level, blood urea level, blood uric acid level, blood potassium level, blood sodium level, blood chloride level, blood calcium level (other biochemical parameters may be included at the physician's discretion);

  • coagulation profile (screening hemostasis test) including the following parameters: prothrombin time, international normalized ratio (INR), activated partial thromboplastin time (APTT), blood fibrinogen level, thrombin time, antithrombin III activity, blood plasminogen level, blood D-dimer concentration;

  • complete urinalysis, as well as urine analysis by Nechiporenko method;

  • determination of glomerular filtration rate: assessment of nephron function via creatinine clearance (Rehberg's test);

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• All treatment-naive patients with malignant bone tumors before starting treatment are recommended to determine the main ABO blood groups and Rhesus D antigen (Rh factor) to enable blood transfusion if indicated before, during, or after therapy [17, 18].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

2.4 Instrumental Diagnostics

• All patients with suspected bone malignancy are recommended to undergo radiography of the primary lesion area with inclusion of two adjacent joints in two projections as a first step [9, 12, 14, 16].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: radiography allows for initial diagnosis, revealing radiological signs characteristic of malignant tumors—a zone of destruction, including cortical bone damage, spiculated periostitis, Codman's triangle (osteosarcoma), "onion-skin" periostitis (Ewing sarcoma), etc.

• All patients with suspected or verified bone malignancy at the initial examination, when assessing the response to therapy during treatment and during follow-up, as well as when a disease relapse is suspected, are recommended to undergo magnetic resonance imaging (MRI) of the affected area with contrast enhancement [9, 12, 14].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comment: MRI is currently the method of choice for evaluating the primary lesion located in the bones of the extremities, pelvis, skull, and spine. It allows for assessing the structure and nature of the lesion, its extent – along the medullary canal, the presence of an extraosseous tumor component, and its interaction with adjacent neurovascular structures.

It is extremely important to perform diagnostic studies before any surgical interventions (manipulations), as biopsy can significantly complicate the analysis of the resulting images.

When referring a patient for an MRI scan, it is necessary to assess risks and contraindications, which are divided into absolute and relative. To clarify the list of contraindications or if the specialist physician lacks sufficient knowledge regarding them, a consultation with a radiologist is required before scheduling the patient for the scan.

MRI is not recommended for patients with established massive metal implants (joint arthroplasties) due to the impossibility of interpretation caused by artifacts. The method of choice in this case is contrast-enhanced computed tomography (CT) of the affected area.

The scan is performed in 3 planes with contrast enhancement. The main pulse sequences are fat-suppressed T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and DWI. Following the administration of a paramagnetic contrast agent, in addition to the T1WI series, a fat-suppressed T1WI sequence is performed in the axial plane.

Tumor volume measurement

Calculation of tumor volume (V) for ellipsoidal or spherical tumors

V = π /6 × a × b × c = 0.52 × a × b × c in cm³

a = length (in cm)

b = width (in cm)

c = thickness (in cm)

Assessment of the initial tumor volume plays a key role in choosing the treatment strategy for patients, and serial measurements over time allow for evaluating the response to ongoing therapy and modifying it if necessary.

• All patients with suspected or verified bone malignancy at initial evaluation, during the assessment of treatment response, during follow-up, and when disease recurrence is suspected, are recommended to undergo contrast-enhanced computed tomography (CT) of the affected area [9, 12, 14].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: CT of the primary lesion can provide additional information about the nature of the lesion (presence of calcification, periostitis, and cortical bone destruction).

CT and MRI do not exclude or replace each other. For accurate assessment of bone pathology, evaluation of tumor spread, and establishing a radiological differential diagnosis, a comprehensive examination combining MRI and CT is optimal.

CT is an integral part of preoperative planning, planning of reconstructive surgery (when feasible), and manufacturing of a custom implant.

• All patients with suspected or identified bone malignancy at initial evaluation, during the assessment of treatment response, during follow-up, and when disease recurrence is suspected, are recommended to undergo chest CT with intravenous bolus contrast enhancement to rule out pulmonary metastases [9, 12, 14].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: The standard for primary diagnosis of pulmonary metastases in bone malignancies is chest CT with intravenous bolus contrast enhancement prior to initiating specific therapy.

The study is performed in 3 phases – native, arterial, and venous – with a slice thickness of no more than 2.5 mm.

Imaging results should be evaluated by an expert radiologist and discussed with the attending oncologist, as pulmonary tumor spread plays a critical role in staging the tumor process.

Several criteria are used to diagnose metastatic lesions: number, size, shape, structure, and location. However, none of these criteria are 100% specific.

A sign of pulmonary metastasis is the presence of one or more pulmonary/pleural lesions measuring ≥10 mm, at least two lesions measuring 5-10 mm, or at least five clearly visible lesions measuring <5 mm (unless there is another clear medical explanation for these lesions).

Smaller isolated lesions (no more than four small lesions <5 mm) are considered equivocal, unless the radiologist is reasonably confident in their metastatic nature. In such cases, a biopsy may be performed, though in most cases it is not recommended.

In children under 10 years of age, special attention should be paid to "atypical pulmonary metastases," as such lesions may be caused by infection. A follow-up scan after a short interval may be useful.

• All patients with suspected or identified bone malignancy at initial evaluation, during the assessment of treatment response, during follow-up, and when disease recurrence is suspected, are recommended to undergo whole-body positron emission tomography combined with computed tomography (PET/CT) with fluorine-18 fluorodeoxyglucose ([¹⁸F]FDG) [9, 12, 14, 19, 20].

LoR AGoE 1Level of Recommendation A (Level of Evidence - 1)

Comments: all lesions detected by ¹⁸F-FDG PET/CT must be confirmed by other additional imaging methods (contrast-enhanced MRI of the lesion area).

To minimize the number of false-positive and false-negative results, the initial study must be performed before the patient starts treatment. The referral for the scan must be accompanied by a detailed medical summary including dates and protocols of surgeries, various instrumental examinations (imaging reports and external storage media – discs), and indicating diagnosed foci of infection (if any).

• All patients with suspected or identified bone malignancy at initial evaluation, during the assessment of treatment response, during follow-up, and when disease recurrence is suspected, if PET/CT is unavailable, and in some cases as an adjunct to PET/CT, are recommended to undergo whole-body bone scintigraphy with technetium (99mTc) radiopharmaceuticals, supplemented by whole-body single-photon emission computed tomography combined with computed tomography (SPECT/CT) if single or multiple equivocal areas of increased tracer uptake are found on planar images [9, 12, 14, 19, 20].

LoR AGoE 1Level of Recommendation A (Level of Evidence - 1)

Comments: all lesions detected by technetium (99mTc) bone scintigraphy require further evaluation with SPECT/CT (if available) and additional imaging methods (contrast-enhanced MRI of the lesion area).

It must be taken into account that physiological increased uptake of bone-seeking radiopharmaceuticals in the growth plates of the skeletal bones does not allow for reliably identifying metastatic involvement in these areas.

• All patients diagnosed with bone malignancy at initial evaluation, during antitumor treatment including anthracyclines, before each polychemotherapy cycle, after treatment completion, and before discharge from therapy, are recommended to undergo electrocardiography (ECG) recording, analysis, description, and interpretation, as well as echocardiography with determination of the ejection fraction to assess cardiovascular function and monitor cardiotoxicity in patients receiving anthracyclines and related compounds [21].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: if a decrease in left ventricular ejection fraction is present, a cardiology consultation is required, along with consideration of dose reduction for anthracyclines and related compounds.

• All patients with suspected or diagnosed bone malignancy at initial evaluation, during the assessment of treatment response, during follow-up, and when disease recurrence is suspected, are recommended to undergo ultrasound examination of lymph nodes and abdominal organs (comprehensive) [12].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: metastatic involvement of regional lymph nodes in malignant bone tumors is extremely rare. If metastatic lymph node involvement is suspected, histological confirmation is required.

• All patients with verified bone malignancy during initial evaluation, during treatment, and in follow-up are recommended to undergo contrast-enhanced brain MRI to assess neurotoxicity [22, 23, 24, 25, 26]

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

2.5 Other Procedures

• All patients with suspected bone malignancy based on the results of clinical examination and instrumental diagnostic methods are recommended to undergo bone biopsy (of the mass lesion) followed by pathomorphological examination of the bone biopsy (surgical) material, including immunohistochemical and, if necessary, cytogenetic methods to verify the diagnosis [1, 9, 12, 14].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comments: histological examination of the tumor tissue is the primary method for definitive diagnosis verification in patients with bone malignancy. The histological specimen must be accompanied by a referral containing patient information, duration and nature of the disease, localization of the lesion, biopsy description, and the surgical protocol.

The full range of diagnostic procedures must be carried out prior to the biopsy. The decision to perform a biopsy or, conversely, to forgo it is made based on these results.

Contrast-enhanced MRI of the affected area helps identify the most representative region within the tumor focus and find the shortest and safest approach to this area. Performing a biopsy (surgical intervention) prior to MRI can lead not only to serious diagnostic errors, but also to complications that make limb-salvage surgery impossible and increase the risk of local disease recurrence.

Biopsy standards:

1. The biopsy site should preferably be planned at a multidisciplinary meeting involving an oncologist (pediatric oncologist), orthopedic trauma surgeon, pathologist, and radiation therapist or radiologist. This is necessary to select the most representative focus [27, 28, 29, 30].

2. The biopsy should be performed in a specialized oncological hospital, preferably in an operating room equipped with a C-arm (image intensifier), under general anesthesia [28, 29]. It is permissible to perform the biopsy in a regional center—a regional hospital (Level 2 medical facility) in coordination with the federal center (access localization, amount of material, type of biopsy) where the local control stage (tumor removal) will subsequently take place.

3. When performing a biopsy, the future surgical approach (tumor removal surgery) must be taken into account; on the extremities, the incision should be longitudinal, and when using a Redon drainage system, its exit point must be in line with the incision. Whenever possible, the incision should not exceed 4–5 cm [27, 31].

4. The technique should be as careful and sparing as possible. Instrument manipulation outside the biopsy tract must be avoided to prevent tumor cell contamination of surrounding tissues. Do not allow damage to anatomical boundaries between compartments [27, 28, 32].

5. Specimen collection is best performed using a scalpel or vascular scissors to avoid tissue damage [28].

6. If bone tissue sampling is necessary, an osteotomy is performed in the shape of an oval or a rectangle with rounded corners. Square, rectangular, and circular shapes must be avoided. If it is necessary to enlarge the bone window to preserve bone structural support, the window should be enlarged longitudinally, under no circumstances transversely [27, 30].

7. The amount of collected material must be sufficient to perform all types of histological examinations (if necessary, a pathologist is invited to the operating room for visual assessment of the material), cytogenetic testing of the biopsy (surgical) material, preservation in a biobank, as well as for archiving and potential review in reference centers [27, 28, 30].

8. In the differential diagnosis with osteomyelitis, an additional portion of the material should be sent for bacteriological examination [27].

9. As a rule, biopsies are performed without a tourniquet, as it may interfere with adequate hemostasis. If a tourniquet is used, it must under no circumstances be applied over the tumor-affected area. It must be released before wound closure to perform hemostasis [27, 28, 29].

Morphological diagnosis of bone tumors is extremely challenging due to the wide variety of nosological forms and tumor subtypes.

The volume of material required for reliable verification of the clinical diagnosis may be considered sufficient and can range from 3–5 mm in diameter to 1–1.5 cm in greatest dimension. If fragmentation of the material is unavoidable, the total volume must be at least 1.5 cm³. The material obtained after surgical manipulations is immediately placed in a 10% buffered formalin solution (pH 7.4) with appropriate legible labeling and sent to the pathology department no later than 24 hours from the time of the biopsy/surgery. Large specimens are described (size, color, condition of resection margins, etc.), sectioned along the long axis of the bone (tumor), and then parallel slices are made to obtain a gross specimen plate no more than 0.3–0.4 cm thick. Following decalcification (exclusively using special decalcifying solutions), quadrant marking is performed, and the resulting gross specimen map is recorded in the examination protocol. If macroscopic examination does not allow for a definitive assessment of tumor excision radicality, special stains are used to mark resection margins (noted in the examination protocol). The turnaround time for the examination must not exceed 14 working days (including all stages: fixation, decalcification, tissue processing, microtomy, staining, and slide review).

If IHC testing is required, the turnaround time must not exceed 5 working days. For the diagnosis of conventional osteosarcoma, one should look for signs of marked cellular atypia and production of pathological osteoid. For the diagnosis of chondrosarcoma, one should look for increased cellularity, invasive growth pattern, myxoid matrix, and presence of mitotic figures. For the diagnosis of Ewing sarcoma, an IHC study must be performed (at least CD99 membranous expression locus) followed by cytogenetic testing (EWSR1/FUS gene rearrangement). For the diagnosis of giant cell tumor, one should look for a mononuclear neoplastic component and multinucleated osteoclast-like giant cells; on IHC, expression of G34W (H3F3A). IDH1 and IDH2 mutations in classical chondrosarcoma and MDM2 amplification in parosteal and low-grade intramedullary osteosarcoma are not mandatory, but may be useful for differential diagnosis.

The conclusion is formulated indicating the localization of the pathological process, the specific nosological entity, and the mandatory ICD code. In addition, for bone tumors, the ICD-O code must be specified.

• All patients with suspected Ewing sarcoma or other undifferentiated small round cell bone sarcoma are recommended to obtain a bone marrow cytology specimen via puncture (bone marrow aspiration) followed by cytological examination of the bone marrow smear (myelogram) during the initial evaluation, during therapy (if bone marrow involvement is confirmed), and after completion of treatment prior to therapy discontinuation, in order to rule out bone marrow metastasis [9, 14].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: bone marrow involvement in Ewing sarcoma and other undifferentiated small round cell sarcomas is focal. Therefore, a single-site bone marrow puncture is not acceptable. Bone marrow aspirations must be performed from 4 different sites. When performing a bone marrow puncture, it is advisable to prepare 10 glass slides from each site. Thus, when performing bone marrow punctures from 4 sites, the total number of slides will be 40.

If bone marrow involvement is detected during initial evaluation before starting antineoplastic therapy, a repeat 4-site bone marrow puncture must be performed after 3 cycles of chemotherapy, and after completion of treatment to assess the response to therapy and confirm bone marrow clearance.

• All patients with suspected Ewing sarcoma or another undifferentiated small round cell sarcoma, high-grade central osteosarcoma, or chondrosarcoma are recommended to undergo molecular genetic testing depending on the suspected tumor type [1].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comment: molecular genetic markers are highly specific (pathognomonic) criteria for individual types of bone sarcomas. The feasibility of detecting them and the required panel are determined by the histological type of the tumor and the diagnostic task facing the pathologist. The material for the study is tumor tissue fixed in formalin and embedded in a paraffin block. The assignment of cytogenetic and molecular genetic diagnostic methods is carried out by a pathologist who prepares the material for the corresponding study. These diagnostic methods can only be performed in a reference laboratory setting.

Table 8. Specific translocations in bone sarcomas

• All patients with newly diagnosed bone malignancies are recommended to undergo a consultation (examination, assessment) by a cardiologist, neurologist, ophthalmologist, and other specialist physicians, depending on comorbid conditions, to determine the need for treatment of concomitant diseases [14, 21].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

2.5.1 Assessments during therapy

Pre-chemotherapy evaluations

• Before each course of chemotherapy, it is recommended to evaluate the general condition with a physical examination and monitor laboratory parameters. When administration of anthracyclines and their derivatives is planned as part of the polychemotherapy (PCT) block, echocardiography (EchoCG) is recommended prior to the initiation of antineoplastic agents. When administration of alkylating agents (ifosfamide**, cyclophosphamide**) is planned, tubular reabsorption tests or evaluation of nephron function via creatinine clearance (Rehberg's test) are recommended prior to chemotherapy initiation to assess organ function [16, 17, 21].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comment: the scope of examinations prior to a PCT course is determined individually for each patient based on the clinical situation, tumor location, tumor spread, scope of therapy, and comorbidities at the physician's discretion.

Follow-up assessments during polychemotherapy

• In order to assess the response to ongoing treatment, it is recommended to perform examinations using the same methods as during the initial evaluation [9, 12, 14].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: for patients with osteosarcoma, it is recommended to perform examinations consisting of contrast-enhanced MRI of the primary lesion area, contrast-enhanced chest CT, and MRI of metastatic lesions in other locations identified during initial diagnosis after 6 weeks of therapy or after 4 courses of neoadjuvant PCT. Subsequent evaluations during treatment are performed at least once every 2 months. In the event of a metal implant placement, contrast-enhanced CT of the primary lesion area is recommended.

For patients with Ewing sarcoma and other undifferentiated small round cell bone sarcomas, it is recommended to perform examinations consisting of contrast-enhanced MRI of the primary lesion area, contrast-enhanced chest CT, MRI of metastatic lesions in other locations identified during initial diagnosis, as well as obtaining a bone marrow cytologic specimen via puncture after 6 and 12 weeks of therapy, which corresponds to 3 and 6 courses of neoadjuvant PCT. Subsequent evaluations during treatment are performed at least once every 2 months. In the event of a metal implant placement, contrast-enhanced CT of the primary lesion area is recommended.

2.5.2 Assessment of response to therapy

• All patients with verified bone malignancies are recommended to undergo treatment response assessment. To determine the response to therapy, volumetric tumor assessment is performed using MRI and/or CT scans. Whenever possible, the same imaging study used in the initial evaluation should be performed. Tumor dimensions in three dimensions must be recorded; for comparison, dimensions at the same levels chosen during initial diagnosis should be used whenever possible [9, 12, 14].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

2.5.3 Examinations before completion of therapy

• All patients with verified bone malignancies are recommended to undergo an evaluation after completing the final course of PCT stipulated by the therapeutic program, prior to the end of therapy [12, 16, 21]:

  1. Detailed physical and neurological examination

  2. Monitoring of laboratory parameters (complete blood count, biochemical blood test, urinalysis, coagulogram [exploratory hemostasis screening])

  3. EchoCG, ECG

  4. Other studies as indicated (e.g., electroencephalography [EEG], audiometry, fundus examination, contrast-enhanced brain MRI)

  5. Contrast-enhanced chest CT

  6. Contrast-enhanced MRI of the primary lesion area or contrast-enhanced CT of the primary lesion area

  7. Cytological examination of a bone marrow smear (myelogram) from 4 sites in cases of initial metastatic involvement

  8. Whole-body PET/CT

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comment: the scope of examinations prior to the completion of therapy is determined individually for each patient based on the clinical situation and tumor spread

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The choice of treatment tactics is determined based on the patient's age, disease stage, tumor size and location, and tumor differentiation grade [9, 16, 33].

