Mediastinal tumors: clinical guidelines

List of Abbreviations

AFP – alpha-fetoprotein

IV – intravenous

WHO – World Health Organization

G-CSF – granulocyte colony-stimulating factor

CT – computed tomography

LDH – lactate dehydrogenase

PT – physical therapy

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

PET-CT – positron emission tomography combined with computed tomography

US – ultrasound examination

hCG – beta-human chorionic gonadotropin

ECOG – Eastern Cooperative Oncology Group

** – vital and essential drugs

# — this symbol indicates a medicinal product used for indications not included in the instructions for use of the medicinal product.

Terms and Definitions

Thoracotomy is a surgical intercostal approach to thoracic organs

Sternotomy is a surgical approach to thoracic organs involving sternal transection

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Mediastinal tumors are a group of benign and malignant tumors of various structures located within the anatomical boundaries of the mediastinum and having a non-organ origin. Exceptions include thymoma and pleural mesothelioma, which are of organ origin.

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

Up to one hundred different forms of neoplasms occur in the mediastinum; however, according to modern concepts, true benign and malignant mediastinal tumors are considered to be those originating from tissues embryogenetically proper to the mediastinum or aberrant ones displaced into the mediastinal space during embryogenesis [1,2].

1.3 Epidemiology of the Disease or Condition

The frequency of mediastinal neoplasms in the structure of oncological diseases is about 1%. Malignant and benign tumors are encountered and diagnosed in a ratio of 4 : 1. Mediastinal tumors are predominantly detected in young and middle-aged individuals, with men and women affected with equal frequency [3].

1.4 Features of Coding the Disease or Condition

-C37 Malignant neoplasm of thymus;

-C38 Malignant neoplasm of heart, mediastinum and pleura:

• C38.0 Malignant neoplasm of heart

• C38.1 Malignant neoplasm of anterior mediastinum

• C38.2 Malignant neoplasm of posterior mediastinum

• C38.3 Malignant neoplasm of mediastinum, part unspecified

• C38.4 Malignant neoplasm of pleura

• C38.8 Lesion of heart, mediastinum and pleura overlapping with more than one of the above sites

-D38 Neoplasm of uncertain or unknown behavior of middle ear and respiratory and intrathoracic organs:

• D38.3 Neoplasm of uncertain or unknown behavior of mediastinum

• D38.4 Neoplasm of uncertain or unknown behavior of thymus

1.5 Classification of the disease or condition

All mediastinal tumors are divided into 3 major groups according to their origin: epithelial, germ cell, and mesenchymal (soft tissue). According to the WHO histological classification of tumors, 5th edition, 2021, all thymomas are classified as malignant neoplasms.

The International Classification of Diseases for Oncology (ICD-O) with corresponding codes is presented in Table 1 (lung, pleural, hematolymphoid neoplasms, and ectopic thyroid and parathyroid tumors are presented in the respective sections):

Tumor aggressiveness is coded as follows:

/0 for benign tumors;

/1 for borderline or uncertain malignant potential;

/2 for carcinoma in situ and grade III intraepithelial neoplasia;

/3 for malignant tumors

For staging thymic tumors, the Masaoka-Koga classification is most widely used and is suitable for both thymomas and thymic carcinomas. The modern TNM staging system for thymoma and thymic carcinoma is based on pooled data from the International Thymic Malignancy Interest Group (ITMIG) and the International Association for the Study of Lung Cancer (IASLC). Both classifications can be used in clinical practice (Tables 2, 3), but the Masaoka-Koga classification more accurately describes microscopic tumor invasion, which determines treatment tactics [75].

TNM classification of epithelial thymic tumors (thymoma, thymic carcinoma) (8th edition AJCC, 2018) (Table 2)

Table 2. TNM classification of epithelial thymic tumors (thymoma, thymic carcinoma)

Table 3. Masaoka-Koga classification

1.6 Clinical presentation of the disease or condition

Clinical symptoms of mediastinal neoplasms depend on their location, size, malignancy, and consequently on the infiltration of surrounding structures, metastasis, and the presence of paraneoplastic syndromes. Acute and chronic mediastinitis can mimic a tumor lesion.

Most clinical manifestations are nonspecific: cough, dyspnea, chest pain, dysphagia, signs of mediastinal compression syndrome (most commonly superior vena cava compression), cardiac arrhythmias.

Clinical manifestations of malignant mediastinal tumors are more pronounced than those of benign ones and progress more rapidly. Small benign tumors are often discovered incidentally on X-ray examination.

Mediastinal neoplasms, predominantly malignant and less often benign, can eventually reach large sizes, sometimes occupying an entire hemithorax, representing so-called giant mediastinal tumors. Pronounced compression of vital organs is accompanied by dyspnea, acrocyanosis, puffiness, dilation of chest wall and neck veins, tachycardia, angina attacks, and headache. Infiltration leads to chest wall deformation, Horner's syndrome, laryngeal and diaphragmatic paresis.

The clinical symptoms of thymic carcinoid are nonspecific, except for cases accompanied by endocrinopathies, and are caused by manifestations of mediastinal compression syndrome. Cushing's syndrome is observed in 25–30% of patients [4,5], along with other endocrine disorders: inappropriate ectopic antidiuretic hormone secretion, hypertrophic osteoarthropathy, and Lambert-Eaton syndrome are sometimes observed. Endocrine disorders manifesting as carcinoid syndrome—attacks of suffocation with marked cyanosis, diarrhea—have been described [6,7]. In such cases, the diagnosis can be established based on elevated urinary 5-hydroxyindoleacetic acid levels (a serotonin metabolite). Rarely, the initial manifestations of these tumors are cervical lymph node, bone, or skin metastases.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria: there are no pathognomonic symptoms. Chest X-ray/CT/MRI reveals a neoplasm in the mediastinum that is not normally present.

2.1 Complaints and Anamnesis

Comments: clinical symptoms of mediastinal neoplasms depend on the location, size of the mass, malignancy and, consequently, on the infiltration of surrounding structures and metastasis, and the presence of paraneoplastic syndromes. Acute and chronic mediastinitis can mimic tumor lesions.

Most clinical manifestations are nonspecific: cough, dyspnoea, chest pain, dysphagia, manifestations of mediastinal compression syndrome (most commonly superior vena cava compression), and cardiac arrhythmias.

Clinical manifestations of malignant mediastinal tumors are more pronounced than those of benign tumors and progress more rapidly. Small benign tumors are often discovered incidentally during X-ray examination.