When choosing tactics and administering therapy, it should be taken into account that the patient may present with atypical disease manifestations or a combination of a specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for selecting optimal diagnostic and treatment tactics.

Treatment of patients with bone sarcomas is based on a multidisciplinary approach and should be carried out in specialized centers with experience in treating this group of patients. The backbone of therapy is the use of adequate systemic therapy and local control [9, 12, 16, 33]. To this end, surgical methods, chemotherapy, and radiation therapy are used. The sequence of prescribing a particular method, as well as its delivery, depends on the tumor size, extent, histological variant, location, resectability, and patient age.

In all cases of verified malignant bone tumors in patients under 2 years of age, discussing treatment tactics within a multidisciplinary team involving a federal-level medical institution is advisable [12].

3.1 Treatment of patients with osteosarcoma.

• All patients with verified high-grade osteosarcoma are recommended combination treatment, which includes neoadjuvant (preoperative) polychemotherapy, surgery, and adjuvant (postoperative) PCT [9, 12, 14, 34, 35].

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

Comment: Neoadjuvant and adjuvant chemotherapy combined with radical surgery can increase the 5-year overall survival rate in osteosarcoma up to 71%, and up to nearly 80% for localized disease.

Optimal initiation of induction chemotherapy is no later than 1-2 weeks from the date of the diagnostic bone biopsy (of the mass). Preoperative medical treatment has an early effect on micrometastases and improves conditions for radical local treatment.

Doxorubicin**, cisplatin**, high-dose methotrexate**, and high-dose ifosfamide** are effective against osteosarcomas [36, 37, 38].

The MAP PCT regimen (AP: doxorubicin**, cisplatin**, M: high-dose methotrexate) is preferred for patients under 18 years of age (see Schema 1).

Schema 1. Treatment of patients with osteosarcoma

AP course:

Doxorubicin** – 37.5 mg/m²/day, 48-hour continuous infusion, days 1-2 (cumulative dose = 70 mg/m²)

Cisplatin** – 40 mg/m²/day, 72-hour continuous infusion, days 1-3 (cumulative dose = 120 mg/m²), or 60 mg/m²/day as a 4-hour infusion, days 1-2 (cumulative dose = 120 mg/m²)

Supportive care [12, 17, 39, 40, 143]:

The chemotherapy block is administered concurrently with hydration at 3000 mL/m²/day via continuous infusion, starting no later than 4 hours before the administration of cisplatin**. To reduce the risk of nephrotoxicity, the target urine output is >100 mL/h. The scheduled administration of #mannitol** (8 g/m²) is mandatory: administer 20% #mannitol** at a dose of 40 mL/m² or 15% #mannitol** at a dose of 53 mL/m² IV slowly immediately before the administration of cisplatin**. In the case of continuous infusion of cisplatin** over 24 hours, #mannitol** (8 g/m²) is administered 4 times a day (i.e., every 6 hours) on the days of cisplatin** administration.

Patients whose chemotherapy course is complicated by severe prolonged neutropenia (regardless of whether it is accompanied by neutropenic fever) are recommended to receive human recombinant granulocyte colony-stimulating factor [rhG-CSF] (G-CSF). G-CSF is administered subcutaneously at a dose in accordance with the drug's instructions for use. It should be administered no earlier than 24 hours after the completion of chemotherapy until the absolute neutrophil count exceeds 0.5 × 10⁹/L in the post-block period [39, 143].

Antiemetic therapy (see Appendix A3)

Criteria for initiating a polychemotherapy (PCT) course:

- neutrophils ≥ 0.75 × 10⁹/L

or leukocytes ≥ 2 × 10⁹/L

- platelets ≥ 75 × 10⁹/L

- bilirubin ≤ 1.25 × upper limit of normal

- GFR ≥ 70 mL/min/1.73 m²

- left ventricular EF ≥ 50%

If the criteria for initiating the PCT course are not met, the start of the block must be postponed with parameter reassessment in 2–3 days.

If the start of the block is delayed by more than 7 days due to myelosuppression despite G-CSF administration, a 25% dose reduction of cisplatin is recommended.

Course M:

Methotrexate** – 12,000 mg/m² IV drip over 4 hours

It is essential to administer precisely a pair of methotrexate infusions on days 1 and 8.

Supportive care [12, 17, 39]:

The chemotherapy block is administered concurrently with hydration at 3000 mL/m²/day via continuous infusion, starting no later than 4 hours before the administration of methotrexate** (with mandatory administration of sodium bicarbonate** – 60 mmol per 1 liter of sodium chloride** or 5% dextrose**: (60 mL of 7.5% sodium bicarbonate** solution or 100–120 mL of 4% sodium bicarbonate** solution)).

Urine pH assessment – target value 7–8

Mandatory administration of calcium folinate** starting 24 hours from the start of the methotrexate** infusion and continuing until the serum methotrexate** level drops below 0.1 µmol/L.

Blood methotrexate concentration is assessed at 24, 48, and 72 hours and continues until the serum methotrexate** level drops below 0.1 µmol/L. Calcium folinate** is administered at a dose of 15 mg/m² every 6 hours, starting 24 hours after the initiation of the methotrexate** infusion, with the last dose given 6 hours after its concentration reaches 0.1 µmol/L.

The upper limit of methotrexate concentration at 24 hours is 8 µmol/L, at 48 hours is 1 µmol/L, and at 72 hours is 0.1 µmol/L.

If methotrexate** excretion is delayed, an increased dose of calcium folinate** is indicated according to the formula: (60 mg/m² × L) : 2 = daily dose of calcium folinate** (mg), where L is the serum methotrexate concentration.

Patients whose chemotherapy course is complicated by severe prolonged neutropenia (regardless of whether it is accompanied by neutropenic fever) are recommended to receive human recombinant granulocyte colony-stimulating factor [rhG-CSF] (G-CSF). G-CSF is administered subcutaneously at a dose in accordance with the drug's instructions for use. It should be administered no earlier than 24 hours after the completion of chemotherapy until the absolute neutrophil count exceeds 0.5 × 10⁹/L in the post-block period [39, 143].

Antiemetic therapy (see Appendix A3)

Criteria for initiating a polychemotherapy (PCT) course:

- neutrophils ≥ 0.25 × 10⁹/L

or leukocytes ≥ 1 × 10⁹/L

- platelets ≥ 50 × 10⁹/L

- bilirubin ≤ 1.25 × upper limit of normal

- GFR ≥ 70 mL/min/1.73 m²

- left ventricular EF ≥ 50%

- urine pH > 7 immediately before methotrexate administration

- ability to assess serum methotrexate concentration

- ALT/AST levels < 5 times the upper limit of normal

- absence of fluid accumulation in the "third space" (i.e., pleural cavities, abdominal cavity, postoperative areas), as methotrexate** may be retained in these spaces and cause chemical burns.

Course A:

Doxorubicin** – 37.5 mg/m²/day, 48-hour continuous infusion, days 1-2 (cumulative dose = 70 mg/m²)

Supportive care [12, 17, 39]:

Hydration – 3000 mL/m², continuous infusion, 24 hours before the start of doxorubicin** administration, on days 1–2 of the PCT course, and 24 hours after

Patients whose chemotherapy course is complicated by severe prolonged neutropenia (regardless of whether it is accompanied by neutropenic fever) are recommended to receive human recombinant granulocyte colony-stimulating factor [rhG-CSF] (G-CSF). G-CSF is administered subcutaneously at a dose in accordance with the drug's instructions for use. It should be administered no earlier than 24 hours after the completion of chemotherapy until the absolute neutrophil count exceeds 0.5 × 10⁹/L in the post-block period [39, 143].

Antiemetic therapy (see Appendix A3)

Criteria for initiating a polychemotherapy (PCT) course:

- neutrophils ≥ 0.75 × 10⁹/L

or leukocytes ≥ 2 × 10⁹/L

- platelets ≥ 75 × 10⁹/L

- bilirubin ≤ 1.25 × upper limit of normal

- GFR ≥ 70 mL/min/1.73 m²

- left ventricular EF ≥ 50%

If the criteria for initiating the PCT course are not met, the start of the block must be postponed with parameter reassessment in 2–3 days.

If the start of the block is delayed by more than 7 days due to myelosuppression despite G-CSF administration, a dose reduction of doxorubicin** to 30 mg/m²/day (cumulative dose = 60 mg/m²) is recommended.

• All patients with localized low-grade central osteosarcoma, periosteal or parosteal osteosarcoma (intermediate-grade) are not recommended to receive PCT [9, 27, 41, 42, 43, 44].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comments: low-grade central osteosarcoma, periosteal, and parosteal osteosarcoma have low metastatic potential; therefore, the key stage of treatment is radical surgery. PCT may be considered in patients with a high-grade osteosarcoma component according to histological examination and/or the presence of distant metastatic lesions [9, 12, 14, 43, 44].

• All patients with verified periosteal or parosteal osteosarcoma are recommended to undergo wide surgical resection regardless of tumor extent [43, 44].

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

• All patients with verified bone malignancies, except those deemed incurable by a multidisciplinary board decision, in the absence of indications for ablative surgery, are recommended to undergo limb-sparing surgery (segmental bone resection with endoprosthesis replacement, segmental resection with a reconstructive-plastic component) [45, 46].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

• In all patients undergoing resection of a bone malignancy, it is recommended to follow these basic resection principles [30, 47]:

- wide resection (en-bloc) involves removing the tumor without damaging the pseudocapsule and within a cuff of visually unaltered surrounding tissue;

- radical resection – removal of the tumor along with the entire anatomical compartment in which it is located.

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

• All patients with a verified malignant bone tumor, except those deemed incurable by a multidisciplinary board decision, are recommended to undergo ablative surgery (amputation or disarticulation) according to the treatment protocol schedule if at least one of the following indications is present [27, 45, 47]:

- giant tumor size involving all surrounding tissues up to the skin

- involvement of the major neurovascular bundle by the tumor, technically precluding the reconstructive-plastic stage of the surgery

- progression during preoperative PCT, necessitating palliative/debulking surgery

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• All patients with metastatic lung involvement are recommended to undergo thoracotomy with manual palpation of the lung parenchyma [48].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comments: in lung metastases, complete surgical resection can achieve a 40% 5-year survival rate. Patients with metastatic disease should receive the same standardized chemotherapy as patients with localized disease, combined with appropriate local treatment of metastases.

• All patients with local or distant metastatic recurrence of osteosarcoma are recommended to undergo radical surgical intervention [9, 12, 14, 49, 50].

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

Comments: recurrence is diagnosed in 40% of patients with localized osteosarcoma and in 80% of patients with initial distant metastases. Upon recurrence, treatment aims to achieve a second remission through surgical removal of all tumor formations [9, 12, 14, 49, 50]. In the event of osteosarcoma recurrence, treatment tactics, feasibility, and extent of surgery must be discussed jointly with a federal medical center.

• All patients with osteosarcoma recurrence or disease progression are recommended second-line and subsequent therapy using the following regimens:

IE + #lenvatinib** [51, 52]:

Ifosfamide** – 3000 mg/m²/day, IV over 3 hours, on days 1 to 3 (cumulative dose = 9000 mg/m²)

Etoposide** – 100 mg/m²/day, IV over 3 hours, on days 1 to 3 (cumulative dose = 300 mg/m²)

#Lenvatinib** 14 mg/m²/day, orally, daily, continuously until unacceptable toxicity or disease progression occurs

Concurrent administration of mesna** 3000 mg/m²/day via continuous IV infusion on days 1–4 + 20% additional dose IV bolus before each ifosfamide** administration. Hydration of at least 3000 mL/m²/day is recommended, starting 12 hours before and ending 24–48 hours after ifosfamide** administration.

GCR ALEL 2Level of Evidence A (Level of Likelihood of Evidence - 2)

HD-I [14, 53, 137]:

#Ifosfamide** – 3000 mg/m²/day, IV over 3 hours, on days 1 to 5 (cumulative dose = 15000 mg/m²) for patients older than 8 years, or 2000 mg/m²/day, IV over 2 hours, every 12 hours, total of 7 administrations (cumulative dose = 14000 mg/m²) for children older than 6 years.

Therapy with #ifosfamide** at a dose of 3000 mg/m²/day for patients older than 8 years is administered concurrently with mesna** 3000 mg/m²/day via continuous IV infusion on days 1–5 + 20% additional dose IV bolus before each #ifosfamide** administration.

Therapy with #ifosfamide** at a dose of 2000 mg/m²/day for patients older than 6 years is administered concurrently with mesna** 4000 mg/m²/day via continuous IV infusion on days 1–4 + 20% additional dose IV bolus before each #ifosfamide** administration.

Gem/Tax [9, 14, 54, 55, 56]:

#Gemcitabine** – 675 or 900 mg/m²/day IV over 90 min, days 1 and 8 (cumulative dose = 1350 mg/m² or 1800 mg/m²) for patients older than 8 years.

#Docetaxel** – 75 mg/m²/day or 100 mg/m²/day IV over 1 hour, day 8 (cumulative dose = 75 mg/m² or 100 mg/m²) for patients older than 8 years.

LeR CLoE 4Level of Recommendation C (Level of Evidence — 4)

#Sorafenib** [9, 14, 57, 58]:

For patients older than 15 years and/or weighing more than 50 kg, the dose of #sorafenib** is 400 mg/day, per os, twice a day, every 12 hours. #Sorafenib** therapy is administered continuously until unacceptable toxicity or disease progression occurs.

For patients younger than 15 years and weighing 15–20 kg, the dose of #sorafenib** is 100 mg twice a day (every 12 hours); for patients younger than 15 years and weighing 20–30 kg, the dose of #sorafenib** is 200 mg twice a day (every 12 hours).

GCR CLEL 4Level of Evidence C (Level of Likelihood of Evidence - 4)

#Regorafenib** [59, 60, 61]:

#Regorafenib** – 160 mg/day, per os, continuously until unacceptable toxicity or disease progression occurs

GCR CLEL 4Level of Evidence C (Level of Likelihood of Evidence - 4)

#Cabozantinib** [60]:

#Cabozantinib** – 60 mg/day, per os, continuously until unacceptable toxicity or disease progression occurs

GCR CLEL 4Level of Evidence C (Level of Likelihood of Evidence - 4)

3.2 Treatment of patients with Ewing sarcoma and other undifferentiated small round cell bone sarcomas.

• All patients with Ewing sarcoma and other undifferentiated small round cell bone sarcomas are recommended combination treatment, which includes neoadjuvant (preoperative) polychemotherapy, surgery, and adjuvant (postoperative) chemotherapy, as well as radiation therapy [9, 12, 14, 62, 63, 64, 65, 66].

GCR CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5)

Comments: multimodality treatment including multi-agent chemotherapy, surgery, and radiation therapy has increased the 5-year overall survival rate to 70%. The most active agents against Ewing sarcoma are vincristine**, doxorubicin**, cyclophosphamide**, ifosfamide**, etoposide**.

An intensive chemotherapy regimen with a 14-day interval (alternating VDC/IE courses) is currently preferred because, according to randomized trials, it allowed patients with localized Ewing sarcoma to achieve a 5-year event-free survival rate of 73% compared to the standard 21-day regimen (65%).

Patients receive a total of 14 chemotherapy courses, of which 9 courses are part of the neoadjuvant treatment stage and 5 courses are administered postoperatively. Upon reaching a cumulative anthracycline and related compound dose of 375 mg/m2, which corresponds to 5 courses of VDC chemotherapy, postoperative blocks are administered without doxorubicin (VC) (see Regimen 2).

Regimen 2. Therapy for patients with Ewing sarcoma

VDC course:

Vincristine** – 2 mg/m² (maximum 2 mg; 0.05 mg/kg for children aged 1 to 3 years and 0.025 mg/kg for children under 1 year of age) slow IV push – day 1

Doxorubicin** – 37.5 mg/m²/day (for children <1 year old, 1.25 mg/kg per day) IV drip via continuous infusion over 48 hours – days 1, 2 (total 75 mg/m²)

Cyclophosphamide** – 1200 mg/m² IV drip over 1 hour – day 1

Supportive care [12, 17, 66]:

Hydration – 3000 mL/m², continuous infusion, 24 hours before the start of doxorubicin** administration, on days 1–2 of the PCT course, and 24 hours after

Concurrent administration of mesna** 1200 mg/m² over 24 hours on the day of cyclophosphamide** administration + 20% additional dose IV bolus before cyclophosphamide** administration. Hydration of at least 3000 mL/m²/day is recommended, starting 12 hours before and ending 24–48 hours after the completion of the chemotherapy course.

Patients who experience severe prolonged neutropenia as a complication of chemotherapy (regardless of whether it is accompanied by neutropenic fever) are recommended to receive recombinant human granulocyte colony-stimulating factor [rhG-CSF] (G-CSF). G-CSF is administered subcutaneously at a dose in accordance with the medication's prescribing information. It should be administered no earlier than 24 hours after the completion of chemotherapy until the absolute neutrophil count exceeds 0.5 × 10⁹/L in the post-block period [66, 143].

Antiemetic therapy (see Appendix A3)

Criteria for initiating a polychemotherapy (PCT) course:

- neutrophils ≥ 0.75 × 10⁹/L

or leukocytes ≥ 2 × 10⁹/L

- platelets ≥75 × 10⁹/L

- bilirubin ≤ 1.25 × upper limit of normal

- GFR ≥ 70 mL/min/1.73 m²

- left ventricular EF ≥ 50%

To maintain the intensive chemotherapy schedule (every 14 days), if the criteria for starting a chemotherapy course are not met on day 22, dose reduction of chemotherapeutic agents is recommended:

- 25% reduction of doxorubicin** and cyclophosphamide** for subsequent courses

IE course:

Ifosfamide** – 1800 mg/m²/day, IV over 1 hour, days 1–5 (cumulative dose = 9000 mg/m²)

Etoposide** – 100 mg/m²/day, IV over 2 hours, days 1–5 (cumulative dose = 500 mg/m²)

Supportive care [12, 17, 66]:

Hydration - 3000 mL/m2, continuous infusion, starting 24 hours before the administration of doxorubicin**, on days 1–2 of the chemotherapy course, and for 24 hours afterwards

Concurrent administration of mesna** 2000 mg/m²/day via continuous IV infusion on days 1–5 + 20% additional dose IV bolus before each ifosfamide** administration. Hydration of at least 3000 mL/m²/day is recommended, starting 12 hours before and ending 24–48 hours after the completion of the chemotherapy course.