Mediastinal neoplasms, predominantly malignant and less frequently benign, can eventually reach large sizes, sometimes occupying an entire hemithorax, representing so-called giant mediastinal tumors. Compression of vital organs is pronounced, accompanied by dyspnoea, acrocyanosis, facial puffiness, dilation of the chest wall and neck veins, tachycardia, angina attacks, and headache. In cases of invasion, chest wall deformation, Horner's syndrome, and laryngeal and diaphragmatic paresis occur.

The clinical presentation of thymic carcinoid is nonspecific, except for cases accompanied by endocrinopathies, and is caused by manifestations of the mediastinal compression syndrome. Cushing's syndrome [4,5] and other endocrine disorders are observed in 25–30% of patients: inappropriate ectopic production of antidiuretic hormone, hypertrophic osteoarthropathy, and Lambert-Eaton myasthenic syndrome are sometimes observed. Endocrine disorders manifesting as carcinoid syndrome—attacks of suffocation with severe cyanosis, diarrhea [6,7]—have been described. In these cases, the diagnosis can be established based on elevated levels of 5-hydroxyindoleacetic acid in the urine (a serotonin metabolite). Rarely, the first manifestations of these tumors are metastases in the cervical lymph nodes, bones, or skin.

2.2 Physical Examination

2.3 Laboratory Diagnostics

Comments: Changes in the morphological composition of peripheral blood are mainly detected in malignant tumors (anemia, leukocytosis, lymphopenia, elevated erythrocyte sedimentation rate), inflammatory, and systemic diseases.

Comments: the presence of an elevated AFP level and a high hCG level (above 1000 mIU/mL) indicates the presence of a malignant non-seminomatous germ cell tumor, even with the morphological variant of "seminoma" or "mature teratoma".

2.4 Instrumental Diagnostics

Comments: X-ray imaging provides a fairly comprehensive picture of the shape and localization of the tumor, the extent of the lesion, the nature of the topographical and anatomical relationships between the pathological formation and surrounding tissues and organs, and in some cases allows for assumptions regarding the true nature of the process. In the anterior superior mediastinum, thymomas, teratomas, and lymphomas [15] are most common. In the anterior inferior mediastinum, lipomas and pericardial cysts are most common. In the posterior mediastinum, neurogenic tumors (neurinomas, schwannomas, etc.) and bronchogenic cysts are more frequently localized.

Comments: Contrast-enhanced CT is the standard for staging and further diagnostic evaluation of mediastinal tumors and plays an important role in diagnosing primary tumor processes in the mediastinum, significantly expanding the volume of information obtained and thereby narrowing the differential diagnostic range of its potential lesion forms, up to establishing a morphological diagnosis in certain patients. CT angiography allows for the identification of the tumor, clarification of its localization and relationship with adjacent organs, ensures targeted tumor biopsy, and facilitates the detection of metastases from organ tumors in the mediastinal lymph nodes [8].

Comments: MRI has opened up fundamentally new diagnostic possibilities. MRI clearly visualizes the mediastinal tumor, major vessels, trachea, and bronchi, whereas determining tumor invasion into vessels and the chest wall is challenging. Performing MRI allows for the differentiation of mediastinal vascular structures (including vascular anomalies) from tumor lesions without the use of additional techniques. When the organ of origin of the neoplasm is unclear, it can be clarified using other imaging modalities.

Comments: combining PET and CT technologies demonstrates new possibilities in clarifying the localization and extent of the tumor process. According to research results, PET-CT has proven to be more effective in assessing the status of mediastinal tumors, as well as in evaluating treatment efficacy and diagnosing recurrences. 18F-FDG PET-CT (Fluorodeoxyglucose [18F]) is not recommended for initial staging, but serves as an adjunct method in diagnosing pleural involvement and as a post-treatment assessment tool prior to radiation therapy planning.

Comments: examination of the tracheobronchial tree makes it possible to detect invasion and obstruction (compression, displacement) of the trachea and bronchi. In the presence of an exophytic component, it becomes possible to perform a tissue biopsy for cytological verification of the diagnosis. If there is no invasion of the tracheal or bronchial wall, but deformation is present, a transbronchial (transtracheal) needle biopsy is feasible.

Comments: transthoracic puncture has high diagnostic capabilities. The diagnostic accuracy of the method reaches 70.0–95.0%. Examination of punctates from mediastinal neoplasms allows determining their nature and, in some cases, histogenesis, which is a decisive factor in establishing a clinical diagnosis and choosing treatment tactics. Transbronchial fine-needle aspiration and transesophageal fine-needle aspiration are also used. These diagnostic procedures can be informative for the morphological verification of posterior mediastinal tumors and metastatic lesions of the bifurcation, aortopulmonary, and paraesophageal lymph node groups [16,17]. Histological verification of the tumor before surgical treatment is not mandatory if, according to clinical and radiological data, the tumor is completely resectable or if myasthenia gravis is present.

Comments: allows detailed visualization of the mediastinal tumor, determination of its extent, relationship with surrounding organs and tissues, targeted biopsy of its various sections, and establishment of a morphological diagnosis in more than 90.0% of studies [18].

• Ultrasound examination (hereinafter referred to as US) of the abdominal cavity (comprehensive), neck lymph nodes, and peripheral lymph nodes is recommended for patients with a mediastinal tumor when contrast-enhanced CT is not feasible [2].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: the main objective of ultrasound examination in malignant mediastinal tumors is the detection of lymphogenic and hematogenous distant metastases in the abdominal cavity, retroperitoneal space, and lymph nodes of the supraclavicular, cervical, and axillary regions.

Comments: performed when metastatic brain disease is suspected.

2.5 Other Procedures

Comment: in this case, the morphological report should reflect the following parameters:

1. Distance to the proximal and distal resection margins.

2. Tumor dimensions.

3. Histological structure of the tumor.

4. Tumor grade of differentiation.

5. Presence of involvement of the proximal resection margin (a negative result must also be stated).

6. Presence of involvement of the distal resection margin (a negative result must also be stated).

7. Presence of lymphovascular or perineural invasion (a negative result must also be stated).

Comments: in the case of undifferentiated tumors, immunohistochemical examination makes it possible to establish their tissue or even organ origin, which helps to prove or rule out the metastatic origin of the neoplasm and helps identify the primary site.

Comment: in lymphoproliferative mediastinal tumors, IHC examination is necessary, which imposes special requirements on the quality and volume of the biopsy material. It has been shown that when an initial core needle biopsy attempt is uninformative, subsequent attempts do not increase the rate of correctly established diagnoses, but can delay the start of anticancer treatment, which is especially important for patients with compression syndrome. In these cases, open tumor biopsy via parasternal mediastinotomy is recommended.

Comment: if morphological verification using minimally invasive methods is not possible in the absence of contact with the chest wall, the possibility of therapeutic and diagnostic tumor removal must be considered. This is advisable for small-sized formations (up to 5 cm), the absence of invasive growth, and superior vena cava compression. Moreover, due to the morbidity of traditional approaches (thoracotomy, sternotomy), the operation in this situation should preferably be performed thoracoscopically.

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

3.1. Treatment of thymic neoplasms

Surgical treatment.

Comments: Stage I is an absolute indication for surgical treatment. The treatment strategy for each patient should be discussed at a multidisciplinary board meeting. Since stage II is more frequently established by the pathologist, the surgical stage remains a priority even in the presence of macroinvasion into the surrounding adipose tissue. Indications for surgical treatment are justified by the slow growth of thymomas and the detection of local tumor capsule invasion in only 30–40% of patients. Medical treatment of myasthenia gravis should begin as early as possible, even in the preoperative period, in cooperation with a neurologist and in accordance with the clinical guidelines for the diagnosis and treatment of myasthenia of the All-Russian Society of Neurologists. [19,20].

A mandatory condition for thymectomy is the complete excision of thymic remnants and surrounding adipose tissue with lymph nodes, locating the "horns" of the tumor, which often extend into the neck (due to the embryogenesis of the thymus) [15]. High mobilization, ligation, and transection of the thymic "horns" are mandatory components of the surgery, as the remaining parts of the thymus can subsequently serve as sources of recurrence [21,22]. In malignant tumors, due to the possibility of lymph node involvement, it is necessary to remove all mediastinal adipose tissue with regional lymph nodes. In striving for radical tumor removal, combined operations up to the resection of several adjacent organs (pericardium, phrenic nerve, great vessels with reconstruction, lung, etc.) are justified. Minimally invasive thoracoscopic surgery is less traumatic, but is not widely recommended in routine practice. However, it can be used for stages I-II in large multidisciplinary centers by an experienced surgeon (for non-invasive thymoma). For locally advanced tumor processes, the optimal approach is full median sternotomy, which can be supplemented by thoracotomy. The thoracotomy approach does not allow for radical tumor removal, is characterized by a high rate of local recurrence, and is therefore not recommended.

The algorithm for the diagnosis and treatment of early-stage thymic tumors is presented in Appendix B.

Adjuvant radiation therapy.

– tumor capsule invasion in type B2 and B3 thymomas;

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: RT for stage II is highly controversial. Following an R0 radical resection with confirmed microinvasive stage IIA (types A, AB, B1, B2) and macroinvasion beyond the glandular capsule, or stage IIB (types A, AB, B1), the question of adjuvant radiotherapy remains open. Currently, there is neither compelling evidence demonstrating the necessity of RT after radical surgery in stage II, nor data refuting it. The appropriateness of adjuvant RT for more aggressive thymoma histological subtypes (stage IIA type B3 and stage IIB types B2–B3) should also be discussed at a multidisciplinary tumor board. Based on the ITMIG database, which provides the most robust evidence for postoperative RT to date, and the sole prospective study by Basse et al. (2016), the greatest benefit in stage II thymoma—even with complete resection—was observed in histological subtypes B2–B3.

For stage III thymoma with macroscopic tumor invasion into adjacent organs following R0 resection, the administration of postoperative RT should also be decided at a multidisciplinary tumor board, taking into account all adverse risk factors and the risk of recurrence.

– detection of tumor cells at the resection margin (R1);

– presence of macroscopic residual tumor (R2);

– morphological confirmation of stage IIA–IIB thymic carcinoma, even with R0.

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: 3D conformal RT, IMRT, VMAT are used with dose constraints to critical organs. The radiation field includes the region of initial tumor spread, anterior, upper, and middle mediastinum. Prophylactic irradiation of regional lymph nodes (mediastinal and supraclavicular lymph nodes bilaterally), mediastinal and costal pleura is not recommended. RT should be initiated no later than 3 months after surgery. In other cases, the appropriateness of its use should be discussed at a multidisciplinary conference.

The postoperative treatment algorithm is presented in Appendix B.

Adjuvant chemotherapy.

Comments: Adjuvant chemotherapy may be considered by a multidisciplinary tumor board following radical R0 surgery for stages II/III/IVa thymic carcinoma, especially if induction chemotherapy was not administered. Adjuvant CT is also necessary for R1 resections in thymic carcinoma and R2 resections regardless of histological type.

Adjuvant chemotherapy is not indicated following radical surgery for stages I–III, regardless of histological type, or for R1 resection of thymoma.

In oligometastatic disease following R0 resection of a metastasis, the administration of adjuvant CT and RT must be discussed at a multidisciplinary tumor board.

The optimal timing for adjuvant chemotherapy is 4–6 weeks postoperatively. The adjuvant CT regimen is not definitively established. The same regimens as for first-line therapy may be used.

Neoadjuvant therapy.

Comments: if initial tumor invasion of mediastinal organs is detected in stages IIIa–IIIb (e.g., T3–T4), treatment should begin with chemotherapy and/or radiotherapy. If an objective positive response is achieved, surgical intervention is considered. Surgeries in these cases are associated with certain technical challenges due to cicatricial and sclerotic changes in the surrounding tissues. Radiotherapy as a standalone modality is used for unresectable tumors in combination with chemotherapy. The radiation field encompasses the mediastinal tumor mass (target volume planning using diagnostic CT and/or MRI data). On average, 2–4 cycles are administered preoperatively, with treatment efficacy evaluated according to RECIST 1.1 criteria. Neoadjuvant and adjuvant therapy are preferred for thymic carcinoma.

Postoperative sequential chemoradiotherapy (#etoposide** + #cisplatin** (Table 4) with RT to a cumulative dose of 60 Gy) can be used for R2 resection in both thymoma and thymic carcinoma. [23]

Comments: due to the rarity of the neoplasm, there is no compelling evidence regarding the preference of specific drugs or their combinations (for evaluation of medical treatment efficacy, see Appendix G3). However, according to many authors, the preferred treatment regimens for thymoma are anthracycline-containing schemes (CAP or ADOC) because they yield the best outcomes. The objective response rate can reach 50–98% in thymomas. Unfortunately, thymic carcinoma responds poorly to medical treatment. Non-anthracycline regimens can be used in patients who have contraindications to anthracyclines (L01DB: Anthracyclines and related substances).

Primary and alternative medical treatment regimens are presented in Table 4.

Table 4. Chemotherapy regimens recommended for thymic tumors.