Patients who experience severe prolonged neutropenia as a complication of chemotherapy (regardless of whether it is accompanied by neutropenic fever) are recommended to receive recombinant human granulocyte colony-stimulating factor [rhG-CSF] (G-CSF). G-CSF is administered subcutaneously at a dose in accordance with the medication's prescribing information. It should be administered no earlier than 24 hours after the completion of chemotherapy until the absolute neutrophil count exceeds 0.5 × 10⁹/L in the post-block period [66, 143].

Antiemetic therapy (see Appendix A3)

Criteria for initiating a polychemotherapy (PCT) course:

- neutrophils ≥ 0.75 × 10⁹/L

or leukocytes ≥ 2 × 10⁹/L

- platelets ≥75 × 10⁹/L

- bilirubin ≤ 1.25 × upper limit of normal

- GFR ≥70 mL/min/1.73 m²

To maintain the intensive chemotherapy schedule (every 14 days), if the criteria for starting a chemotherapy course are not met on day 22, dose reduction of chemotherapeutic agents is recommended:

- 25% reduction of etoposide** for subsequent courses.

VC course:

Vincristine** – 2 mg/m² (maximum 2 mg; 0.05 mg/kg for children aged 1 to 3 years and 0.025 mg/kg for children under 1 year of age) slow IV push – day 1

Cyclophosphamide** – 1200 mg/m² (for children under 3 years of age, 40 mg/kg once daily) IV drip over 1 hour – day 1

Supportive care [12, 17, 66]:

Hydration – 3000 mL/m², continuous infusion, 24 hours before the start of doxorubicin** administration, on days 1–2 of the PCT course, and 24 hours after

Concurrent administration of mesna** 1200 mg/m² over 24 hours on the day of cyclophosphamide** administration + 20% additional dose IV bolus before cyclophosphamide** administration. Hydration of at least 3000 mL/m²/day is recommended, starting 12 hours before and ending 24–48 hours after the completion of the chemotherapy course.

Patients who experience severe prolonged neutropenia as a complication of chemotherapy (regardless of whether it is accompanied by neutropenic fever) are recommended to receive recombinant human granulocyte colony-stimulating factor [rhG-CSF] (G-CSF). G-CSF is administered subcutaneously at a dose in accordance with the medication's prescribing information. It should be administered no earlier than 24 hours after the completion of chemotherapy until the absolute neutrophil count exceeds 0.5 × 10⁹/L in the post-block period [66, 143].

Antiemetic therapy (see Appendix A3)

To maintain the intensive chemotherapy schedule (every 14 days), if the criteria for starting a chemotherapy course are not met on day 22, dose reduction of chemotherapeutic agents is recommended:

- 25% reduction of cyclophosphamide** for subsequent courses.

• All patients with localized Ewing sarcoma whose initial primary tumor volume exceeds 200 cm³ are recommended high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) [64, 65, 66, 68, 69, 70].

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

Comments: Stem cell harvest is performed according to the principles adopted at the center where the procedure is planned. Conditioning prior to auto-HSCT includes the use of #busulfan** in combination with #melphalan** [66].

Regimen 4. #Busulfan**/#melphalan** conditioning regimen

#busulfan**: from day -7 to day -3, every 6 hours, IV over 30 min (total 16 administrations),

<9 kg = 1 mg/kg

9–<16 kg = 1.2 mg/kg

16–23 kg = 1.1 mg/kg

>23–34 kg = 0.95 mg/kg

>34 kg = 0.8 mg/kg

#melphalan**: 140 mg/m², IV, over 30 min, day -2

• All patients with localized Ewing's sarcoma whose initial primary tumor volume is less than 200 cm³ and whose post-therapeutic pathomorphosis corresponds to grades 0–3 (>10% viable tumor cells), are recommended high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) [64, 65, 66, 68, 69, 70].

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

Comments: except for patients with the primary tumor located in the pelvic bones, vertebrae, and cranial bones.

• All patients with verified Ewing's sarcoma and other undifferentiated small round cell sarcomas of bone with initially detected distant metastases are recommended maintenance therapy starting from week 29 from the onset of therapy for 12 months [71, 72, 73, 74, 75, 76, 77, 78].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comments: maintenance therapy is one of the key stages of treatment for patients with metastatic soft tissue sarcomas (STS), including the group of patients with rhabdomyosarcoma-like tumors, which currently include extraskeletal Ewing's sarcoma and other undifferentiated small round cell soft tissue sarcomas with CIC, BCOR, or EWSR1-non-ETS gene rearrangements [71, 72, 78].

Administering maintenance therapy to patients with Ewing's sarcoma and other undifferentiated small round cell sarcomas of bone with initial metastatic lesions of the lungs, skeletal bones, bone marrow, etc. may help improve disease control by increasing the duration of specific therapy, as well as increase overall and event-free survival rates in this group of patients [73, 74, 75, 76, 77, 78]

Maintenance therapy consists of 28-day treatment cycles including cyclophosphamide** and #vinorelbine** [33, 78]. Cyclophosphamide** at a dose of 25 mg/m²/day is administered per os continuously from days 1 to 28, #vinorelbine** is administered on days 1, 8, and 15 of each cycle IV at a dose of 25 mg/m². Thus, a total of 12 courses of maintenance chemotherapy are administered over 12 months [57, 78].

• All patients with a verified malignant bone tumor, except for those deemed incurable by a multidisciplinary team decision and in the absence of indications for organ-ablative surgery, are recommended limb-sparing surgery (segmental bone resection with endoprosthesis replacement, segmental resection with a reconstructive-plastic component) [45, 46].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

• In all patients undergoing resection of a bone malignancy, it is recommended to follow these basic resection principles [30, 47]:

- wide resection (en-bloc) involves removing the tumor without damaging the pseudocapsule and within a cuff of visually unaltered surrounding tissue;

- radical resection – removal of the tumor along with the entire anatomical compartment in which it is located.

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

• All patients with a verified malignant bone tumor, except for those deemed incurable by a multidisciplinary team decision, are recommended organ-ablative surgery (amputation or exarticulation) according to the treatment protocol timeline in the presence of at least one of the following indications [27, 45, 46]:

- giant tumor size involving all surrounding tissues up to the skin

- involvement of the major neurovascular bundle by the tumor, technically precluding the reconstructive-plastic stage of the surgery

- progression during preoperative PCT, necessitating palliative/debulking surgery

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

• All patients with Ewing's sarcoma are recommended radiotherapy [9, 12, 14].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comments: radiotherapy in patients with Ewing's sarcoma is generally used in combination with surgery, but may be administered as a standalone treatment in unresectable patients. Irradiation of metastatic sites and total lung irradiation may also be performed. Specifics of radiotherapy in Ewing's sarcoma.

• All patients with relapsed Ewing's sarcoma and other undifferentiated small round cell sarcomas of bone or disease progression are recommended second-line and subsequent-line therapy using the following regimens:

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

VIT [80]:

For patients older than 1 year.

Vincristine** – 1.5 mg/m²/day, IV over 30 min, day 1

#Irinotecan** – 50 mg/m²/day IV over 1 hour, days 1 to 5 (cumulative dose = 250 mg/m²)

#Temozolomide** – 150 mg/m²/day, per os, days 1 to 5 (cumulative dose = 750 mg/m²)

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

TC [82, 83, 84]:

#Topotecan** – 0.75 mg/m²/day IV infusion over 1 hour, days 1 to 5

Cyclophosphamide** – 250 mg/m²/day IV over 1 hour, days 1 to 5

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

HD-I [85, 144]:

#Ifosfamide** – 3000 mg/m²/day, IV over 24 hours, days 1 to 5 (cumulative dose = 15000 mg/m²) for patients older than 4 years.

Concurrent administration of mesna** according to the schedule: 400 mg/m²/day IV as a prolonged infusion 1 hour before starting #ifosfamide**, then 3000 mg/m²/day as a continuous infusion on days 1–5 during administration, 800 mg/m³/day after administration is completed. Hydration of at least 3000 mL/m⁴/day is recommended, starting 12 hours before and ending 24–48 hours after #ifosfamide** administration.

Level of Recommendation CLevel of Evidence 2Level of Recommendation C (Level of Evidence - 2)

#Pazopanib** [77,86]:

#Pazopanib** – 800 mg/day, per os, continuously until unmanageable toxicity or disease progression

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

#Regorafenib** [60,87]:

#Regorafenib** – 160 mg/day, per os, continuously until unacceptable toxicity or disease progression occurs

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

#Cabozantinib** [60]:

#Cabozantinib** – 60 mg/day, per os, continuously until unacceptable toxicity or disease progression occurs

GCR CLEL 4Level of Evidence C (Level of Likelihood of Evidence - 4)

• Patients with early relapses at the consolidation stage with existing indications are recommended high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) [88, 89].

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

3.3 Treatment of patients with chondrosarcoma

• All patients with chondrosarcoma (regardless of the grade of differentiation) are recommended radical surgical intervention [9,12,14].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

Comments: in patients with small tumors and G1 differentiation grade, tumor curettage with meticulous cavity treatment and preliminary coordination of the surgical scope with a federal center is possible in some cases. Classical chondrosarcoma is characterized by low sensitivity to drug therapy and radiotherapy; therefore, careful preparation and planning of the surgical intervention are necessary to reduce the risk of disease relapse.

Before performing surgical intervention, a comprehensive examination of the patient is necessary to rule out a systemic nature of the disease.

3.4 Treatment of patients with other bone neoplasms.

• All patients with giant cell tumor are recommended radical surgical intervention [9, 12, 14].

LoE CGoE 5Level of Evidence C (Level of Confidence - 5)

• All patients with the goal of improving the functional result of surgical intervention or in case of unresectable GCT are recommended therapy with #Denosumab** [9, 12, 14, 90, 91, 92].

LoE CGoE 4Level of Evidence C (Level of Reliability of Evidence - 4)

Comments: considering the locally aggressive nature of giant cell tumor, the high risk of local disease relapse with inadequate surgical intervention, and the possibility of malignant transformation of GCT, mandatory consultation of patients at a federal center is recommended to coordinate treatment tactics and indications for prescribing #Denosumab**.

#Denosumab** – Days 1, 8, 15, 28: 120 mg subcutaneously, then every 28 days; preoperative administration duration depends on the volume of surgery and tumor localization. Maintenance therapy: 120 mg subcutaneously every 3 months, long-term (in agreement with specialists of federal centers).

3.5 Transfusion support

• Children with malignant neoplasms receiving chemotherapy and/or radiotherapy who have severe anemia (Hb <70 g/L, Ht <25%) with symptoms and signs of anemic hypoxia and without bleeding are recommended red blood cell transfusions [93-102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: Transfusions may not be required for well-compensated patients recovering from induced aplasia. However, in the event of upcoming intensive chemotherapy in the absence of clinical manifestations of anemic syndrome, red blood cell transfusions may be justified. The decision to use transfusions should be based primarily on clinical rather than laboratory data [93-102].

• In stable pediatric patients with malignancies in the absence of bleeding, it is recommended to transfuse red blood cell components of donor blood at a dose of 10-15 mL per kg of body weight [93-102].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• Pediatric patients with oncological diseases are recommended to receive leukoreduced blood components [93-102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: it has been shown that the use of leukoreduced blood components reduces the incidence of febrile non-hemolytic transfusion reactions, and also significantly decreases the likelihood of HLA alloimmunization of the patient and the transmission of certain transfusion-transmissible infections (cytomegalovirus, Epstein-Barr virus).

• To prevent transfusion-associated graft-versus-host disease, patients with malignancies receiving chemo- and/or radiation therapy who are immunosuppressed are recommended to receive transfusions of cellular blood components irradiated with ionizing radiation at a dose of 25 Gy [93-102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• In children with malignant neoplasms and hypoproliferative thrombocytopenia caused by the underlying disease and/or its treatment, prophylactic platelet concentrate transfusions are recommended under the following conditions [93-102].

  • stable neonates with a platelet count drop to ≤25×10⁹/L;

  • stable patients with a platelet count drop to ≤10×10⁹/L;

  • febrile patients with a platelet count drop to ≤15×10⁹/L;

  • patients at high risk of bleeding with a platelet count drop to ≤20×10⁹/L;

  • prior to minor surgical procedures in non-critical sites with a platelet count drop to ≤20×10⁹/L;

  • prior to lumbar puncture, with a platelet count drop to ≤40×10⁹/L;

  • prior to percutaneous liver biopsy, if the platelet count is ≤50×10⁹/L;

  • during surgical interventions in critical sites (e.g., central nervous system), if the platelet count is ≤75-100×10⁹/L;

  • prior to other surgical interventions with a platelet count of ≤50×10⁹/L

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: patients receiving antithrombotic agents, patients with DIC, sepsis, etc., are at an increased risk of bleeding.

• Platelet concentrate transfusions in children with hypoproliferative thrombocytopenia and hemorrhagic syndrome are recommended in case of [93-102]:

  • minor hemorrhagic syndrome and a platelet count drop to ≤10×10⁹/L;

  • moderate hemorrhagic syndrome and a platelet count drop to ≤20×10⁹/L;

  • severe hemorrhagic syndrome and a platelet count drop to ≤30×10⁹/L;

  • bleeding in a critically important location (e.g., CNS) and a platelet count drop to ≤100×10⁹/L

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• Platelet transfusions in children with malignant neoplasms are recommended at the following dose [93-102]:

  • neonates 10-15 mL/kg

  • children with a body weight of more than 10 kg: 10 mL/kg

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• Granulocyte concentrate transfusions are recommended for children with oncological diseases and severe, prolonged neutropenia (neutrophil count less than 200/µL) in the presence of a severe bacterial or fungal infection refractory to adequate antimicrobial therapy [93-102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• Donor plasma transfusions are recommended for children with oncological diseases in the presence of clinically significant bleeding combined with an elevation of activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) of more than 1.5 times the upper limit of normal [93-102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• Donor plasma transfusions in children with malignant neoplasms are recommended at a dose of 15 mL/kg of body weight [93-102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• Cryoprecipitate transfusions in children with oncological diseases are recommended when the fibrinogen concentration decreases below 1-1.5 g/L [93-102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: Cryoprecipitate transfusions for acquired fibrinogen deficiency caused by various reasons are advisable when its serum concentration drops below 1 g/L. Cryoprecipitate transfusions when its blood concentration drops below 1.5 g/L are advisable for patients with acute promyelocytic leukemia, severe intraoperative bleeding, and patients with sepsis who develop hemorrhagic syndrome.

• Cryoprecipitate transfusion is recommended at a dose of 1 unit per each 5 kg of the patient's body weight [93-102].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

3.6 Prevention and treatment of nausea and vomiting

• All patients with verified bone malignancies for the duration of treatment, for the purpose of treating and preventing nausea and vomiting caused by antitumor therapy, are recommended to evaluate the emetogenic level of medicinal products, and to carry out treatment and prevention of nausea and vomiting using medicinal products (see Appendix A3.1) [103-112].

GCR ALeE 2Grade of Recommendation A (Level of Evidence - 2)

3.7 Nutritional support

Diet therapy

Medical nutrition is an essential component of the therapeutic process and preventive measures, and includes diets that have a established chemical composition, energy value, consist of specific products, including specialized medical nutrition products, including dry protein composite mixtures and vitamin-mineral complexes subjected to appropriate technological processing, as well as medical enteral nutrition products (medical nutrient mixtures).

• Medical nutrition is recommended to be prescribed to patients upon admission to a medical organization for inpatient medical care. Medical nutrition is prescribed by the attending physician or the on-duty physician of the medical organization in accordance with the nosological form of the disease according to the primary and/or comorbid diagnosis [113-133].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: The diet variant depends on the patient's condition, gastrointestinal and metabolic disorders, primary or comorbid pathology, and is regulated by Appendix No. 3 "To the Procedure for Providing Patients with Medical Nutrition", approved by the Order of the Russian Ministry of Health dated September 23, 2020, No. 1008n

• All patients with protein-energy malnutrition or a high risk of its development (regardless of nutritional status) are recommended to receive nutritional support (NS) [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: the presence of protein-energy malnutrition or a high risk of its development in children with malignancies during antitumor treatment causes associated risks of increased disability, increased duration and scope of primary and supportive treatment, low success rate of the ongoing treatment, increased mortality, and overall financial costs for therapeutic and rehabilitation measures—during active antitumor treatment and after its completion. Occult PEM (e.g., masked by excess fat mass during prolonged systemic glucocorticosteroid therapy) is accompanied by the same risks. Therefore, given the high probability of worsening nutritional problems during treatment, it is advisable to prescribe nutritional support to patients in addition to their existing diet or replacing it.

Nutritional screening and monitoring (assessment of nutritional status)

Comments: detection of nutritional disorders in the early stages of their development, especially before the start of antitumor therapy, allows for timely initiation of nutritional correction. Criteria for protein-energy malnutrition, obesity, and nutritional risk factors—see Appendix G3, Appendix G4. Primary screening is performed either by assessing anthropometric indicators and identifying risk, or by using standard scales/instruments for nutritional screening. Nutritional screening consists of initial and then regular assessment of nutritional status and the risk of developing protein-energy malnutrition, including occult PEM, in each patient from the moment of hospital admission. The frequency should be determined by the specific clinical situation and the characteristics of the treatment being administered [113-133].