¹ preferred regimen

² in case of intolerance or contraindications to chemotherapy, for patients with Octreoscan-positive thymoma, and in carcinoid syndrome

Targeted therapy and immunotherapy

Comments: The detection of elevated plasma concentrations of VEGF, FGF, membrane overexpression of PDGF in the tumor, and c-KIT mutations (exons 9–17) served as the rationale for studying targeted agents (L01: Antineoplastic agents). Mutations in the c-KIT gene occur in no more than 10% of thymic carcinoma cases and are absent in thymomas.

Pembrolizumab** has demonstrated efficacy in the second-line therapy of patients with thymic carcinoma, with an objective response rate of 22.5%, tumor growth control of 75%, and a median OS of 24.9 months; however, this type of treatment was associated with a high risk of autoimmune complications (15%). Grade 3–4 autoimmune myocarditis occurred in 5–9% of cases. Pembrolizumab** is not recommended for thymomas.

#Sunitinib** is prescribed regardless of the c-KIT mutation status in the second-line therapy of thymic carcinoma and is not indicated for thymoma. In a phase 2 study by Thomas A. et al. (2015), the objective response rate was 26% and tumor growth control was 91% in thymic carcinoma. After 17 months of follow-up, the median overall survival was 15.5 months for patients with thymoma and was not reached for patients with thymic carcinoma. The most severe adverse event associated with #sunitinib** was grade 3 cardiomyopathy in 8% of patients. In the STYLE phase 2 study (2023), an objective response was achieved in 21.7% (90% CI: 9.0%–40.4%) of cases. The median progression-free survival was 8.8 months (95% CI: 5.3–11.1), and the median overall survival was 27.8 months (95% CI: 13.2–53.2) in patients with thymic carcinoma. The most common complications of any grade were fatigue, hypertension, diarrhea, and oral mucositis. Consequently, treatment schedule modifications were required in 45.2% of cases and dose adjustments in 41.9%. In the Italian retrospective TYME study (2022), a dose of 37.5 mg was evaluated and demonstrated efficacy and a manageable toxicity profile (objective response rate of 31.6% of cases) [111].

#Everolimus** may be used in both refractory thymoma and thymic carcinoma, with an objective response rate of 11% and tumor growth control in 88% of cases. It should be noted that the primary severe complication of everolimus** therapy is grade 4 pneumonitis in 5% of patients.

Immunotherapy and targeted therapy regimens are presented in Table 5.

Table 5. Targeted therapy and immunotherapy regimens for thymoma and thymic carcinoma.

Despite a locally advanced tumor process in stages III–IVa, in the event of a recurrence (which occurs in 10–15% of cases in thymomas and up to 30% in thymic carcinomas and thymic neuroendocrine tumors) or disease progression, it is advisable to re-evaluate the feasibility of surgical treatment. Management tactics depend on the nature of previous treatment and metastatic sites. It should be borne in mind that prior mediastinal radiation therapy increases the risk of chemotherapy-induced cardiotoxicity. The treatment algorithm for this category of patients is presented in Appendix B.

3.2. Treatment of extragonadal mediastinal germ cell tumors

The treatment of mediastinal germ cell tumors does not fundamentally differ from that of gonadal germ cell tumors and is detailed in the clinical guidelines "Treatment of Germ Cell Tumors in Men", including the treatment regimens used in the management of mediastinal germ cell tumors.

Comments: an initial elevation in AFP and/or hCG levels indicates the presence of a malignant component, which requires first-line chemotherapy according to the principles of non-seminomatous tumor management. Surgical treatment is the main stage in the management of benign teratomas. Surgery for teratoma has specific features and is associated with certain technical difficulties due to pronounced fibrous adhesions, primarily involving the great vessels, trachea, and esophagus. Resection of the pericardium and phrenic nerve is frequently required, whereas resection of the great vessels requiring grafting is rarely performed. The prognosis for mature teratoma following radical resection is favorable [11, 12, 14].

Comments: the localization of a non-seminomatous malignant tumor in the mediastinum implies an unfavorable disease prognosis. Medical treatment is recommended to be carried out in specialized centers dealing with the management of germ cell tumors.

The surgical component is essential for assessing the efficacy of chemotherapy. Pathological examination of the surgical specimen may reveal necrosis, a mature teratoma, or viable malignant tissue [35].

Comments: mediastinal seminoma is a rare tumor that occurs predominantly in young men under 30 years of age. It can reach large sizes, infiltrate surrounding tissues, and metastasize via lymphatic and hematogenous routes. At the same time, it is highly sensitive to chemo- and radiotherapy. Radiation therapy was previously considered the first-line treatment for localized mediastinal seminoma, with survival rates ranging from 66 to 100% [11]. The residual tumor after chemotherapy requires observation, as in most cases it consists of necrotic masses.

3.3. Treatment of mesenchymal mediastinal tumors

Comments: lipomas are benign tumors originating from mature adipose tissue. Their frequency is 5–8% of all mediastinal neoplasms. Lipomas have a variable, most commonly nodular shape, with a well-defined fibrous capsule; on cross-section, they are composed of adipose tissue [2]. The surgical approach is chosen taking into account the location of the neoplasm. An anterolateral or lateral thoracotomy through the 4th–5th intercostal space is most frequently used. As a rule, there are no technical difficulties: the tumor (or its multiple nodes) is excised within its capsule without resection of neighboring organs. Cervicomediastinal lipomas can be removed via a cervical approach. If comprehensive examination data confirm that the tumor is benign, of small size, and asymptomatic—particularly in elderly patients—observation is an option.

Comments: liposarcoma is significantly less common than benign adipose tumors. It affects men and women with equal frequency at any age, can be primary multiple in the mediastinum, or be combined with tumor nodes of other localizations. It is most often located in the anterior mediastinum and can reach giant sizes. The tumor presents with numerous variants that differ in histological structure and clinical course. Surgery is the mainstay of treatment for liposarcomas, but it is often palliative, especially for large and massive tumors (reaching 4–6 kg) due to infiltration of mediastinal tissues and involvement of vital organs. Subsequent recurrence (or continued growth) necessitates repeat surgeries (two, three, or more times). This is especially true for well-differentiated liposarcomas and can significantly prolong patients' lives. Poorly differentiated tumors have a greater tendency to invasion and metastasis; radiation therapy is advisable in the postoperative period.

Comments: fibroma is a benign tumor originating from mature connective tissue. In the mediastinum, it develops from fasciae, fibrous pleural tissue, etc. They are localized in any compartments. These are dense tumors reaching large sizes, which determines their clinical manifestations. Malignant transformation is possible in a quarter of patients. It may be accompanied by invasive growth without histological signs of malignancy. The prognosis is favorable [37].

Comments: fibrosarcoma is a malignant tumor originating from immature connective tissue, accounting for up to 4% of all malignant mediastinal neoplasms. As a rule, it is located in the posterior mediastinum paravertebrally and can reach large sizes. It is characterized by infiltrative growth, which complicates radical surgery. Following radical surgery, long-term remissions (up to 4–5 years) are possible.

Comments: benign mesenchymoma occurs at any age. It consists of various mature mesenchymal tissues (adipose, cartilaginous, bone, vascular, muscular). Depending on the predominance of tissues, they differ in consistency, color, and microscopic picture (angiofibromas, angiomyxomas, angiolipomas, rhabdomyolipomas, etc.). When small, it runs a benign course, but as it increases significantly in size, it can infiltrate surrounding organs.

Comments: malignant mesenchymoma consists of two or more sarcomatous tissues. These are nodular, dense formations without a capsule. The tumor can be localized in both the posterior and anterior mediastinum and can reach enormous sizes. It occurs at any age and is characterized by rapid infiltrative growth and metastasis, which determines the clinical picture and prognosis.

Comments: vascular tumors account for 1.5–2% of all mediastinal neoplasms, one-third of which are malignant. Their development is associated with mesenchymal elements—pericytes, which give rise to numerous variants of vascular tumors. They are most often located in the anterior-superior mediastinum, can reach large sizes, and occur in middle-aged individuals. The possibility of massive blood loss during surgery must be kept in mind.

Comments: lymphangiomas (arising from lymphatic vessels) are usually cystic and may originate from the mediastinal mesenchyme or from a detached primitive lymphatic sac, the precursor of the lymphatic system. They present as single-chambered or multi-chambered thin-walled cysts, most often solitary. Clinical manifestations are scant; they are mainly detected during routine check-ups in children or in the presence of a bulge in the jugular notch.

Comments: tumors of arteriovenous anastomoses are rare mediastinal tumors that develop without the participation of the capillary bed; these include glomus tumors and angioleiomyomas.

Comments glomus tumors develop from glomus arteriovenous anastomoses, which are most commonly located in the skin. Three varieties are distinguished: angiomatous, solid, and mixed. The first variant is the most common. They are rare in the mediastinum in both men and women. They are localized in the posterior mediastinum and reach significant sizes. In diagnosis, a long medical history and the presence of nodes in other locations should be taken into account; a fairly strong pain syndrome is characteristic. Surgical treatment does not present technical difficulties due to a well-developed fibrous capsule.

Comments: angioleiomyomas are tumors originating from the smooth muscles of sphincter arteries. They are located in the posterior mediastinum as small, dense nodes. Men and women aged 35–50 are affected with equal frequency. A pain syndrome is characteristic. During pathomorphological examination, differential diagnosis with schwannomas is difficult.

Comments: hemangiopericytomas consist of blood vessels and Zimmermann pericytes. They are rare in the mediastinum. In most cases, they are well-demarcated, rounded, and smooth. However, when large, they acquire an irregular shape and can occupy an entire hemithorax. They are most often localized in the anterior mediastinum. Both men and women of any age are affected. Diagnosis is simplified in the presence of external tumors (pericytomas). As they grow, they tend to undergo malignant transformation. Malignant hemangiopericytoma is extremely rare in the mediastinum; these include transitional variants between mature hemangiopericytoma and angiosarcoma, with significant variability in cellular atypia [42]. Treatment is surgical, which presents no difficulties for benign variants of small size.

Comments: angiosarcomas developing from blood vessels are immature, with marked structural atypia. They can be localized in both the posterior and anterior mediastinum and reach large sizes; men and women are affected with equal frequency, mainly at the age of 30–50 years. They rapidly infiltrate surrounding tissues and metastasize extensively. The clinical picture is severe, which is associated with damage to vital organs. Treatment is mainly surgical, but most often palliative. Even with radical resection of relatively small neoplasms, the likelihood of recurrence and metastasis is high. Following any type of surgical treatment, adjunctive radiation therapy and modern chemotherapy are justified. The prognosis is unfavorable.

Comments: muscle tissue tumors are very rare in the mediastinum and are represented by neoplasms originating from: smooth muscles of arteries, veins, and other mediastinal tissues—leiomyomas (leiomyosarcomas). These tumors originating from the esophagus cannot be classified as true mediastinal tumors. They are most often located in the posteroinferior mediastinum, manifesting with dysphagia, chest pain, and possible autonomic disorders in case of paravertebral location and involvement of the sympathetic trunk. Treatment is surgical.

Comments: striated muscle tissue tumors are rhabdomyomas (rhabdomyosarcomas). They occur in the anterior mediastinum as derivatives of teratomas. Neoplasms originating from the heart or muscular walls of the mediastinal space are not true mediastinal tumors. They are more frequently observed in men.

3.4. Treatment of neurogenic mediastinal tumors

Comments: benign neurogenic tumors predominate in adults, while malignant ones are more common in children and adolescents. These neoplasms have a rounded shape and a dense consistency, sometimes with areas of softening or cyst formation due to necrosis. They are usually surrounded by a connective tissue capsule and have a "stalk" directed toward the spine. Tumors of the sympathetic ganglia may have 2–3 "stalks". A specific feature of neurogenic neoplasms of the posterior mediastinum is that they frequently extend into the spinal canal, assume a dumbbell shape, and can compress the spinal cord. Extension to adjacent mediastinal regions—the neck or abdominal cavity—is also possible. Due to slow growth, these lesions can reach giant proportions without causing clinical manifestations.

Comments: neurosarcoma is a malignant variant of nerve sheath tumor, frequently a malignant schwannoma or malignant neurofibroma. It accounts for 2–3% of all tumors of this origin. The histological picture is variable due to cells of varying degrees of maturity. Four grades of maturity are distinguished in neurogenic sarcomas: the first borders on benign neurofibroma, while the latter borders on giant-cell sarcoma. Clinical manifestations and prognosis depend on the degree of maturity.

Comments: neuroblastoma is a sympathogonioma or sympathetic neuroblastoma. It is formed by sympathogoniocytes and resembles the structure of a sympathetic ganglion at the embryonic stage of development. It is frequently localized in the posterior superior mediastinum on the right. It is a highly malignant tumor, usually occurring in infants and children, and extremely rarely in adults. It is characterized by rapid infiltrative growth, lymphatic and hematogenous metastasis. In isolated cases, it may mature into a benign tumor, which is accompanied by calcification of both the primary lesion and metastases. The prognosis is unfavorable.

Comments: ganglioneuroblastoma is a malignant variant of ganglioneuroma. It occurs mainly in children and is characterized by rapid growth and occasional metastasis.