Comment: most screening tools (questionnaires) are aimed at combining data on the primary diagnosis, clinical status, anthropometric indicators, body weight dynamics, nutritional state, and integrating these data into a total score with subsequent division of patients into 2 or 3 cohorts: do not need nutritional correction (support); require repeat screening dynamically ("at-risk" group); need nutritional correction (support). A clinical department (or institution) has the right to use the tool, or combination of tools, that it considers most acceptable for conducting nutritional screening among its patients. It must be remembered that existing screening tools are not designed to answer the question about the volume and method of necessary nutritional support, nor do they carry prognostic information for a specific patient, since their application is aimed exclusively at medical triage. Moreover, there is no universal screening tool in pediatrics

• If there is a need for a detailed anthropometric study for the primary and regular assessment of nutritional status, it is recommended to use the following as additional anthropometric parameters: measurement of circumferences, lengths, skinfold thickness, and handgrip dynamometry [113-133].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: WHO growth charts are commonly used "by default" in the Russian Federation; for convenience, freely available software (WHO Anthro and WHO Anthro Plus) allows for the rapid calculation of key anthropometric parameters in relation to WHO reference data. However, other reference data may also be used to correlate patient data with norms—in such cases, the specific references used must be indicated.

• For patients with nutritional disorders or those at high nutritional risk identified during initial screening, it is recommended to perform a more detailed assessment of nutritional status, including dietary analysis, laboratory parameter evaluation, as well as a detailed physical examination and interview to identify nutritional-metabolic disorders and their predictors [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• Due to the high prevalence of body composition disorders and tissue imbalance in the pediatric oncology population—manifesting as occult protein-energy malnutrition (sarcopenia), occult obesity (accumulation of fat mass), and the prevalence of edema (including occult edema) as well as altered fluid compartment distribution—it is recommended to assess body composition using various available methods as an additional confirmatory method for evaluating nutritional status. These include bioelectrical impedance analysis (determining the percentage of water, muscle, and fat tissue using a bioelectrical impedance analyzer), dual-energy X-ray absorptiometry (whole-body X-ray densitometry), MRI, and CT for a confirmatory and in-depth assessment of body composition in risk groups. These groups include: chronic protein-energy malnutrition, prolonged requirement for parenteral nutrition exceeding 2 months, inclusion of hormonal drugs in therapy, central nervous system tumors, chronic eating disorders, and hematopoietic stem cell transplantation (HSCT) recipients with identified anthropometric nutritional disorders [113-133].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• All patients receiving nutritional support are recommended to undergo nutritional monitoring, which includes an interview, anthropometry, and, if necessary, body tissue composition analysis and laboratory parameters (general clinical biochemical blood test, coprological examination) [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Nutritional support

Nutritional support is provided by prescribing specialized enteral nutrition products. Enteral nutrition products or therapeutic nutritional formulas are liquid or dry (reconstituted to ready-to-use) dietary foods for special medical purposes or dietary prophylactic nutrition intended for oral consumption directly or administration via a tube when the body's needs for nutrients and energy cannot be met in the usual manner [113-133]. Therapeutic formulas are specially developed food products with a specified chemical composition, energy value, physical properties, and proven therapeutic effect that meet the physiological needs of the body while taking into account the metabolic disorders of a sick person. When choosing the form, method, type, and volume of nutritional support, it is recommended to be guided, first of all, by the principle of an individual patient-oriented approach—in accordance with the clinical situation and logic [113-133].

• Patients with obesity (excess fat mass) may develop occult protein-energy malnutrition, defined by a deficit of fat-free mass and a critical reduction in its skeletal muscle compartment; therefore, it is recommended to correct this type of deficiency. Obesity itself is not a contraindication for enteral or parenteral nutritional support [113-133].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• It is recommended to calculate the volume of nutritional support by calculating nutritional requirements or total energy expenditure (TEE) [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: the calculation of total energy expenditure (TEE) is carried out using the formula: TEE = REE × CC, where REE is resting energy expenditure and CC is the conversion coefficient. Indirect calorimetry is the gold standard for determining REE. If indirect calorimetry is not feasible, REE can be calculated using a formula (e.g., Schofield). To avoid overfeeding during the initial stages of nutritional support in children with chronic protein-energy malnutrition and/or an estimated history of inadequate nutrient intake for 3 or more consecutive months, a CC of 0.85–1.4 is used to calculate TEE. The exact volume of nutritional intervention is determined based on the specific clinical situation [113-133].

• When choosing the route of nutritional support, it is recommended to prioritize the use of enteral nutrition (EN) [113-133].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: EN is the most physiological method, providing intraluminal trophism of the gastrointestinal mucosa, preventing microbial translocation from the intestinal lumen into the bloodstream, and being more cost-effective than parenteral nutrition

• If the patient cannot, does not want to, or is not ready to independently consume the prescribed volume of the formula in the required regimen, it is recommended to use a nasogastric (nasojejunal) tube or gastrostomy for enteral nutrition (as part of the puncture gastrostomy kit, medical device registration number RZN 2013/1309) [113-133].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: lack of appetite, unwillingness to consume food and EN formulas, swallowing disorders, and the inability to meet nutrient and energy requirements orally are indications for EN via a nasogastric tube. The presence of pathological conditions in which the patient must not ingest food naturally (acute pancreatitis, gastric outlet stenosis, high proximal fistulas) indicates the need for EN via a nasojejunal tube (sterile single-use nasojejunal tube with a guide wire and nasal tube).

• If there is a current or anticipated need for tube feeding lasting more than 6 weeks, gastrostomy placement is recommended [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: when long-term enteral nutrition is required and there is a predicted risk of nutritional deficiency (including during chemoradiotherapy), preventive gastrostomy placement can be performed, bypassing the tube-feeding stage

• If a child has severe chronic protein-energy malnutrition with a high risk of further deterioration, especially if they are yet to undergo further anti-tumor treatment, it is recommended to place a gastrostomy, bypassing the stage of tube feeding and even sipping [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• For patients with gastrointestinal disorders, it is recommended to start enteral nutritional support with a specialized therapeutic formula for enteral nutrition with a caloric density of 1 kcal/ml (isocaloric formula) and, if necessary, subsequently switch to a therapeutic enteral nutrition formula with a caloric density of >1 kcal/ml (hypercaloric formula), under tolerance monitoring [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: formulas are divided by their energy density into isocaloric (1 kcal/ml for children over one year of age and 0.67-0.69 kcal/ml for children under one year) and hypercaloric (more than 1 kcal/ml for children over one year, and 1 kcal/ml for children under one year). It is advisable to start nutritional support with isocaloric formulas, especially in children with a history of or current gastrointestinal disorders and/or those who have never received enteral nutrition before.

• In the presence of malabsorption/severe gastrointestinal disorders (but in the absence of contraindications to EN), severe food allergy (or cow's milk protein allergy), it is recommended to prescribe a semi-elemental/oligomeric (или, по показаниям, elemental) specialized therapeutic formula for enteral nutrition [113-133].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comment: based on their chemical composition, formulas are divided into polymeric (primarily containing intact protein) and oligomeric (containing protein hydrolysate) or semi-elemental. Elemental formulas do not contain intact protein: their protein component is represented by amino acids. Elemental formulas are usually prescribed for confirmed cow's milk protein allergy.

• For all patients in whom the estimated nutritional requirements cannot be met enterally and/or in cases where EN cannot cover basal metabolic energy needs, it is recommended to prescribe parenteral nutrition (in the absence of contraindications to parenteral nutrition). Among these patients, special attention should be paid to children with protein-energy malnutrition, particularly moderate and severe forms [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: the key indication for prescribing parenteral nutrition (PN) is the inability to meet the estimated nutritional requirements (at least at the level of basal energy expenditure) enterally – either currently or potentially in the short term.

• Parenteral nutrition is recommended to be initiated gradually, step-by-step increasing the volume (and rate) of daily infusion, starting from one-third to one-half of the calculated target volume. Under the monitoring of general clinical blood biochemistry parameters (primarily glucose, direct bilirubin, urea), acid-base balance, and blood gases, the volume should be brought to the target over several days (the rate of reaching the target volume is determined individually based on the clinical situation). Discontinuation of parenteral nutrition is also recommended to be performed gradually, step-by-step, in the reverse order [113-133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: initiating parenteral nutrition immediately at full volume is highly discouraged, as is a one-time discontinuation ("starting the next day") of total parenteral nutrition. It is especially dangerous to prescribe full parenteral nutrition to patients with a prolonged lack of alimentation due to the possible development of refeeding syndrome. The volume of PN should be gradually (stepwise) increased with parallel monitoring of blood acid-base balance, electrolytes, glucose, urea, and direct bilirubin. If necessary, the volume and composition of PN must be adjusted.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• All patients with verified bone malignancy at all stages of disease therapy, as well as after treatment completion, are recommended to undergo comprehensive rehabilitation measures, and supportive therapy if necessary, to improve treatment outcomes and the patient's quality of life, depending on comorbid conditions and complications of the primary therapy [134, 135, 136].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: rehabilitation is an integral part of the treatment process in patients with diagnosed malignant neoplasms. Rehabilitation includes a set of measures aimed at restoring the patient's well-being and working capacity (restorative rehabilitation), improving their quality of life, social adaptation, and prolonging life as much as possible while relieving pain (palliative rehabilitation).

A properly selected rehabilitation course will allow the patient to return to a full life and/or continue scheduled therapy.

The course of rehabilitation measures is developed individually, taking into account the patient's condition, functional capabilities, and motivation.

The initiation of rehabilitation measures depends on the stage and risk group, starting during the initial polychemotherapy phases and continuing after its completion across all stages of follow-up observation. Rehabilitation measures are conducted under the supervision of a pediatric oncologist at the medical institution where the patient received the main stages of therapy. Rehabilitation is divided into medical, psychological, social, etc. The program involves educators (preschool and school education), social workers, psychologists, and physicians of various specialties (medical rehabilitation specialists, neurologists, endocrinologists, cardiologists, orthopedic traumatologists, etc.).

• All patients with an established diagnosis of bone malignancy are recommended to undergo rehabilitation measures in regional centers based on outpatient clinics and in specialized medical and rehabilitation centers. The frequency of rehabilitation is 3-4 times a year and can be increased depending on the patient's psycho-somatic and orthopedic status [134, 135, 136].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: one of the rehabilitation stages for patients after major joint arthroplasty is the lengthening of endoprostheses to correct limb length discrepancy alongside active physical rehabilitation methods.

5. Prevention and Dispensary Observation

• All patients who have completed treatment for bone malignancy are recommended to undergo follow-up observation by a district pediatrician and a pediatric oncologist within the established timeframes (see Table 9) [9, 12, 14].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Table 9. Follow-up of patients with bone malignancies

6. Organization of Medical Care

Indications for hospitalization in a medical organization

1. Need for biopsy, surgical treatment, radiotherapy, chemotherapy;

2. Correction of post-treatment anemia, thrombocytopenia, neutropenia, febrile neutropenia;

3. Correction of endoprosthesis or other replacement implantable device;

4. Infection of the endoprosthesis or other replacement implantable device;

5. Need for procedures under general anesthesia;

6. Need to establish or clarify the diagnosis.

Indications for patient discharge from a medical organization

1. End of the treatment phase, provided the patient is in a stable satisfactory somatic status

2. Completion of all treatment, achievement of remission, provided the patient is in a stable satisfactory somatic status

3. Incurability of the patient with the possibility of transfer to palliative care or hospice care

7. Additional Information

1. Features of pathomorphological examination of bone malignancies

1.1 Sample preparation

The referral for morphological examination of soft tissue and bone tumors must include essential information about the patient, study objectives, prior treatment, and specimen characteristics. Native tissue is delivered in a 10% neutral buffered formalin solution. Tissues after radical resections are sectioned before fixation for better preservation.

Small bone fragments are decalcified in an EDTA solution and then placed in histological cassettes. Small soft tissue fragments and biopsy specimens are also placed in cassettes. Bone plates are decalcified, labeled, and distributed into marked cassettes.

Afterwards, the material undergoes tissue processing and paraffin embedding to form paraffin blocks. Sections of no more than 4 µm thickness are produced from the resulting blocks.

The sections must be uniformly stained, free of folds and tears, allowing the evaluation of the cytologic properties of the cells. Microscopic examination describes the components of the pathological tissue, cytologic properties of the cells, heterogeneity, necrosis, fibrosis, chondrogenesis, osteogenesis, mitotic and apoptotic activity, and the relationship with surrounding tissues. The identified changes are correlated with clinical data.

1.1 Classical Osteosarcoma

Classical osteosarcoma (COS) typically presents as a large (>5-10 cm) intramedullary mass located in the metaphyseal region with varying degrees of extension into the adjacent diaphysis and epiphysis. The cut surface is heterogeneous and depends on the type and degree of mineralization of the predominant matrix. Histologically, the identification of neoplastic bone formation is essential for the diagnosis of COS. Tumor cells typically demonstrate marked anaplasia and pleomorphism; they may be spindle-shaped, plasmacytoid, or epithelioid. Mitotic activity is usually high, and atypical mitoses are frequently present. COS has a broad histomorphologic spectrum and is subdivided into osteoblastic (76-80%), chondroblastic (10-13%), and fibroblastic (10%) types.

Telangiectatic osteosarcoma (TOS) manifests as a hemorrhagic, multilocular lesion filled with blood clots, classically described as a "bag of blood". Solid fleshy or sclerotic areas are usually not observed. Histologically, TOS consists of blood-filled or empty cystic spaces closely mimicking an aneurysmal bone cyst. The septa are of variable thickness and are populated by pleomorphic cells with substantial nuclear hyperchromasia. Atypical mitoses are readily identified.

The macroscopic features of small cell osteosarcoma (SMOS) are indistinguishable from those of COS. Histologically, SMOS consists of small cells with scant cytoplasm associated with osteoid production. The nuclei are round or oval, the chromatin may be fine or coarse, and mitoses are readily detectable. In the less common spindle cell type, the nuclei are short, oval, or spindle-shaped, with granular chromatin and inconspicuous nucleoli. A focal hemangiopericytoma-like pattern may be observed.

Immunohistochemically, COS has a broad immunoprofile that lacks diagnostic specificity. Antigens such as SATB2, osteocalcin (BGLAP), osteonectin (SPARC), osteoprotegerin (TNFRSF11B), RUNX2, S100, actins, and CD99 are frequently expressed. TOS and SMOS have an immunophenotype similar to that of COS. SATB2 is considered a highly sensitive marker of osteoblastic differentiation, but it lacks specificity. It can help distinguish SMOS from Ewing sarcoma.

1.3 Parosteal Osteosarcoma

Parosteal osteosarcoma (POS) macroscopically presents as an exophytic lobulated mass attached to the cortex by a broad base. On the cut surface, the tumor is yellowish-white, hard, and granular, with possible cartilage nodules. Histologically, POS consists of bone trabeculae with intertrabecular strips of spindle cells. The tumor is usually hypocellular with minimal atypia and low mitotic activity. In 20% of cases, the tumor is more cellular with moderate atypia. Cartilaginous differentiation is observed in 50% of cases. Dedifferentiation occurs in 15-43% of cases. Immunohistochemical staining for MDM2 and CDK4 is useful for the diagnosis of POS, especially in small biopsies. Differential diagnosis includes benign fibrous and fibro-osseous lesions. Analysis of MDM2 amplification or immunohistochemical staining for MDM2 and CDK4 assists in differential diagnosis. POS is morphologically distinct from periosteal and high-grade surface osteosarcomas. The presence of a focal low-grade spindle cell component and/or MDM2 amplification suggests dedifferentiated POS.

1.4 Periosteal Osteosarcoma

Periosteal osteosarcoma macroscopically has a well-circumscribed, lobulated appearance with a broad base, attached to the surface of the cortical plate and elevating the periosteum. The tumor consists of lobular cartilaginous tissue. A spiculated reaction may be noticeable, and there is usually a well-defined superficial capsule formed by the periosteum. Histologically, the tumor consists of poorly demarcated lobules of cytologically atypical cartilage with intertrabecular strips of primitive sarcomatous cells in which bone formation is present. Atypical fibroblastic areas may be encountered. Primitive undifferentiated mesenchymal cells with nuclear atypia and mitoses predominate at the periphery of the tumor. A transition to osteoid matrix occurs in the cartilaginous areas. Immunohistochemical expression of SATB2 does not distinguish chondroblastic osteosarcoma from high-grade chondrosarcoma and is not helpful in diagnosis. Differential diagnosis includes periosteal chondrosarcomas, parosteal osteosarcoma, and high-grade surface osteosarcoma. Periosteal chondrosarcomas occur in older individuals, have a metaphyseal distribution, coarse calcification, and contain large lobules of well-differentiated hyaline cartilage without tumor bone. Parosteal osteosarcoma has a prominent mushroom-like architecture arising from the outer layers of the periosteum and is fibroblastic with more mature bone formation. High-grade surface osteosarcoma exhibits high-grade features throughout.

1.5 High-Grade Surface Osteosarcoma

High-grade surface osteosarcoma (HGSOS) is macroscopically usually well-circumscribed and located on the periosteum. It frequently extends through the periosteum, attaching to or even destroying the cortical plate. Endosteal extension may be present, but the bulk of the tumor is located extraskeletally. Histologically, HGSOS is identical to classical osteosarcoma. Immunohistochemistry is of no value for diagnosis. In the differential diagnosis, it should be taken into account that the degree of cytologic atypia is higher than in periosteal osteosarcoma. Areas of low-grade osteosarcoma must not be present.

1.6 Central Atypical Chondromatous Tumor / Grade 1 Chondrosarcoma

Central atypical chondromatous tumor / grade 1 chondrosarcoma (CACT/CS1) macroscopically consists of translucent, bluish-gray or grayish-white tissue with yellowish-white areas of calcification. The tumor is well-circumscribed and may cause erosion of the cortical plate. Extension into soft tissues is uncommon. Histologically, CACT/CS1 has an abundant hyaline cartilage matrix and a lobular growth pattern. The lobules are separated by fibrous septa. Tumor lobules permeate and entrap bone trabeculae. Cellularity is low, nuclei are uniform in size, and binucleation is frequently observed. Mitoses are absent. Zones of myxoid change and necrosis may be present. Immunohistochemically, tumor cells express S100. The differential diagnosis between enchondroma and CACT/CS1 is based on higher cellularity, uneven cell distribution, the presence of binucleated cells, and the growth pattern (entrapment of preexisting bone and absence of encapsulation) in CACT/CS1. The presence of >20% myxoid matrix changes also favors CACT/CS1. Differentiation can be difficult on small biopsies, and clinicoradiologic correlation is necessary. The location of the lesion and the patient's age play an important role. In long tubular bones, the described changes indicate CACT/CS1, whereas in short tubular bones, in enchondromatosis, and in premenarchal/prepubertal patients, these features are permissible for enchondroma. Grade 2 chondrosarcoma differs from CACT/CS1 by increased cellularity, mitoses, myxoid matrix degeneration, peripheral spindle cell changes at the periphery of the lobules, increased vascularity, and nuclear polymorphism.

1.7 Secondary Peripheral Atypical Chondromatous Tumor / Grade 1 Chondrosarcoma

When performing morphological diagnosis of secondary peripheral atypical cartilaginous tumor/grade 1 chondrosarcoma, special attention should be paid to the macroscopic description, carefully documenting the thickness of the cartilage cap, which usually exceeds 2 cm (mean thickness, 3.9 cm). Measurement must be performed perpendicularly to the bone-cartilage interface at the thickest part of the cap, as thickness is one of the most critical factors in osteochondroma progression. There are no universally accepted histological criteria for the progression of osteochondroma into this tumor. Coarse and irregular calcifications are frequently identified, along with features of a preexisting osteochondroma. A lobular pattern is typically observed; occasionally, nodules detach from the main mass and are located in the surrounding soft tissues. Binucleated cells, cystic changes (areas of cystic spaces containing myxoid material), and necrosis may be present within the cartilage cap but should not be interpreted as signs of progression, as they also occur in osteochondromas. Increased vascularity may be observed. Mitoses and nuclear polymorphism are absent. Invasion into the stalk is rare and indicates progression. Correlation of clinical and radiological findings with cartilage cap thickness is of key importance. On immunohistochemical examination, tumor cells intensely express S100. Differential diagnosis between osteochondroma and secondary peripheral atypical cartilaginous tumor/grade 1 chondrosarcoma cannot be made on the basis of morphology alone, as cystic degeneration, nodularity, or necrosis have been shown not to indicate progression. The differential diagnosis must be conducted on a multidisciplinary level, where cartilage cap thickness is of primary importance. Secondary peripheral grade 2 and 3 chondrosarcomas reveal mitoses and nuclear polymorphism, which must be absent in secondary peripheral atypical cartilaginous tumor/grade 1 chondrosarcoma.

1.8 Central grade 2 and 3 chondrosarcoma

On macroscopic examination of the resection specimen, central grade 2 and 3 chondrosarcoma presents a translucent, frequently lobular, bluish-gray or white cut surface with possible cystic changes, areas of myxoid material, and calcification in the form of yellowish-white chalky areas. Erosion and destruction of the cortical layer with soft tissue extension are frequently present. Histologically, the tumors are highly cellular with a lobular architecture, where the tumor lobules infiltrate and engulf preexisting bone trabeculae. The tumor cells are located within a cartilage matrix with myxoid changes. Cellularity is higher than in ACT/CS1, with present mitoses, nuclear atypia, and polymorphism. In grade 3 chondrosarcomas, the cells at the periphery of the myxoid lobules are spindle-shaped and less differentiated. Immunohistochemically, tumor cells may express S100. Grade 2 chondrosarcoma is distinguished from ACT/CS1 by increased cellularity, nuclear atypia, hyperchromasia, nuclear size, matrix myxoid changes, and the presence of mitoses. In differential diagnosis, skull base chondrosarcoma should be distinguished from chordoma, and grade 3 chondrosarcoma from chondroblastic osteosarcoma.

1.9 Periosteal chondrosarcoma

Macroscopically, periosteal chondrosarcoma presents as a large (often >5 cm) lobular mass located on the bone surface. On cross-section, the tumor is gray and shiny, frequently associated with granular white areas of calcification. The tumor destroys or invades the cortical layer; the medullary canal is typically uninvolved. Histologically, a lobular, moderately cellular cartilaginous tumor with a myxoid matrix is observed. Calcification and endochondral ossification may be present. Invasion of the underlying cortical layer is frequently observed. Intramedullary extension is noted in a subset of cases. Demarcation from soft tissues is usually distinct. Differential diagnosis also includes periosteal chondroma, periosteal osteosarcoma, and parosteal osteosarcoma. Distinction between periosteal chondroma and chondrosarcoma is based on cortical invasion. In periosteal chondrosarcoma, the tumor is frequently >5 cm. Histological grading is not applicable.

1.10 Clear cell chondrosarcoma

On macroscopic examination, clear cell chondrosarcomas present as lesions ranging from 2 to 13 cm in diameter. The tumor contains granular material, occasionally with cystic areas. Features characteristic of hyaline cartilage may be focal or absent. Histologically, the tumors consist of lobules of cells with abundant pale, clear, or slightly eosinophilic cytoplasm, resembling hypertrophic cells of the growth plate. The cells have distinct cytoplasmic membranes and large round cells with minimal atypia and central nucleoli. Mitotic figures are rare. Other frequently observed characteristics include the formation of coarse woven bone intermingled with osteoclast-like giant cells. In approximately half of the cases, areas of conventional low-grade chondrosarcoma with minimally atypical nuclei may be observed. Hyaline cartilage may undergo calcification and/or ossification, which can be detected radiologically. Areas of cystic degeneration resembling aneurysmal bone cyst may also occur. Infiltrative growth may be observed. Immunohistochemically, clear cells strongly express S100. Aberrant immunoreactivity for cytokeratins (AE1/AE3 and CK18) is also observed. Differential diagnosis includes metastatic clear cell renal cell carcinoma, chondroblastoma, and osteosarcoma, as well as (depending on location) notochordal tumor.

1.11 Mesenchymal chondrosarcoma

Macroscopically, mesenchymal chondrosarcoma presents as tissue fragments of various colors (gray/white/pink), of firm or soft consistency. Histologically, mesenchymal chondrosarcoma is composed of small to medium-sized poorly differentiated round cells with a high nuclear-cytoplasmic ratio and a characteristic staghorn vascular pattern, mixed in varying proportions with islands of well-differentiated hyaline cartilage. Spindle cell morphology may be present. In some areas, the matrix may mimic osteoid production. Immunohistochemically, tumor cells may be positive for S100, CD99, SOX9, NKX2.2, and NKX3.1. Aberrant expression of EMA, desmin, myogenin (MYF4), and MYOD1 may be detected, whereas SMARCB1 (INI1) is preserved. SMA, GFAP, and keratins are negative. Biopsy of the undifferentiated component alone may pose diagnostic challenges in differentiating from the group of undifferentiated round cell sarcomas.

1.12 Dedifferentiated chondrosarcoma

Macroscopically, dedifferentiated chondrosarcoma demonstrates cartilaginous and non-cartilaginous components in varying proportions. Histologically, a sharp transition between hyaline cartilage and high-grade sarcomatous components is observed. The cartilaginous portion may resemble enchondroma or grade 1-2 chondrosarcoma. The dedifferentiated component usually has the appearance of undifferentiated pleomorphic sarcoma or high-grade osteosarcoma, and less commonly, angiosarcoma, leiomyosarcoma, or rhabdomyosarcoma. The ratio of components varies, with the percentage of the dedifferentiated component ranging from 2% to 98%.

The immunophenotype of the non-cartilaginous component corresponds to its histological differentiation. H3K27me3-deficient cases resembling malignant peripheral nerve sheath tumors have been described. Overexpression of p53 and MDM2, as well as PD-L1 expression, may be observed.

In differential diagnosis on biopsy material, correlation with imaging findings is essential. IDH mutation analysis can be useful. Cytokeratin positivity complicates distinction from metastatic sarcomatoid carcinoma. Thorough radiological and pathomorphological examination helps identify the cartilaginous component.

1.13 Adamantinoma of long bones

Macroscopically, the tumor presents as a well-circumscribed, lobular, whitish-gray granular mass with peripheral sclerosis. Small lesions remain intracortical, whereas larger tumors may demonstrate intramedullary extension and cortical destruction with soft tissue invasion. Cystic spaces filled with straw-colored or hemorrhagic fluid are frequently encountered. Tumor size ranges from less than 1 cm to more than 10 cm.

Histologically, two main subtypes of adamantinoma are distinguished: classic and osteofibrous dysplasia-like (OFD-like). In classic adamantinoma, the epithelial component predominates, which can be tubular, squamous, basaloid, or spindle cell. Basaloid cells typically demonstrate peripheral palisading and central stellate or spindle-shaped cells. OFD-like areas are inconspicuous. Dedifferentiated adamantinoma is the rarest subtype, in which areas of classic adamantinoma gradually merge with a diffusely growing proliferation that lacks characteristic epithelial differentiation and contains pleomorphic cells with high mitotic activity. Chondroid differentiation, osteoid deposition, and clear cell changes may be observed.

Immunohistochemical examination shows that epithelial cells co-express keratin, EMA, vimentin, p63, and podoplanin. Keratin expression reveals predominantly basal epithelial cell differentiation regardless of subtype, with a widespread presence of basal epithelial cell keratins CK5, CK14, and CK19. Keratins CK1, CK13, and CK17 are also variably present, whereas CK8 and CK18 are virtually absent.

The differential diagnosis of adamantinoma includes OFD-like adamantinoma, synovial sarcoma, and Ewing sarcoma. OFD-like adamantinoma contains a predominance of OFD-like areas with only small nests of epithelial cells, which may be difficult to discern. Classic adamantinoma, consisting predominantly of a spindle cell epithelial component, must be distinguished from synovial sarcoma because the treatment of these tumors differs significantly. Morphological and immunohistochemical overlap is sometimes observed with Ewing sarcoma, but Ewing sarcoma-specific translocations are absent in adamantinoma.

OFD-like adamantinoma is a variant of adamantinoma of long bones characterized by a predominance of areas resembling osteofibrous dysplasia (OFD), with only small nests of epithelial cells. These epithelial nests may be difficult to discern or distinguish from endothelial cells on light microscopy.

Histologically, OFD-like areas are characterized by intersecting trabeculae of woven bone with osteoblastic rimming, embedded in a fibrous stroma consisting of spindle cells. Mitoses in this component are extremely rare, and cartilage is absent.

Immunohistochemical examination of OFD-like areas reveals small nests of epithelial cells expressing keratins. These keratin-positive epithelial nests are a key distinction from OFD, in which only occasional keratin-positive stromal cells are present. The fibrous stroma of OFD-like areas, as in OFD, may express p63 and, in some cases, S100.

The differential diagnosis of OFD-like adamantinoma primarily includes OFD. The presence of small nests of epithelial cells is the key to diagnosing OFD-like adamantinoma. Furthermore, since OFD-like adamantinoma represents a variant of adamantinoma, areas of classic adamantinoma with a more prominent epithelial component may be present if the biopsy material is sufficient in volume, which also assists in making the correct diagnosis.

1.14 Ewing sarcoma

Macroscopically, on cross-section, it is grayish-white in color, soft in consistency, with areas of hemorrhage and necrosis.

Histologically, it consists of small round cells with finely granular nuclei and scant cytoplasm (classic variant) or larger cells with prominent nucleoli (atypical variant). Neuroectodermal differentiation is sometimes present, which may be manifested in the histological structure (formation of rosette-like structures with fine fibrillar material in the center) and/or immunophenotypically (expression of neuroendocrine markers).

Immunohistochemically, expression of CD99 (95% of cases), NKX2-2 (more specific), keratin (25%), FLI1 and ERG (with corresponding gene fusions), neuroendocrine markers, and S100 is characteristic.

Adamantinoma-like Ewing sarcoma is a subgroup with the same gene fusions, frequently expressing markers of squamous differentiation. Its relationship to classic Ewing sarcoma is unclear.

1.15 Round cell sarcomas with EWSR1-non-ETS rearrangements

Macroscopically, EWSR1-NFATC2 sarcomas present as solid masses of varying sizes (ranging from 4 to 18 cm in greatest dimension), yellow-tan on cross-section, and firm or soft in consistency. Most tumors are poorly demarcated and locally destructive or infiltrate adjacent tissues, although some primary soft tissue and bone lesions have been described as well-circumscribed or confined to the medullary cavity. EWSR1-PATZ1 sarcomas are solid-cystic masses ranging in size from 3.5 to over 10 cm.

Histologically, EWSR1-NFATC2 and FUS-NFATC2 sarcomas consist of small to medium-sized round and/or spindle cells with a small amount of eosinophilic or clear cytoplasm, arranged predominantly in cords, small nests, trabeculae, and pseudoacinar structures against a fibromyxoid or myxoid-hyaline stroma. Featureless sheets of cells are less common. Tumor cell nuclei are small, round, monotonous, or markedly pleomorphic, with smooth or irregular contours, dense hyperchromatic or vesicular chromatin, and small or prominent nucleoli. Necrosis and mitotic activity are variable. Tumor cells diffusely express CD99 in half of the cases; expression of PAX7 and NKX2-2, focal dot-like staining for keratin AE1/AE3, and focal CD138 expression are possible. Cases have frequently been misdiagnosed as myoepithelial tumor, plasmacytoma, and lymphoma.

The histological and immunophenotypic features of EWSR1-PATZ1 sarcomas are quite diverse. Tumor cells are small, round, and/or spindle-shaped, frequently associated with a fibrous stroma. Necrosis and mitotic activity may be present or absent. Co-expression of myogenic markers (desmin, myogenin, MYOD1) and neurogenic markers (S100P, SOX10, MITF, GFAP) is observed to varying degrees. CD34 may be positive. CD99 expression is inconstant.

1.16 CIC-rearranged sarcoma

Macroscopically, they appear as large, well-circumscribed, white or brownish, soft masses, frequently with hemorrhage and necrosis.

Histologically, they show diffuse sheets of undifferentiated round, predominantly epithelioid cells with a lobular growth pattern, separated by a fibrous stroma. A spindle cell architecture is possible. The cells are uniform, but with moderate nuclear pleomorphism, vesicular chromatin, and prominent nucleoli. The cytoplasm is faintly eosinophilic, occasionally with clearing. Necrosis is frequent, and mitoses are numerous. In one-third of cases, myxoid stromal changes with a reticular or pseudoacinar cell arrangement are present. Tumors with CIC-non-DUX4 fusion variants are similar to CIC-DUX4.

Immunophenotype: frequently CD99 (focally), WT1 (90-95%), ETV4 (95-100%); NKX2-2 is usually negative. CIC-NUTM1 sarcomas express NUT. Keratin, S100, and myogenic markers are rare. Calretinin and ERG may be positive.

1.17 Sarcoma with genetic alteration of the BCOR gene

Macroscopically, these are large (>5-10 cm), greyish-tan, soft or fleshy tumors with necrosis. Bone lesions frequently demonstrate cortical destruction and extension into soft tissues. Histologically, tumors of the BCOR family show striking similarities. BCOR-CCNB3 sarcomas typically consist of a uniform proliferation of primitive small round or ovoid cells arranged in solid sheets or a nested pattern, surrounded by a rich capillary network. Less cellular areas of spindle cells in a myxoid matrix or solid areas of large spindle cells arranged in fascicles resembling synovial sarcoma may be encountered. Nuclei have finely dispersed chromatin, and nucleoli are usually inconspicuous. Mitotic activity is variable. Metastatic/recurrent lesions sometimes demonstrate pleomorphic nuclei and osteoid deposition. Tumors with BCOR-ITD abnormalities demonstrate variable cellularity, ranging from solid sheets of small cells to hypocellular areas of spindle cells in a myxoid matrix with a vascular network. Immunohistochemically, all tumors with various BCOR genetic aberrations demonstrate strong and diffuse nuclear expression of BCOR and frequently express SATB2, TLE1, and cyclin D1. CD99 is positive in approximately 50% of cases. However, BCOR expression is non-specific and is frequently observed, for example, in synovial sarcoma. BCOR-CCNB3 sarcomas also express cyclin B3, which is not observed in other BCOR family tumors.

1.18 Giant cell tumor of bone

Macroscopically, GCTB is a well-circumscribed lesion in the epiphysis, often with thinning and destruction of the cortical bone. On cross-section, the tumor is soft, friable, reddish-brown, with areas of fibrosis. Hemorrhages and cystic cavities may be observed. Malignant GCTB is usually denser and more fleshy.

Microscopically, GCTB is a cellular tumor characterized by a predominance of non-neoplastic giant cells and monomorphic neoplastic cells with mild atypia. The typical histological picture may be obscured by necrosis, hemorrhage, hemosiderin deposition, aneurysmal changes, clusters of xanthoma cells, and reactive bone formation. Focal nuclear polymorphism in typical GCTB usually represents degenerative changes. The surrounding bone is frequently resorbed with the formation of a peripheral reactive rim. Pulmonary metastases with a similar histological structure have been described.

Primary malignant GCTB is a rare event, usually represented by a nodule of highly polymorphic cells within conventional GCTB. Malignant transformation of GCTB following treatment, including radiation therapy, is more common. The malignant component is represented by undifferentiated sarcoma or osteosarcoma. In some cases of malignant transformation, tumor cells retain the H3.3 p.Gly34 (G34W) mutation. Bone sarcomas with this mutation lacking features of GCTB are likely related to GCTB.

GCTBs following denosumab treatment show prominent bone formation, depletion of giant cells, and the presence of monomorphic spindle cells. These changes may mimic osteosarcoma or malignant GCTB; however, marked atypia, high mitotic activity, and bone invasion are typically absent.

Immunohistochemical detection of the H3.3 p.Gly34Trp (G34W) mutation is a reliable surrogate marker replacing molecular testing.

2. Specifics of bone tumor biopsies in children

2.1 Biopsy planning

When planning a biopsy, the biological characteristics of bone and soft tissue sarcomas must be taken into account. Sarcomas grow centripetally, such that the most immature part is located at the growing margin. A reactive zone forms between the tumor and the surrounding normal tissues compressed by it. The reactive zone consists of induced mesenchymal cell proliferation, neoangiogenesis, and an inflammatory process. This zone may be infiltrated by tumor cells, clusters of which are called satellites; these are not metastases. The type of mesenchymal proliferation is determined by the anatomical location of the tumor: soft tissue tumors stimulate a fibrous reaction, whereas intraosseous lesions stimulate an osteoblastic reaction. Thus, the same pathological lesion in different anatomical regions will stimulate different mesenchymal responses. Unlike sarcomas, carcinomas typically infiltrate surrounding tissues rather than displacing them, and generally do not induce the formation of a reactive zone. Consequently, a sarcoma lesion is more heterogeneous, whereas a carcinoma lesion is more homogenous [21]. To establish a diagnosis in the case of carcinoma, a core-needle biopsy is often sufficient. In sarcoma, this can lead to a diagnostic error because the sample will not be taken from a representative focus. In international literature, this is referred to as a "sampling error" [21].