Comments: mediastinal non-chromaffin paragangliomas: chemodectoma is a mature tumor. Immature form is a malignant variant of non-chromaffin paraganglioma. Tumors of chromaffin tissue: mature pheochromocytoma. Immature form is malignant pheochromocytoma. The tumor originates from chemoreceptor cells located along blood vessels. Embryogenetically, it belongs to the parasympathetic division of the nervous system. Isolated localization in the mediastinum is extremely rare. Based on the histological picture, it is often difficult to judge the degree of malignancy, but up to half of patients exhibit invasive growth. It metastasizes mainly to regional lymph nodes. They are frequently multicentric, and clinical manifestations, aside from local spread, are related to catecholamine secretion: hyperglycemia, tachycardia, headache. Episodes of paroxysmal hypertension are very common. Multiple endocrine neoplasia syndromes also occur, and associations with gastric leiomyosarcoma and pulmonary chondroma have been described. It should be taken into account that surgeries for paraganglioma can be accompanied by massive blood loss. In pheochromocytoma, furthermore, preoperative alpha-adrenergic blockade must be used for 10–14 days until blood pressure normalizes. Surgery may be performed after 2 days to avoid delayed hypotension. The prognosis depends on the degree of tumor maturity: it is favorable for benign variants.

3.5 Other treatments

3.5.1 Symptomatic therapy

Comments: the goal of so-called best supportive care is the prevention and relief of disease symptoms, as well as the maintenance of the quality of life for patients and their loved ones, regardless of the disease stage and the need for other types of therapy. In the case of mediastinal tumors, measures aimed at alleviating primary symptoms help increase life expectancy.

3.5.2 Pain management

Principles of pain management and optimal selection of analgesic therapy in patients with a mediastinal tumor with chronic pain syndrome (see Appendix G4, G5) correspond to the pain management principles outlined in the guidelines "Practical Guidelines for the Treatment of Chronic Pain Syndrome in Cancer Patients" (Authors: Kogonia L.M., Voloshin A.G., Novikov G.A., Sidorov A.V., DOI:10.18027/2224-5057-2018-8-3s2-617-635, https://rosoncoweb.ru/standarts/ Russian Society of Clinical Oncology RUSSCO/2018/2018-47.pdf).

3.5.3 Supportive care in patients with mediastinal tumors

The principles of treatment and prevention of nausea and vomiting in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Prevention and Treatment of Nausea and Vomiting" (Authors: Vladimirova L.Yu., Gladkov O.A., Kogonia L.M., Koroleva I.A., Semiglazova T.Yu. DOI: 10.18027/2224-5057-2018-8-3s2-502-511, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-35.pdf).

The principles of treatment and prevention of bone complications in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Use of Osteomodifying Agents for the Prevention and Treatment of Bone Pathology in Malignant Neoplasms" (Authors: Manzyuk L.V., Bagrova S.G., Kopp M.V., Kutukova S.I., Semiglazova T.Yu. DOI: 10.18027/2224-5057-2018-8-3s2-512-520, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-36.pdf).

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Treatment of Infectious Complications of Febrile Neutropenia and Administration of Colony-Stimulating Factors" (Authors: Sakaeva D.D., Orlova R.V., Shabaeva M.M. DOI: 10.18027/2224-5057-2018-8-3s2-521-530, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-37.pdf).

The principles of prevention and treatment of hepatotoxicity in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Management of Hepatotoxicity" (Authors: Tkachenko P.E., Ivashkin V.T., Maevskaya M.V. DOI: 10.18027/2224-5057-2018-8-3s2-531-544, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-38.pdf).

The principles of prevention and treatment of cardiovascular complications in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Practical Guidelines for the Management of Cardiovascular Toxicity of Antineoplastic Drug Therapy" (Authors: Vitsenya M.V., Ageev F.T., Gilyarov M.Yu., Ovchinnikov A.G., Orlova R.V., Poltavskaya M.G., Sycheva E.A. DOI: 10.18027/2224-5057-2018-8-3s2-545-563, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-39.pdf).

The principles of prevention and treatment of skin complications in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Practical Guidelines for the Drug Treatment of Dermatological Reactions in Patients Receiving Antineoplastic Drug Therapy" (Authors: Koroleva I.A., Bolotina L.V., Gladkov O.A., Gorbunova V.A., Kruglova L.S., Manzyuk L.V., Orlova R.V. DOI: 10.18027/2224-5057-2018-8-3s2-564-574, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-40.pdf).

The principles of nutritional support in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Practical Guidelines for Nutritional Support in Cancer Patients" (Authors: Sytov A.V., Leiderman I.N., Lomidze S.V., Nekhaev I.V., Khoteev A.Zh. DOI: 10.18027/2224-5057-2018-8-3s2-575-583, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-41.pdf).

The principles of prevention and management of nephrotoxicity in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Practical Guidelines for the Correction of Nephrotoxicity of Antineoplastic Drugs" (authors: Gromova E.G., Biryukova L.S., Dzhumabaeva B.T., Kurmukov I.A. DOI: 10.18027/2224-5057-2018-8-3s2-591-603, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-44.pdf).

The principles of prevention and management of thromboembolic events in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Practical Guidelines for the Prevention and Treatment of Thromboembolic Complications in Cancer Patients" (authors: Somonova O.V., Antukh E.A., Elizarova A.L., Matveeva I.I., Selchuk V.Yu., Cherkasov V.A., DOI: 10.18027/2224-5057-2018-8-3s2-604-609, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-45.pdf).

The principles of prevention and management of drug extravasation sequelae in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Guidelines for the Treatment of Sequelae of Antineoplastic Drug Extravasation" (author: Buydenok Yu.V. DOI: 10.18027/2224-5057-2018-8-3s2-610-616, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-46.pdf).

The principles of prevention and management of immune-mediated adverse events in patients with mediastinal tumors correspond to the principles outlined in the guidelines "Practical Guidelines for the Management of Immune-Mediated Adverse Events" (authors: Protsenko S.A., Antimonik N.Yu., Berstein L.M., Novik A.V., Nosov D.A., Petenko N.N., Semenova A.I., Chubenko V.A., Yudin D.I., DOI: 10.18027/2224-5057-2018-8-3s2-636-665, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-48.pdf).

3.5.4 Medical nutrition therapy

To date, no reliable evidence has been obtained regarding the effect of dietary habits on the risk of developing mediastinal tumors or the risk of recurrence or progression of this disease in individuals with an established diagnosis. Therefore, no changes to the patients' usual diet are required unless dictated by the need to correct comorbid conditions or to relieve or prevent complications of ongoing treatment (surgical, drug therapy, or radiation therapy).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, for most types of medical rehabilitation, there are no clinical trials involving patients with mediastinal tumors. These recommendations are based on the fact that numerous studies, including meta-analyses (Steffens D. et al., 2018, etc.) and systematic reviews (Nicole L. Stout et al., 2017, and Segal R. et al., 2017, etc.), have proven that various types of medical rehabilitation significantly accelerate functional recovery, shorten hospital stays after surgery, and reduce the incidence of complications and mortality in patients with other malignant neoplasms.

4.1. Pre-rehabilitation

4.2. Rehabilitation after surgical treatment

4.2.1. First stage of rehabilitation

4.2.2. Second stage of rehabilitation

4.2.3. Third stage of rehabilitation

4.3. Rehabilitation after chemotherapy

4.4. Rehabilitation after radiation therapy

4.5. Principles of Psychological Rehabilitation of Patients with Malignant Neoplasms of the Mediastinum

Comments: scientific research in psycho-oncology most frequently identifies 3 coping styles among patients with mediastinal tumor:

1) active behavioral overcoming of emotional, physical, and social difficulties associated with the disease and treatment;

2) active cognitive overcoming, including attitudes, beliefs, and reflections about the disease;

3) avoidance coping, involving attempts to actively avoid problems or indirectly reduce emotional tension through distraction.

Overall, studies show that patients who use active (problem-oriented) coping strategies demonstrate better adaptation to illnesses than those who use passive or avoidant survival styles [68].

Patients who used active behavioral coping methods reported higher levels of self-esteem and energy, fewer physical symptoms, and reduced irritability and asthenization [68].

5. Prevention and Dispensary Observation

Primary prevention of the disease is not available.

• In order to enable early detection of disease progression for the prompt initiation of radiation/chemotherapy or surgical treatment of resectable metastatic lesions and recurrent tumors, all patients following the completion of treatment for tracheal cancer are recommended to undergo follow-up examinations every 3–6 months during the first 1–2 years, and every 6–12 months between years 3 and 5, in the following scope:

1. History taking and physical examination.

2. AFP, hCG, LDH (if initially elevated) every 3 months for the first 2 years, and subsequently every 6 months for the next 3 years.

3. Tracheobronchoscopy is initially performed at 1 and 3 years after primary tumor resection, and every 5 years thereafter [69].

4. Ultrasound of the abdominal organs, neck, and peripheral lymph nodes every 3–6 months, depending on the risk of progression.

5. Chest CT with IV contrast is performed 3 months after primary tumor resection, then every 3 months for 1 year, then every 6 months during the 2nd year of follow-up, and subsequently once a year or upon the onset of symptoms [8].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: after 5 years from the date of surgery, visits are conducted annually or upon the appearance of symptoms. In patients with a high risk of recurrence, the interval between examinations may be shortened [8].

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation," is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized Federal Executive Authority;

2) in accordance with the procedure for the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized Federal Executive Authority.

Primary specialized health care is provided by an oncologist and other specialist physicians at an outpatient oncological care center or in a primary oncological office, or in the outpatient department of an oncological dispensary (oncological hospital).

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.

Consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or the outpatient department of the oncological dispensary (oncological hospital)) shall arrange for the acquisition of biopsy (surgical) material, as well as other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

In the event of the impossibility of acquiring biopsy (surgical) material or performing other diagnostic tests within the medical organization that incorporates the outpatient oncological care center (primary oncological office), the attending physician shall refer the patient to an oncological dispensary (oncological hospital) or to a medical organization providing medical care to patients with oncological diseases.

The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).

The timeframes for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.

The diagnosis of an oncological disease is established by an oncologist, and in the case of malignant neoplasms of lymphoid, hematopoietic, and related tissues included in ICD-10 categories C81–C96, also by a hematologist.

An oncologist from an outpatient oncological care center (primary oncology office) refers the patient to an oncological dispensary (oncology hospital) or another medical organization providing medical care to cancer patients, including one subordinate to a federal executive body (hereinafter referred to as a federal medical organization), to clarify the diagnosis (if establishing the diagnosis is impossible, including the extent of the oncological process and disease stage), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

For oncological diseases included in ICD-10 categories C37, C38, C40–C41, C45–C49, C58, D39, C62, C69–C70, C72, C74, as well as those corresponding to the codes of the International Classification of Diseases for Oncology (ICD-O), 3rd Edition 8936, 906-909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, an oncologist at an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall organize a consultation or a medical board (consilium), including via telemedicine technologies, at federal state budgetary institutions subordinate to the Russian Ministry of Health that provide medical care (hereinafter referred to as national medical research centers for the purposes of this Procedure), in order to determine the treatment tactics.

In complex clinical cases, to clarify the diagnosis (in the event of the impossibility of establishing the diagnosis, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist shall arrange for the referral of:

digital images obtained from pathomorphological studies to the pathoanatomical bureau (department) of the fourth group (reference center) [1] via information interaction, including the use of telemedicine technologies during remote interaction between medical workers;

of digital images obtained from diagnostic imaging methods to the remote diagnostic imaging consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;

biopsy (surgical) material for re-examination of pathomorphological, immunohistochemical, and molecular genetic studies: to the department of pathological anatomy of the fourth group (reference center), as well as to molecular genetic laboratories for molecular genetic testing.

Treatment tactics are established by a medical board (consilium) comprising oncologists, a radiation therapist, and a neurosurgeon (in cases of nervous system tumors) of the medical organization that includes departments of surgical methods for treating malignant neoplasms, antineoplastic drug therapy, and radiotherapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians when necessary.

Dispensary follow-up by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for dispensary observation of adults with oncological diseases.

For record-keeping purposes, information about a newly diagnosed case of an oncological disease shall be sent within 3 working days by the oncologist of the medical organization where the respective diagnosis was established to the oncological dispensary or the organization of the subject of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population for oncological diseases is provided based on medical indications stipulated by the regulations on organizing the provision of specialized, including high-tech, medical care.

Specialized medical care, excluding high-tech care, in medical organizations subordinate to federal executive authorities is provided based on medical indications stipulated by paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, as provided in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care.

Waiting times for the provision of specialized (excluding high-tech) medical care shall not exceed the timeframes established in the program of state guarantees of free medical care to citizens, approved by the Government of the Russian Federation.

If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.

If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.

Palliative medical care for a patient with oncological diseases is provided in accordance with the regulations on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations and other non-profit organizations operating in the field of health protection.

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

Indications for hospitalization in a medical organization in an emergency or urgent form are:

1) the presence of complications of the oncological disease requiring the provision of specialized medical care in an emergency and urgent form;

2) presence of complications of treatment (surgical intervention, RT, drug therapy, etc.) of the oncological disease.