During the biopsy procedure, contamination of the surgical field with tumor cells occurs, which may increase the risk of local recurrence. This is caused by the size of the surgical approach, rough instrument manipulation, inadequate hemostasis, and failure to mark the biopsy tract. Regardless of whether an open biopsy or a core-needle biopsy was performed, it must subsequently be assumed that the biopsy tract is contaminated with tumor cells and therefore must be excised in accordance with all oncological principles (wide margins, leaving the tract attached to the specimen, excision of the drain site) [23]. Therefore, the skin incision and biopsy tract must be placed strictly in line with the future surgical approach [21]. The approach to the tumor should be as short as possible, traverse no more than one muscle compartment, and be located at a safe distance from the major neurovascular bundle [21, 22].

2.2 Surgical approaches for biopsy

For each primary localization in the skeletal bones, there are classic surgical approaches for local control. These approaches must be considered when performing a biopsy.

Pectoral girdle

Fig. 6.1 Projection for scapular biopsy [21]

When performing a biopsy on the upper extremity, the standard Tikhor-Linberg surgical approach must be taken into account. Depending on the location and extent of the tumor, either the entire approach or a part of it is used.

Fig. 6.1 shows the posterior part of the approach, which can be used for resection of a scapular tumor. This same line also serves as the projection for selecting the scapular biopsy site.

Fig. 6.2 Projection for humerus tumor biopsy [21]

In Fig. 6.2, part of the approach is used for humerus tumor resection, both proximally and distally.

The biopsy incision line for the forearm and hand is generally chosen individually, depending on the location, size, and planned surgery. Since these locations are quite rare, there are no classic guidelines.

Pelvic girdle

Biopsy of pelvic bone tumors is a challenging procedure due to the anatomy of this region. Open biopsy should be performed after careful preoperative planning and multidisciplinary discussion. If core needle biopsy is chosen, it must be performed under CT guidance [54].

For pelvic tumor resection, there is a unified pelvic approach (Figs. 6.3 and 6.4); similarly to the shoulder girdle, depending on the tumor location and size, it can be used entirely or in part. However, a number of specialized centers sometimes use its modifications.

Fig. 6.3. Posterior part of the unified pelvic approach; if necessary, it can be extended distally along the line of the sacroiliac joint [21].

Fig. 6.4. Anterior part of the unified pelvic approach.

Bone biopsy (open or core needle) should be performed only within the projection of the unified pelvic approach or its modification shown in Figure 6.5 [54]. Performing a biopsy within the projection of other approach modifications is only possible in centers where the subsequent tumor resection surgery will be performed.

Fig. 6.5. Modification of the unified pelvic approach. Instead of its inguinal part and additional T-shaped incision, it is extended distally along the medial surface of the thigh. This approach is preferred.

When the lesion is localized in the upper two-thirds of the femur, a lateral approach biopsy is preferred (Fig. 6.6). As a rule, this presents no difficulties, as the muscle bulk on the lateral side is smaller in volume. In the lower third, biopsy is possible from either the medial or lateral side, depending on the location of the soft tissue component.

Fig. 6.6. Approach for lesions in the proximal two-thirds of the femur [21]

Fig. 6.7. Approach for lesions in the lower third of the femur [21]

On the lower leg, due to soft tissue deficit and blood supply characteristics, correct biopsy execution is extremely critical. Errors in approach selection, biopsy site ulceration, and rough handling of soft tissues can make limb-sparing surgery impossible.

Fig. 6.8. Approach for lower leg tumors [21].

The preferred biopsy site is the anteromedial approach. In rare cases, biopsy via the anterior approach is possible (Fig. 6.8). The lateral approach should be avoided as much as possible and may be used in exceptional cases in agreement with the federal center where the local control stage will subsequently be performed. For fibular tumors, a lateral approach is used, making it extremely important to know the topography of the common fibular nerve (Fig. 6.9).

Fig. 6.9. Approach to tumors of the upper third (black arrow) and distal two-thirds (green arrow) of the fibula [21].

The distal lower leg and foot are extremely rare sites for tumors. Therefore, unlike sites such as the shoulder or the knee joint area, there are no equally widespread techniques for this region. Tumor localization in the distal and middle parts of the foot generally requires amputation, so the biopsy approach is chosen individually. A medial approach is preferred for a calcaneal biopsy. However, a lateral approach may also be chosen if necessary. The talus is biopsied via an anterior approach. A medial approach can also be used if necessary. With the advent of new techniques, ankle joint arthroplasty has become possible, so it is also important to consider the future surgical approach here. A anterolateral approach is preferred in this area. Fig. 6.10.

Due to the pronounced soft tissue deficit, it is extremely critical to avoid their contamination with tumor cells.

Fig. 6.10 Projection of the approach to the distal tibia

Vertebrae

Special mention should be made of such a complex location as the vertebrae. Given that tumors of this localization typically manifest with neurological symptoms and pain, in most cases patients require emergency decompressive laminectomy. If this procedure is performed not in an oncological hospital, but as often happens, in a neurosurgical department, it is imperative that the operating surgeon sends the removed, compressing tissues for histological examination and performs thorough hemostasis before wound closure. If a defect is present in the vertebra, it should be closed with a hemostatic agent, bone wax, or bone cement [11].

When a vertebral tumor is detected without extension into the spinal canal and without neurological symptoms, a CT-guided transpedicular core needle biopsy is performed [54] (Fig. 6.11). This procedure must be performed in a specialized federal center.

Fig. 6.11 Transpedicular core needle biopsy

Ribs and Sternum

In the presence of a chest wall bone mass (ribs/sternum), an extrathoracic biopsy is preferred to prevent tumor dissemination along the pleural cavity. Performing thoracoscopy/thoracotomy is discouraged, but not completely ruled out, and may be performed when the tumor process is disseminated within the hemithorax, with signs of tumor breakdown and pleuritis.

If pleural effusion is present on the affected side, involvement of the parietal pleura in the tumor process can be suspected. In this case, if the effusion volume is sufficient for pleural puncture and fluid sampling, thoracentesis is performed in parallel with the biopsy of the primary pathological focus. The obtained aspirate is sent for cytological examination of the pleural fluid.

If a rib/sternal tumor has an extraosseous component, it is preferable to biopsy the soft tissue component rather than a bone tissue fragment, which subsequently eliminates the need for decalcification of the obtained material, thereby allowing an adequate molecular genetic study to be performed.

When choosing the biopsy site, the intended approach for subsequent surgical treatment must be taken into account; in the case of a rib tumor biopsy, the skin incision should be made longitudinally along the course of the rib, and in the case of a sternal tumor biopsy, longitudinally along the body's midline.

When performing a rib tumor biopsy with suspicion of a malignant neoplasm (MN), there is no need to preserve the rib periosteum.

Skull Bones

In the presence of a skull bone mass (maxillofacial region, cranial vault), depending on the location of the tumor process, the main principles in choosing an approach are the preservation of functional areas in the head region, the cosmetic outcome, and striving for minimally invasive approaches to ensure faster patient recovery in the early postoperative period.

When choosing the biopsy site, the intended approach for subsequent surgical treatment must be taken into account.

When a tumor is localized in the mandible and maxilla, performing the biopsy via an intraoral approach is preferred, both from a cosmetic perspective and to reduce the likelihood of injury to the branches of the facial nerve.

When a tumor is localized in the anterior/central skull base, transnasal/transoral tumor biopsy is recommended, including the use of navigation systems.

In the presence of a skull bone tumor (maxillofacial region, cranial vault) with an extraosseous component, sampling the soft tissue component for histological examination is preferred because it eliminates the need to decalcify the surgical material, enabling histological examination in a shorter timeframe and allowing an adequate molecular genetic study.

If the tumor is connected to the dura mater, a lumbar puncture is recommended to rule out tumor cells in the cerebrospinal fluid system.

If imaging data indicate metastatic disease, it is recommended to consider a biopsy of the metastatic lesion.

3. General Principles of Surgical Treatment for Malignant Bone Tumors

The main goal of surgical treatment is the radical removal of the tumor, which should guarantee the absence of local recurrence [18, 96, 97].

3.1 Basic Principles of Malignant Tumor Resection

To date, there are 4 basic principles for resecting malignant tumors [18, 37, 97]:

1. Intralesional resection consists of removing the tumor in pieces, with damage to the pseudocapsule, carrying a high risk of tumor cell contamination of the surgical field.

2. Marginal resection involves removal along the edge of or through the tumor pseudocapsule. This type of surgery may lead to the microscopic resection margin passing through tumor tissue.

3. Wide resection (en-block) implies removal of the tumor without damaging the pseudocapsule and within a cuff of visually unchanged surrounding tissues.

4. Radical resection is the removal of the tumor together with the entire anatomical compartment in which it is located.

Modern onco-orthopedics recommends the use of wide resection or radical resection when removing malignant bone tumors. However, the width of the cuff of unaffected tissue and the bone margin remain debatable. A number of sources recommend a margin of 3 to 7 cm, which is problematic to apply in pediatric patients due to their anthropometric data. Several modern sources, including ESMO guidelines, advise a safe resection margin of 2 cm on a "fresh" resected specimen and 1 cm after its fixation. First and foremost, this applies to nosologies such as osteosarcoma and chondrosarcoma. For Ewing sarcoma, a margin of at least 3-5 cm in bone and at least 2-3 cm in soft tissues is desirable [13, 98].

Radical resection is also applicable, especially in cases where skip metastases are detected in the patient [18, 97].

To date, studies have emerged allowing marginal resection in malignant bone tumors, especially in low-grade osteosarcoma, but not in Ewing sarcoma. However, due to the small number of studies, most of which are retrospective and have a follow-up period of less than 5 years, applying this type of surgical treatment is not advisable [13, 98].

It is important to note that in some cases, extra-articular resection is indicated—a segmental resection of the tumor together with the adjacent joint, without opening the capsule of the latter. Indications for this procedure include: the biopsy tract passing through the joint cavity, tumor spread along intra-articular ligaments and the joint capsule, a pathological fracture with joint contamination, tumor location within the joint cavity, and a tumor located in the area of the dorsal surface of the femoral condyles involving the attachment site of the gastrocnemius muscle heads. Given the rarity and complexity of performing the surgery, as well as the need for muscle plasty, this procedure should be performed in a specialized center with extensive experience in such operations.

Intralesional resection is contraindicated in malignant bone tumors. An exception may be giant cell tumor, especially with a positive response to Denosumab** therapy. There is still no consensus on the malignancy of this nosology. According to ICD-10, this tumor is classified as benign, but a number of foreign specialists classify it as potentially malignant.

3.2 Organ-Removing Surgeries

The decision to perform organ-removing surgery must be made collectively, involving a pediatric oncologist, trauma and orthopedic surgeon, radiation oncologist, diagnostic radiologist, pathologist, and psychologist. Parents must be thoroughly informed about the reasons for the decision made [96].

Types of organ-removing surgeries:

1. Hand amputation

2. Amputation at the middle third of the forearm

3. Amputation at the middle third of the arm

4. Shoulder disarticulation

5. Forequarter amputation

6. Foot amputation

7. Lower leg amputation at the middle third level

8. Thigh amputation at the middle third level

9. Hip disarticulation

10. Hindquarter amputation (hemipelvectomy)

3.3 Limb-sparing treatments

If there are no indications for an ablative surgery, a limb-sparing surgery may be performed, the types of which include:

1. Endoprosthetic replacement

2. Biological reconstruction (use of a vascularized fibular autograft, allograft)

3. Reconstructive and plastic surgeries

Endoprosthetic replacement

In modern musculoskeletal oncology, among various methods of restoring defect and limb function after tumor removal, high-tech surgeries using endoprostheses play a leading role. The use of modular endoprosthesis systems is the preferred method for reconstructing bone defects in malignant bone tumors in adolescent patients who have reached skeletal maturity. Modern technologies allow for endoprosthetic replacement of almost any anatomical location. For pediatric patients with an immature skeleton, it is necessary to use custom-made expandable endoprostheses that lengthen as the patient grows [34,52,56]. These implants can be lengthened mechanically using a screwdriver or a special key, which requires a surgical procedure, most often through a mini-access. Such implants are called invasive. There is also a type of implant that does not require surgery for lengthening – non-invasive. They are lengthened using special devices via a magnetic field or an electrical impulse. The use of non-invasive expandable prostheses is preferred for pediatric patients.

The following types of reconstructive surgeries involving endoprosthetic replacement are distinguished:

• standard primary surgeries in adolescent patients using modular endoprosthesis systems;

• standard primary surgeries in pediatric patients using custom-made expandable implants;

• endoprosthetic replacement of rare anatomical limb zones: wrist joint, elbow joint, ankle joint, including the use of custom devices;

• revision endoprosthetic replacement (due to aseptic loosening, infectious complications, breakage of endoprosthesis components, complete depletion of the implant lengthening mechanism);

• endoprosthetic replacement after pelvic bone resection using 3D-printed implants;

• vertebral endoprosthetic replacement;

• Endoprosthetic replacement of rare anatomical locations using custom-made implants, including the use of additive technologies

Features of primary endoprosthetic replacement in children and adolescents [39, 98, 99, 100]:

• fabrication of a custom implant for patients with an immature skeleton, in some cases without the possibility of intraoperative variation in the use of intramedullary stems and fixation methods;

• strict adherence to preoperative planning in patients with expandable endoprostheses;

• expandable mechanism of the endoprosthesis (invasive and non-invasive);

• preservation of conditions for re-endoprosthesis replacement and correction of limb length discrepancy.

The growing number of primary endoprosthetic replacement cases and the success of chemotherapy for bone sarcomas lead to an annual increase in the number of patients requiring repeat (revision) orthopedic surgeries due to complications such as aseptic loosening, infectious complications, breakage of endoprosthesis components, complete depletion of the implant lengthening mechanism, occurrence of growth plate arrest, or development of limb axis deformity. Revision surgeries, regardless of their cause, require a trained team of musculoskeletal oncologists and appropriate equipment. The use of a modular endoprosthesis system in patients with a mature skeleton simplifies subsequent revision surgeries and increases the biological bone reserve due to the ability to replace individual elements and install special revision intramedullary stems. The revision endoprosthesis for patients with an immature skeleton is custom-made, which in rare cases allows replacing part of it without removing the entire endoprosthesis. Special mention should be made of revision surgeries for infectious complications. In the case of a short interval since surgery (up to 4 weeks), absence of skin defects, isolation of low-virulence flora with good sensitivity to systemic antibacterial drugs, a single-stage surgery can be performed – debridement of the periprosthetic bed, replacement of plastic components, and repeated sterilization of the implant if technically feasible. Prolonged antibiotic therapy is mandatory. For long intervals after surgery (more than 4 weeks), presence of skin defects (fistulae), and isolation of high-virulence flora, two-stage surgeries are recommended. The first stage is debridement of the periprosthetic bed, removal of all endoprosthesis components, and installation of a cement spacer with a systemic antibacterial drug. This is followed by prolonged antibacterial therapy for at least 4 weeks. In the absence of signs of infection (laboratory parameters, no growth in the aspirate from the endoprosthesis bed), the second stage is performed – removal of the cement spacer and re-endoprosthetic replacement with a new endoprosthesis. Also, in infectious complications, a positive effect can be achieved by using negative pressure wound therapy (vacuum therapy) [37].

Features of surgical technique [21, 39, 99, 100]:

1. leaving the biopsy tract ad mass with the tumor;

2. compliance with oncological principles of surgical treatment of sarcomas (wide or radical resection);

3. compliance with orthopedic principles of fixation of endoprosthesis intramedullary stems;

4. maintenance of the physiological axis of the limb and restoration of its pre-operative length;

5. presence of surgical skills to perform muscle transposition if necessary;

6. adequate reconstruction of the muscle component to cover the implant and restore function.

Biological reconstruction

When the tumor focus is localized in the diaphysis of a limb segment, the patient's joints should be preserved whenever possible. For this purpose, only the diaphysis is removed – intercalary resection [101, 102]. Replacement of the post-resection defect in this case can be performed using an endoprosthesis, as well as biological reconstruction – using a vascularized fibular autograft, an allograft if necessary, and osteosynthesis with one or two angle-stable plates [103-105].

To perform this surgery, the following conditions must be met [92, 93]:

7. Ability to comply with all oncological principles of resection

8. Availability of autologous fibula harvesting capability for the patient

9. Presence of a microsurgical team and microsurgical equipment at the hospital

10. Proficiency in osteosynthesis skills

Surgeries for space-occupying lesions in the ribs and sternum

In Ewing's sarcoma of the rib, the preferred scope of surgery is thoracotomy with extirpation of the affected rib and resection (less frequently extirpation) of adjacent ribs if there are signs of their involvement in the pathological process. Resection of the affected rib is considered feasible if the tumor is of limited length along the rib and there is no spread of tumor involvement along the medullary canal beyond the tumor according to MRI with intravenous contrast enhancement.

The rib tumor must be removed en bloc as a full-thickness specimen with excision of the post-biopsy scar/tract.

To assess the involvement of the soft tissues of the intercostal spaces, intraoperative frozen section histological examination of the tumor resection margins along the soft tissues of adjacent intercostal spaces is recommended. In the absence of evidence of involvement of adjacent ribs, the "upper" and "lower" boundaries of tumor resection should pass along the lower edge of the overlying rib and the upper edge of the underlying rib, respectively, with periosteum harvesting. After removal of the macro-specimen, marking of the resection margins is mandatory (it is preferable to designate 5 margins – upper, lower, anterior, posterior, and medial).

Reconstruction of the chest wall defect using biomaterials, synthetic meshes/plates, metal meshes/structures, or a combination thereof should be performed in the presence of a defect of >1 rib in the anterior and lateral parts of the chest wall, >2-3 ribs in the posterior parts of the chest wall, as well as in the presence of a sternal defect. In other cases, reconstruction with local tissue flap closure is possible.

Surgeries for space-occupying lesions in the cranial bones

For patients with a localized space-occupying lesion in the cranial bones (maxillofacial region, cranial vault), the scope of surgical intervention is determined within an interdisciplinary board. Local control planning should begin 1.5–2 months prior to surgery due to the need for customized reconstruction planning of the postoperative defect.

When a malignant neoplasm is localized in the mandible or maxilla, the preferred scope of surgical treatment is a resection of the maxilla or mandible with a reconstructive-plastic component. The choice of the reconstruction method depends on the tumor location, lesion size, and the presence of an extraosseous component. In the presence of an extraosseous component, intraoperative frozen section histological examination of the soft tissue resection margins at the site of greatest tumor infiltration is recommended.

In osteosarcoma of the cranial bones (maxillofacial region, cranial vault), the tumor must be removed en bloc with excision of the post-biopsy scar/tract.

In Ewing sarcoma of the cranial bones or other undifferentiated small round cell bone sarcomas (maxillofacial region, cranial vault), if an en-block resection is unfeasible due to tumor location and spread or involvement of critical anatomical structures, an interdisciplinary discussion regarding the feasibility of an R1 resection is advisable in view of the option for adjuvant radiotherapy.

After removal of the macro-specimen, marking of the resection margins is mandatory.

Surgical treatment of pulmonary metastatic disease

Surgical treatment is the primary modality for local control of osteosarcoma metastases, predominantly pulmonary metastases. Cure of a patient with metastatic osteosarcoma is only possible if surgical remission is achieved. The 5-year overall survival rate following complete resection of pulmonary metastatic lesions ranges from 32% to 39%, whereas if complete resection is not feasible, it ranges from 0% to 2% [39,40]. An attempt at complete metastasectomy should be undertaken whenever possible, provided two key conditions are met: complete control over the primary tumor and preservation of sufficient pulmonary function capacity after resection [94].

If a patient with pulmonary metastatic disease is undergoing curative treatment, all lesions must be completely resected, regardless of their number and location.

The gold standard for treating pulmonary metastases in osteosarcoma remains thoracotomy, which allows manual palpation of the lung and detection of small and deeply seated metastases not identified on preoperative MSCT.

Currently, for unilateral pulmonary involvement in osteosarcoma, most researchers recognize the following approach: performing a unilateral thoracotomy with resection of all identified lesions followed by careful postoperative observation. Performing an exploratory thoracotomy on the contralateral side in unilateral involvement is considered unjustified.

In bilateral pulmonary involvement, surgical options include simultaneous bilateral thoracotomies (synchronous), staged bilateral thoracotomies separated in time (metachronous), and median sternotomy. Each option has both advantages and disadvantages. The advantage of simultaneous bilateral thoracotomies is the ability to adequately inspect each hemithorax and perform two procedures under a single anesthetic management. The disadvantage is the duration of anesthesia, which includes the need to restore adequate cardiopulmonary function when transitioning from single-lung ventilation on one side to single-lung ventilation on the contralateral side. A factor limiting synchronous thoracotomies is multiple pulmonary involvement, specifically the presence of 10 or more lesions in one or both lungs according to preoperative contrast-enhanced chest CT. The most widely accepted and recommended approach is staged bilateral thoracotomies, which allow adequate inspection of each hemithorax without the prolonged anesthetic duration associated with simultaneous thoracotomies. Furthermore, this type of surgical intervention is indicated for multiple pulmonary lesions. The disadvantage of staged procedures is the potential delay in the subsequent thoracotomy due to slow recovery and postoperative complications, which may lead to disease progression and an increased scope of subsequent resection. Some surgeons prefer median sternotomy [74–76]. There are several contraindications for this surgical approach, namely: predominant localization of metastases in the posterior lung segments, large and/or multiple metastases in the lower lobe of the left lung, and previous thoracic surgeries. In addition, this approach requires greater coordination between the surgeon and anesthesiologist throughout the entire procedure. The high invasiveness of repeat sternotomy, should it be required, should also be noted [70]. The advantages of sternotomy include a single access for bilateral exposure and resection and less pronounced postoperative pain compared to thoracotomy. The study by Abbo O describes the performance of a bilateral anterior sternothoracotomy ("clamshell" incision) in children with osteosarcoma lung metastases [68].

Multiple lesions (≥5) should not be a contraindication to surgery. The operation must be performed strictly on a collapsed lung under single-lung ventilation conditions. For subpleurally located lesions, atypical wedge resections of the lung are indicated to preserve a greater parenchymal volume; for lesions located in the hilar regions, anatomical resections (lobectomy/bilobectomy/pneumonectomy) are indicated [77].

4. Features of chemotherapy courses

Before starting each course of systemic chemotherapy, it is necessary to perform:

1. Anthropometric studies (height measurement, body weight measurement, body surface area)

2. Physical examination of the patient

3. Complete blood count with differential

4. General clinical blood biochemistry (serum creatinine, serum blood urea, serum sodium, serum potassium, serum total calcium, serum total magnesium, blood alkaline phosphatase activity, serum total protein, alanine aminotransferase activity, aspartate aminotransferase activity, serum C-reactive protein, serum total bilirubin)

5. Echocardiography, ECG (prior to courses containing doxorubicin**)

5. Specifics of radiation therapy in Ewing sarcoma

5.1 Technical equipment requirements for external beam radiation therapy (EBRT)

Medical linear accelerator with a photon energy of 6–10 MeV, equipped with a multileaf collimator and, highly desirably, image-guided radiation therapy (IGRT) systems: cone-beam computed tomography (CBCT), portal imaging.

Head and body immobilization devices (thermoplastic masks, vacuum mattresses, etc.).

X-ray computed tomography scanner for simulation, featuring a flat tabletop with attachment capabilities and indexable immobilization systems.

3D treatment planning system, highly desirably with the capability for dose calculation using intensity-modulated radiation therapy (IMRT/VMAT) in static and dynamic modes.

5.2 Pre-radiation preparation

CT-simulation must be performed using an X-ray computed tomography scanner adapted for radiation therapy needs.

Marking is performed using individual immobilization devices:

• for head and neck localization – thermoplastic masks and a vacuum mattress,

• for mediastinal, abdominal, and pelvic localization – a vacuum mattress, etc.

Postoperative and post-biopsy scars must be marked with radiopaque markers.

Scanning is performed with a slice thickness of:

• 1–3 mm in the head and neck region,

• 2–5 mm in the mediastinal, abdominal, and pelvic regions.

The field of view (FOV) must be maximized to include all body parts and immobilization systems.

It should be taken into account that simulation and radiation therapy in patients under 5 years of age may require general anesthesia.

Planning is performed on a native CT-simulation series.

5.3 Definition of radiation volumes

Gross tumor volume (GTV) is defined as the maximum extent of the tumor—prior to the initiation of therapy or disease progression during treatment.

To clarify this, it is necessary to fuse planning CT scans with diagnostic CT or MRI images, and PET/CT data obtained before the start of the entire treatment course or during disease progression.

The clinical target volume (CTV) includes the GTV with a 2 cm margin, taking into account anatomical barriers to tumor spread. The area of the postoperative scar from the biopsy or resection must be included in the irradiation volume [82].

Exception: see the section "Radiation therapy for specific tumor sites".

The planning target volume (PTV) includes the CTV with an additional margin of 3-10 mm in accordance with the internal standards of the clinic and should be:

• for the head and neck – 3-7 mm

• for the mediastinum, retroperitoneum, and pelvis – 5-10 mm

• for the extremities – 10 mm

A reduction of PTV margins is permissible when performing daily image-guided radiotherapy using cone-beam computed tomography (CBCT) prior to the irradiation session.

5.4 Fractionation

Conventional fractionation (one fraction per day, five fractions per week, with a single dose of 1.8-2.0 Gy) is the preferred fractionation regimen.

Only conventional fractionation is permissible when a large volume of the intestine is involved in the irradiation field. It is also strictly mandatory if CNS structures are included in the irradiation field (e.g., for spinal tumors), as longer intervals between fractions are required for the recovery of CNS tissues.

5.5 Combined use of radiation therapy and chemotherapy

Dactinomycin must be excluded from the treatment regimen during radiation therapy.

Doxorubicin**: in the event of a severe skin or intestinal reaction, the dose of doxorubicin** should be reduced or completely omitted in subsequent courses during radiation therapy.

Busulfan**: lung irradiation both before and after the use of busulfan** can cause severe pulmonary fibrosis. Total lung irradiation must be excluded. Local irradiation is possible with minimal involvement of the lung tissue in the irradiation volume. When the primary tumor is located in the chest wall area, with persistent malignant pleural effusion, or following a non-radical tumor resection, the possibility of using radiation therapy in combination with busulfan** requires further discussion. Inclusion of large volumes of the intestine in the field should be avoided. If necessary, radiation therapy should be administered no earlier than 8-10 weeks after the administration of busulfan** [82]. When CNS structures are involved in the irradiation volume, the dose to them must not exceed 30 Gy [83].

5.6 Preoperative radiation therapy

Indications:

• progression during neoadjuvant chemotherapy

• impossibility of performing R0 surgical treatment

• presence of pathological conditions requiring urgent correction, such as spinal cord compression (provided that correction using other treatment options is impossible).

Administered concurrently with the 3rd-4th or 5th-6th courses of induction chemotherapy.

With conventional fractionation, the total tumor dose is 54.0 Gy [107].

5.7 Postoperative radiation therapy

Indications:

• poor histological response to neoadjuvant chemotherapy (10% or more viable tumor cells) [108, 109].

• positive resection margins after surgery (R1 or R2 resection)

• surgical treatment at the diagnostic stage, if a "second-look" surgery was not subsequently performed.

• location of the tumor in the paravertebral region or the pelvis [110, 111].

Patients indicated for a postoperative course of radiation therapy first continue courses of postoperative (consolidation) chemotherapy.

Radiation therapy should be initiated after the healing of postoperative wounds, usually after the 2nd-4th cycle of consolidation therapy.

In patients with macroscopic or microscopic residual disease, radiation therapy may be initiated earlier.

In postoperative radiation therapy, doses depend on the resection margin and the tumor response to the administered induction (neoadjuvant) chemotherapy:

• R2 resection – 45-54 Gy (with the possibility of dose escalation up to 60.0 Gy to the residual tumor, depending on the size and location of the primary tumor, as well as the patient's age)

• R1 resection with a poor histological response (10% or more viable tumor cells) – 54 Gy

• R1 resection with a good histological response (less than 10% viable tumor cells) – 45 Gy

• R0 resection with a poor histological response (10% or more viable tumor cells) – 45 Gy [107]

5.8 Radical radiation therapy

Radical radiation therapy is used only for inoperable patients. Radiation therapy begins after the completion of neoadjuvant chemotherapy.

Total doses are 54-60 Gy. After reaching a dose of 45 Gy, the irradiation volume should be reduced (CTVboost = GTV).

In children under 10 years of age with favorable prognostic factors (small tumor size <100 ml, complete response to chemotherapy according to MRI or "second-look" biopsy data), the dose may be reduced.

5.9 Radiation therapy for specific tumor sites.

Extremity tumors

Safe margins for CTV in the proximal and distal directions must be at least 3-5 cm, and at least 2 cm in the lateral directions.

If there are signs of extensive intramedullary involvement, irradiation of the entire bone is advisable.

The surgery area and postoperative scar must be included in the irradiation field.

When irradiating after endoprosthetics, the prosthesis must be included in the irradiation area with a 2 cm safe margin.

If possible, the radiation dose to the area of the metaepiphyseal plates (bone growth plates) should be reduced to 20 Gy.

To avoid the development of fibrosis, the dose to the skin and subcutaneous tissue on the side furthest from the primary tumor site should be reduced throughout the entire length of the target.

When irradiating areas adjacent to a joint, the dose to the latter must not exceed 45 Gy.

When irradiating at high doses, after reaching 45 Gy, the fields should be reduced to the volume of maximum tumor extent – before the start of therapy or progression during treatment (GTV) with a safe margin in the proximal and distal directions of 2 cm, and at least 1-2 cm in the lateral directions (CTV).

Tumors of the trunk, head, and neck/skull

The safe margin in all directions must be at least 2 cm, taking into account anatomical barriers. Smaller margins are permitted if critical structures are included in the volume without tumor invasion into them.

Pelvic and chest wall tumors

Tumors of this localization often have a large intra-abdominal or intrathoracic extent, which decreases significantly with chemotherapy.

The clinical target volume (CTV) must include the extent of the tumor in the soft tissues and bones at the start of therapy (GTV) with a 2 cm margin in all directions and be adjusted for potential spread into the abdominal and pleural cavities.

If the tumor infiltrates the pleural cavity, irradiation of the entire lung on the affected side is indicated:

• in patients younger than 14 years with a fractional dose (FD) of 1.5 Gy up to a cumulative dose (CD) of 15 Gy;

• in patients older than 14 years with an FD of 1.8 Gy up to a CD of 19.8 Gy

The primary tumor area should be irradiated to a total dose of 45 Gy. Dose escalation up to 54 Gy is possible in the area of maximum tumor relapse risk.

Important! In patients with chest wall tumors receiving busulfan**-containing chemotherapy, irradiation of large volumes of lung tissue should be avoided and requires additional discussion.

Spine

The irradiation volume (CTV) must include one healthy vertebra above and below the tumor, as well as the paravertebral soft tissue component with a safe margin of 2 cm.

Preferred irradiation techniques include dynamic arc conformal radiotherapy or intensity-modulated radiotherapy (IMRT).

Scapula

For tumors in the upper part of the scapula, inclusion of the shoulder joint and the humeral head is mandatory.

Total lung irradiation

Lung irradiation is indicated for patients with lung metastases at the time of diagnosis [87].

Both lungs must be irradiated:

• in patients under 14 years of age at a dose per fraction (DPF) of 1.5 Gy to a total cumulative dose (TCD) of 15 Gy

• in patients under 14 years of age at a DPF of 1.5 Gy to a TCD of 18 Gy.

Additional irradiation of individual metastatic lesions to equivalent doses of 45 Gy is possible.

Important! Exclude total lung irradiation in patients receiving regimens containing busulfan**.

Irradiation of bone metastases

Irradiation of bone metastases requires additional discussion. Equivalent doses of at least 45 Gy are indicated without the use of wide margins.

In patients who have received busulfan**, radiation therapy should be administered 8–10 weeks after the completion of high-dose chemotherapy [107,112].

Brain metastases

Whole-brain radiation therapy using a conventional fractionation regimen with a DPF of 2 Gy to a TCD of 30 Gy.

A boost to individual lesions up to a dose of 50 Gy is possible if there are no more than 2 lesions and their size does not exceed 2–3 cm.

Normal tissue tolerance doses

• Spinal cord: maximum dose not exceeding 40 Gy (Dmax <40 Gy). Exceptions are spinal tumors where the maximum allowable dose is 50–54 Gy. When using busulfan**, the dose to the spinal cord and brain must not exceed 30 Gy.

• Heart: Dmean <30 Gy.

• Liver: the volume of liver tissue receiving a dose of 20 Gy or more must not exceed 33% (V20 <33%)

• Kidneys:

  • mean dose not exceeding 15 Gy (Dmean <15 Gy),

  • the volume of renal tissue receiving a dose of 20 Gy or more must not exceed 32% (V20 <32%),

• in a single preserved kidney – maximum dose less than 12 Gy (Dmax <12 Gy),

• the volume of renal tissue receiving 10 Gy or more – no more than 25–30% (V10 <25–30%)

5.10 Adverse Effects

Acute radiation toxicities occur during radiotherapy and within the first 90 days after its completion. These effects are specific to the irradiated tissues and are usually well tolerated by patients. However, they can sometimes be quite severe, requiring additional medical management and treatment interruption. Acute effects are largely temporary and do not cause permanent deterioration of tissue and organ function.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Alexander Isakovich Karachunsky, Professor, Doctor of Medical Sciences, Director of the Institute of Oncology, Radiology and Nuclear Medicine, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

2. Nikolay Sergeevich Grachev, Professor, Doctor of Medical Sciences, General Director of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

3. Svetlana Rafaelevna Varfolomeeva, Professor, Doctor of Medical Sciences, Director of the L.A. Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

4. Kirill Igorevich Kirgizov, Candidate of Medical Sciences, Deputy Director for Science, L.A. Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

5. Elena Ivanovna Konopleva, Pediatric Oncologist, Researcher, Department of Musculoskeletal Sarcoma Research, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

6. Nikolay Anatolyevich Bolshakov, Candidate of Medical Sciences, Head of the Department of Oncology and Pediatric Surgery, Head of the Division of Oncoorthopedics, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

7. Natalia Gennadievna Uskova, Candidate of Medical Sciences, Pediatric Surgeon, Researcher, Department of Thoracoabdominal Surgery, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

8. Alexey Vladimirovich Nechesnyuk, Candidate of Medical Sciences, Head of the Department of Radiation Therapy, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

9. Yury Nikolaevich Likar, Candidate of Medical Sciences, Head of the Department of Radionuclide Diagnostics, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

10. Ilya Vladimirovich Sidorov, Pathologist, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

11. Galina Viktorovna Tereshchenko, Candidate of Medical Sciences, Head of the Department of Diagnostic Radiology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

12. Tatiana Viktorovna Gorbunova, Candidate of Medical Sciences, Deputy Chief Physician, L.A. Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

13. Olga Mikhailovna Romantsova, Pediatric Oncologist, Head of Pediatric Oncology Department No. 2 (Chemotherapy of Musculoskeletal Tumors), L.A. Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

14. Andrey Yuryevich Vashura, Candidate of Medical Sciences, Head of the Department of Scientific Foundations of Nutrition and Nutritional-Metabolic Therapy

15. Denis Borisovich Khestanov, Candidate of Medical Sciences, Senior Researcher, Pediatric Oncology Department No. 2 (Chemotherapy of Musculoskeletal Tumors), L.A. Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

16. Vasily Andreevich Grigorenko, Head of the Department of Radiation Therapy, L.A. Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatric oncologists;

2. Medical students, residents, postgraduate students.

Methodology for evidence collection

Methods used for collecting/selecting evidence: search for publications in specialized peer-reviewed journals with an impact factor >0.3.

Search in electronic databases.

The evidence base for the recommendations includes publications from the Cochrane Library, PubMed, and MEDLINE databases. The search depth was 30 years.

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• evaluation of the significance of evidence in accordance with the evidence rating scheme (Tables A1–A3).

These clinical guidelines present the levels of evidence certainty and grades of recommendation strength in accordance with the guidelines for the development and revision of clinical guidelines (Order of the Russian Ministry of Health No. 103n dated February 28, 2019).

Table 10. Scale for assessing levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)

Table 11. Scale for assessing levels of evidence certainty (LEC) for methods of prevention, treatment, medical rehabilitation, including those based on the use of natural therapeutic factors (prophylactic, therapeutic, rehabilitative interventions)

Table 12. Scale for assessing grades of recommendation strength (GRS) for methods of prevention, diagnostics, treatment, medical rehabilitation, including those based on the use of natural therapeutic factors (prophylactic, diagnostic, therapeutic, rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Prevention and treatment of nausea and vomiting induced by antitumor therapy

A3.1.1. Determination of emetogenicity level and CINV prevention option

To select an adequate CINV prophylaxis regimen at the first stage, it is necessary to determine the emetogenic level (risk of CINV) of the antitumor therapy regimen planned for the patient. The level of emetogenicity influences the choice of drugs for CINV prophylaxis, their doses, and duration of use. Appendix A 3.1.2 (Table 1) presents the general classification of emetogenicity of chemotherapy agents according to ASCO (American Society of Clinical Oncology) and COG (Children's Oncology Group) recommendations [103-111].

A3.1.2. Table 1 – Emetogenicity level of antineoplastic agents

A3.1.3. Prevention of nausea and vomiting during highly emetogenic chemotherapy

For optimal prophylaxis of acute CINV occurring on the day(s) of chemotherapy administration, for children aged 5 years and older and/or weighing 15 kg or more, use a four-drug regimen including a 5-HT3 serotonin receptor blocker, an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics), #dexamethasone**, and #olanzapine** [103-111]. Regimens and doses are presented in Appendix A3.1.4 (Table 2).

If the antitumor therapy regimen includes a glucocorticoid at a dose equal to or exceeding the dose indicated for antiemetic use, additional administration of a glucocorticoid (to the antitumor therapy regimen) for CINV prophylaxis on that day is not required. The use of #olanzapine** in children under 5 years of age and/or weighing less than 15 kg has not been studied and cannot be recommended.

For optimal prophylaxis of delayed CINV, administered within 3 days after the completion of chemotherapy infusions, use a combination of #dexamethasone** and #olanzapine** [103-111]. Regimens and doses are presented in Appendix A3.1.4 (Table 2).

If it is not possible to prescribe an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics), use a combination consisting of any 5-HT3 serotonin receptor blocker, #dexamethasone**, and #olanzapine** [103-111]. Regimens and doses are presented in Appendix A3.1.4 (Table 2).

If it is not possible to prescribe #dexamethasone**, palonosetron** is used as the preferred 5-HT₃ receptor blocker in combination with an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics) (if administration is possible) and #olanzapine** [103-111]. Regimens and doses are presented in Appendix A3.1.4 (Table 2).

A3.1.4. Table 2 – Doses and regimens of antiemetic drugs [147]

A3.1.5. Prevention of nausea and vomiting during moderately emetogenic chemotherapy

For optimal prophylaxis of acute chemotherapy-induced nausea and vomiting (CINV) occurring on the day(s) of chemotherapy administration, a two-drug regimen is used, including a serotonin 5-HT3 receptor blocker and #dexamethasone** [103-111]. Regimens and doses are presented in Appendix A3.1.4 (Table 2).

If the antitumor therapy regimen includes a glucocorticoid at a dose equal to or exceeding the dose indicated for antiemetic use, additional administration of a glucocorticoid (to the antitumor therapy regimen) for CINV prophylaxis on that day is not required.

For optimal prophylaxis of delayed CINV, administered within 1 day after the completion of cytostatic administration (according to the ATC classification L: Antineoplastic and immunomodulating agents), use #dexamethasone** [103-111]. Regimens and doses are presented in Appendix A3.1.2 (Table 1).

If #dexamethasone** cannot be prescribed, use a combination consisting of any serotonin 5-HT3 receptor blocker and an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics) [103-111]. Regimens and doses are presented in Appendix A3.1.4 (Table 2).

If neither #dexamethasone** nor NK₁ receptor antagonists (according to the ATC classification A04AD: Other antiemetics) can be prescribed, palonosetron is used as the preferred serotonin 5-HT3 receptor blocker [103-111]. Regimens and doses are presented in Appendix A3.1.4 (Table 2).

A3.1.6. Prevention of nausea and vomiting associated with low- and minimally emetogenic chemotherapy

Prophylaxis of CINV during low- and minimal-emetogenic chemotherapy includes single-agent prophylaxis with a 5-HT₃ receptor antagonist for low-emetogenic therapy, or no prophylaxis at all in the case of chemotherapy with minimal emetogenic activity [103-111]. Regimens and doses are presented in Appendix A3.1.4 (Table 2).

A3.1.7. Treatment of breakthrough and refractory vomiting

For patients with breakthrough and refractory emesis during cytostatic therapy, it is recommended:

1. If breakthrough CINV occurred during cytostatic therapy (and, accordingly, prophylaxis) corresponding to the minimal, low, or moderate emetogenic level, it is necessary to use the drugs provided for the next, higher level of prophylaxis.

2. If the patient is already receiving prophylaxis intended for highly emetogenic therapy, the development of breakthrough CINV warrants considering the addition of #olanzapine** (if it was not used previously due to inappropriate age or body weight). If #olanzapine** cannot be used, metoclopramide** may be used as an alternative.

3. If the patient exhibits refractory CINV and is not yet receiving the maximum level of prophylaxis, antiemetic therapy must be escalated. If refractory CINV is observed despite the maximum level of prophylaxis, the currently used serotonin 5-HT3 receptor blocker may be switched to palonosetron, and additional doses of serotonin 5-HT3 receptor blockers administered. If these prophylactic approaches fail, it is recommended to permanently add #olanzapine**, metoclopramide**, or other drugs that have proven effective in the patient for treating breakthrough emesis [103-111].

Appendix B. Physician Action Algorithms

Diagram 4. Algorithm of physician actions in case of suspected bone malignant neoplasms

Diagram 5. Algorithm of physician actions in case of suspected bone malignant neoplasms

Appendix C. Patient Information

Bone malignant neoplasms are a diverse group of tumors in terms of origin and biological behavior, the treatment of which requires the involvement of specialists from various medical fields – pediatric oncologists, orthopedic surgeons, neurosurgeons, diagnostic radiologists, pathologists, radiation therapists, rehabilitation specialists, etc.

Clinical manifestations of the disease are determined by the localization and size of the tumor, and the stage of the disease, but the leading symptom is usually pain in the area of the formation, which bothers the patient predominantly at night. Subsequently, claudication may develop, movements in the adjacent joint may be restricted due to the size of the mass, and swelling appears in the area of the affected bone.

When a bone mass is suspected, radiography is performed as the initial step. Based on the radiographic findings, an area of bone destruction is identified. To clarify the nature of the lesion and determine the biopsy site, computed tomography (CT) and magnetic resonance imaging (MRI) of the affected bone are performed.

Computed tomography (CT) provides a more detailed study of the tumor, evaluating both the intraosseous component and its spread into surrounding soft tissues (extraosseous component). Magnetic resonance imaging (MRI) offers additional information on the size of the mass, soft tissue involvement, and its relationship with blood vessels and nerves. Based on the diagnostic workup, a biopsy of the mass is performed, followed by microscopic, immunohistochemical, and, if necessary, cytogenetic examination.

The most common malignant bone tumors in children and adolescents are osteosarcoma and Ewing sarcoma.

Osteosarcoma is a highly aggressive malignant bone tumor. This type of tumor can occur at any age, but it is most frequently diagnosed in patients aged 10–15 years, which is associated with the period of rapid growth in children, particularly of the skeletal bones. In addition, an increased risk of osteosarcoma is observed in certain genetic abnormalities. For instance, this tumor is more common in children with hereditary retinoblastoma (a retinal tumor) and Li-Fraumeni syndrome. The development of osteosarcoma is also possible if a child has previously undergone radiation therapy, for example, during the treatment of another malignancy. However, in the majority of cases, the disease occurs in children and young adults who have none of the aforementioned risk factors.

The primary focus of osteosarcoma is most commonly located in the long tubular bones of the extremities—both upper and lower—with the parts of the lower extremity that form the knee joint being the favored site for the primary lesion.

Exhibiting highly aggressive behavior, osteosarcoma destroys the bone and forms an extraosseous (soft tissue) component that invades the muscles, blood vessels, and nerves adjacent to the affected bone segment. Via the bloodstream, tumor cells can spread to distant parts of the body, forming distant metastases. The lungs are the most common site for metastases, while metastatic (secondary) involvement of other skeletal bones occurs less frequently. The presence of distant metastatic lesions is assessed using contrast-enhanced chest CT, whole-body PET/CT, or Tc-99 bone scintigraphy.

Based on the histological examination and diagnostic workup results, the patient is staged, which will subsequently determine the treatment strategy for the child. The cornerstone in the treatment of patients with osteosarcoma is surgical resection of the tumor. If this cannot be performed, the prognosis worsens significantly. In the presence of distant metastases in the lungs or skeletal bones, their surgical removal is also performed. The second key treatment method for patients with osteosarcoma is specific therapy, otherwise known as polychemotherapy. Specific therapy is administered immediately after the biopsy—preoperative (neoadjuvant chemotherapy)—and following surgical resection of the tumor—postoperative (adjuvant chemotherapy).

Radiation therapy is used very rarely, as osteosarcoma cells have low sensitivity to radiation. Irradiation is sometimes employed when complete surgical removal of the tumor is not feasible.

Ewing sarcoma is a malignant tumor that usually affects the bones. Among malignant bone tumors in children, it ranks second in frequency after osteosarcoma. It most commonly arises in long tubular bones (such as the femur, tibia, fibula, and humerus), as well as in the pelvic bones, ribs, vertebrae, scapulae, etc. Involvement of flat bones, such as the pelvic bones, ribs, or scapulae, is significantly more common in Ewing sarcoma than in osteosarcoma. From the primary bone lesion, the tumor rapidly spreads into the surrounding soft tissues, including muscles and tendons.

Sometimes the primary tumor in Ewing sarcoma originates not in the bone, but in the soft tissues. In such cases, it is referred to as extraosseous (extraskeletal) Ewing sarcoma.

There is an entire family of similar aggressive malignant tumors related to Ewing sarcoma, hence the term "Ewing sarcoma family of tumors." In addition to osseous and extraosseous Ewing sarcoma, this group also includes peripheral primitive neuroectodermal tumors (PNETs) (which must be distinguished from cerebral PNETs, which have a different nature!). A specific form of PNET is the so-called Askin tumor.

Ewing sarcoma and PNET cells are not completely identical, but they share similar molecular-biological and cytogenetic characteristics—thus, in the vast majority of cases, tumor cells harbor the t(11;22) translocation. The treatment strategies for these tumors are also similar.

For Ewing sarcoma, localized and metastatic stages of the disease are distinguished. This is important for treatment planning and prognostic evaluation. In the localized stage, the tumor may spread from the primary site to surrounding soft tissues, but standard diagnostic methods do not detect distant metastases. The metastatic stage is diagnosed when the tumor has already spread to other parts of the body. Common sites of metastasis include the lungs, bones, and bone marrow; metastasis to lymph nodes, the central nervous system, the liver, etc., is also possible.

Ewing sarcoma is the second most common bone tumor in children (after osteosarcoma). In European countries, the overall incidence of tumors belonging to the Ewing sarcoma family is approximately 2–3 cases per 1 million population under the age of 20. The majority of cases are osseous Ewing sarcoma, with only about 15% accounting for extraosseous Ewing sarcoma and PNET.

Ewing sarcoma is rare in children under 5 years of age and in adults over 30. It most frequently occurs in adolescents aged 10–15 years. Boys are affected slightly more often than girls. Among Europeans, this tumor occurs several times more frequently than among individuals of Asian and African descent.

There is evidence that the risk of Ewing sarcoma is slightly elevated in the presence of certain benign bone tumors (such as enchondroma) and specific urogenital anomalies. Ewing sarcoma is not a genetically determined disease, but in rare cases, a hereditary predisposition can be noted—for instance, cases of PNET occurring in children within the same family have been documented. The lifestyle of children and their parents apparently does not play a role in the development of Ewing sarcoma.

It is a common belief that the development of bone sarcomas, including Ewing sarcoma, is often triggered by trauma. However, the time intervals between trauma and tumor detection can vary widely, and it is difficult to reliably prove a causal relationship between the onset of sarcoma and preceding bruises or fractures. It is quite possible that trauma simply draws attention to that area of the body, resulting in the discovery of a tumor that was already pre-existing.

A characteristic symptom of osseous Ewing sarcoma is pain in the affected bone area. Unlike pain caused by trauma, it does not subside with limb immobilization, and over time it intensifies rather than diminishes. Sometimes this pain is mistaken for a sign of inflammation, but antibiotic therapy does not relieve it.

In the majority of patients with osseous Ewing sarcoma and virtually all patients with extraosseous sarcoma, a swelling gradually develops at the tumor site. The edema may extend to the nearest joint, impairing its function. The swollen area is usually tender to the touch (palpation) and rapidly increases in size over time. In approximately 1/3 of cases, local hyperthermia is observed, meaning the tumor area feels warmer than the surrounding tissues. The skin over the affected area may be erythematous, with prominent dilated veins.

Significant tumor involvement of the bone can lead to a pathological (i.e., disease-induced) fracture of that bone.

If the tumor affects the spine or its surrounding tissues, motor disturbances and/or pelvic organ dysfunction may occur.

As the tumor spreads throughout the body (metastasis), "systemic" symptoms appear: weakness, fatigue, weight loss, and fever.

Ewing sarcoma is often diagnosed quite late, only several months after the onset of the first symptoms. This is because pain and swelling are initially attributed to trauma or inflammation. Therefore, in cases of persistent, unexplained bone pain, a consultation with an oncologist or pediatric oncologist is indicated.

Radiography of the affected bone area is usually the first investigation that allows the detection of Ewing sarcoma. This tumor has a characteristic appearance on radiographs, which makes it possible to establish a provisional diagnosis. Ultrasonography (US) of the same area is used to assess the size and nature of the soft tissue component of the tumor.

More detailed information about tumor spread can be obtained using other imaging modalities, such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI). These methods make it possible to clarify the localization and size of the tumor, determine the extent of soft tissue involvement around the affected bone, assess the condition of the medullary canal, and detect metastases. Positron emission tomography (PET) may also be performed.

To clarify the nature of the detected tumor, a biopsy of the soft tissue component or the affected bone area itself is necessary. Various cell studies are performed, including immunohistochemistry, as well as cytogenetic analysis for the presence of the t(11;22) translocation and other chromosomal abnormalities.

Since Ewing sarcoma frequently metastasizes to the lungs, chest X-ray and computed tomography are advisable for their detection. Ewing sarcoma can also produce multiple bone metastases, for the detection of which bone scintigraphy is used.

Bone marrow involvement is not uncommon in Ewing sarcoma. To detect it, a bone marrow puncture or trephine biopsy is used, followed by analysis of the obtained bone marrow samples for the presence of tumor cells.

Routine laboratory tests are also performed. Changes in the complete blood count may be observed: leukocytosis, anemia, elevated ESR. In the biochemical blood test, the level of lactate dehydrogenase (LDH) is important, as its elevation is more commonly observed with a more aggressive disease course.

Unfortunately, in 20–30% of all cases, Ewing sarcoma is diagnosed when it has already metastasized, as detected by routine imaging methods.

Ewing sarcoma is a highly aggressive tumor that rapidly develops micrometastases. Therefore, its treatment necessarily includes systemic exposure to the entire body using multi-agent chemotherapy—otherwise, relapses are practically inevitable. In addition, surgical treatment and/or radiotherapy are required.

In many cases of Ewing sarcoma, surgical removal of the tumor is possible—for example, if it affects the bones of the lower or upper extremities, ribs, scapulae, etc. Both the affected bone area and the soft tissue component of the tumor are removed, and the removed bone section is replaced with an endoprosthesis. Sometimes, unfortunately, amputation of an arm or leg may be necessary, but modern treatment methods often make it possible to avoid it. After tumor removal, radiotherapy of the site where it was located may be performed to destroy remaining tumor cells.

If complete surgical removal of the tumor is impossible, doctors attempt to control it using radiotherapy, as Ewing sarcoma cells are sensitive to this type of treatment. However, in these cases, the risk of disease recurrence increases. Chemotherapy in modern Ewing sarcoma treatment protocols is used both before and after surgery. After tumor removal, it is examined to assess the response to prior chemotherapy and select the subsequent treatment strategy.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1.

Assessment of general condition using the Karnofsky performance scale

Russian title: Karnofsky Performance Scale.

Original title: Karnofsky Performance Status.

Source: Karnofsky D.A., Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C. (ed.). Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949:191–205 [45].

Type: rating scale.

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Contents:

Table 1. Assessment of general condition using the Karnofsky performance scale

Appendix G2.

General condition assessment scale ECOG

Russian title: ECOG performance status scale

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649–65 [46]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Contents:

Table 2. ECOG performance status scale

Appendix G3.

Interpretation of nutritional status based on Z-score according to WHO reference data

Russian title: Interpretation of nutritional status based on Z-score according to WHO reference data

Source: Vashura AYu, Kucher MA, Kovtun TA, Alymova YuA, Litvinov DV, Zubarovskaya LS, Kulagin AD. Role and relevance of nutritional diagnosis in pediatric oncology. Medical Council. 2023;(12):99-109 [121]

Type: rating scale

Contents:

Table 1. Interpretation of nutritional status based on Z-score according to WHO reference data

Notes: nutritional status in pediatric oncology is assessed based on cumulative data (clinical, laboratory, instrumental), taking into account nutritional risk; anthropometric indicators allow a criteria-based orientation in determining nutritional status and cannot be the sole determining factors; * – the indicator with the minimum SDS is used in determining nutritional status; SDS – standard deviation score; obesity: simple; hypothalamic; in neuroendocrine diseases; iatrogenic; monogenic; syndromic

Appendix G4.

Risk factors for the development of nutritional status disorders

Russian title: Scale for assessing the risk of developing nutritional status disorders

Source: Vashura AYu, Kucher MA, Kovtun TA, Alymova YuA, Litvinov DV, Zubarovskaya LS, Kulagin AD. Role and relevance of nutritional diagnosis in pediatric oncology. Medical Council. 2023;(12):99-109 [121]

Type: scale for assessing the risk of developing nutritional status disorders

Contents:

Table 2. Factors of high risk for the development of nutritional status disorders