Indications for hospitalization in a medical organization in a planned form are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-hospital setting;

2) the presence of indications for specialized antitumor treatment (surgical intervention, RT, including contact, EBRD and other types of RT, drug therapy, etc.) requiring monitoring in an inpatient or day hospital setting.

Indications for discharging a patient from a medical organization are:

1) completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in an inpatient or day hospital setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day hospital setting established by the multidisciplinary team of the medical organization providing cancer care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) in cases of non-compliance by the patient with prescriptions or the internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;

4) the need to transfer the patient to another medical organization according to the relevant medical specialty profile.

The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Pikin Oleg Valentinovich (Working Group Chair), MD, PhD, Head of the Thoracic Surgery Department, Thoracoabdominal Oncology Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of RASS, ESTS, IASLC.

2. Barmin Vitaliy Valerievich, MD, PhD, Thoracic Surgeon, Researcher at the Thoracic Surgery Department, Thoracoabdominal Oncology Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of RASS, ESTS, IASLC.

3. Barbolina Tatyana Dmitrievna, MD, PhD, Oncologist, Researcher at the Oncology Department of Drug Treatment (Chemotherapy) No. 3, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, and Assistant at the Department of Oncology, N.D. Yushchuk Research and Educational Institute of Continuing Professional Education, Russian University of Medicine of the Russian Ministry of Health, member of RASS, RUSSCO, iMig.

4. Vazhenin Andrey Vladimirovich, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Chief Physician, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine, member of RASS.

5. Gorbunova Vera Andreevna, MD, PhD, Professor, Leading Researcher at the Oncology Department of Drug Treatment (Chemotherapy) No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, member of RASS, RUSSCO, ASCO, and ESMO.

6. Grinevich Vyacheslav Nikolaevich, MD, PhD, Head of the Pathomorphology Department, Outpatient Care Center, P.A. Herzen Moscow Oncology Research Institute.

7. Drapkina Oksana Mikhailovna, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Director, National Medical Research Center for Therapy and Preventive Medicine of the Russian Ministry of Health.

8. Kononets Pavel Vyacheslavovich, MD, PhD, Deputy Director for Scientific and Clinical Work, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Director, N.N. Trapeznikov Institute of Clinical Oncology.

9. Levchenko Evgeniy Vladimirovich, MD, PhD, Head of the Surgical Thoracic Department, Head of the Scientific Department of Thoracic Oncology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

10. Meshcheryakova Irina Arnoldovna, PhD in Medicine, Radiologist, Senior Researcher at the Department of Radiotherapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

11. Novikov Sergey Nikolayevich, MD, PhD, Professor, Head of the Department of Radiotherapy, N.N. Petrov National Medical Research Centre of Oncology of the Russian Ministry of Health, member of ESTRO, EANM, EAFO.

12. Snegovoy Anton Vladimirovich, MD, PhD, Professor, Head of the Department of Antitumor Drug Therapy, N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health, MD, PhD.

13. Tryakin Aleksey Alexandrovich, MD, PhD, Deputy Director for Research, Head of the Department of Antitumor Drug Therapy No. 2, Department of Drug Therapy, N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health, Board Member of the Russian Society of Clinical Oncology (RUSSCO), member of AOR.

14. Tuzikov Sergey Alexandrovich, MD, PhD, Professor, Head of the Thoracoabdominal Department, Oncology Clinic of the Tomsk National Research Medical Centre.

15. Turkin Igor Nikolayevich, MD, PhD, Head of the Thoracic Surgery Department, Rostov Research Institute of Oncology of the Russian Ministry of Health.

16. Chernichenko Andrey Vadimovich, MD, PhD, Head of the Department of Radiotherapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

17. Chkhikvadze Vladimir Davidovich, MD, PhD, Professor, Head of the Department of Surgery and Surgical Technologies in Oncology, Head of the Surgical Clinic, Russian Scientific Center of Roentgenoradiology of the Russian Ministry of Health.

Medical Rehabilitation and Supportive Care Section:

1. Butenko Alexey Vladimirovich, MD, PhD, Prof., Chief Physician of National Clinical Research Centre No. 2, Petrovsky National Research Centre of Surgery, Chairman of the Scientific Board of the «Association of Specialists in Oncological Rehabilitation».

2. Olga A. Okhokhova, Cand. of Sci. (Med.), Senior Research Fellow, Head of the Medical Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, member of the All-Russian Public Organization "Russian Society of Head and Neck Tumor Specialists", member of the European Society for Clinical Nutrition and Metabolism (ESPEN), member of the Russian Society for Parenteral and Enteral Nutrition (RESPEN).

Healthcare Organization Section:

1. Tigran G. Gevorkyan, Deputy Director of the Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology, Chief Oncologist of the Moscow Region.

2. Sergey A. Ivanov, Dr. of Sci. (Med.), Professor of the RAS, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Nevolskikh Alexey Alekseevich, MD, PhD, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Zhanna V. Khaylova, Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

Conflict of interest: none declared by all members of the working group.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Oncologists.

2. Surgeons.

3. Radiologists.

4. Radiation oncologists.

5. Pathologists.

6. Otolaryngologists.

7. Physical and rehabilitation medicine physicians.

8. Clinical pharmacologists.

9. General practitioners.

10. Medical students, residents, and postgraduate students.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Methods used for evidence collection/selection:

• searching electronic databases;

• analysis of current scientific developments on tracheal cancer in the Russian Federation and abroad;

• summarizing the practical experience of Russian and foreign specialists.

To assess the grades of recommendation (GR) and levels of evidence (LE) for each recommendation thesis, a separate systematic review of the efficacy and/or safety of the medical intervention was performed, including the following stages:

1. Definition of search and selection criteria for publications on clinical trials (CT) regarding the efficacy and/or safety of the medical intervention described in the recommendation statement.

2. Systematic search and selection of clinical trial publications in accordance with predefined criteria.

3. Determination of LTE and GOR based on the results of the systematic search and selection of clinical trial publications.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• evaluation of LE and GR is carried out based on the standardized scales presented in Tables P1–3.

Table P1. Level of evidence rating scale for diagnostic methods (diagnostic interventions)

Table P2. Level of evidence rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table P3. Grade of recommendation rating scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Good Practice Points. Good practice recommendations are based on the qualifications and clinical experience of the authoring group.

Methods used for formulating recommendations: expert consensus.

Economic analysis. Cost analysis was not performed, and pharmacoeconomic publications were not reviewed.

Methods of recommendation validation:

• external expert review;

• internal expert review.

Description of the recommendation validation method. The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

Comments were received from primary care pediatric oncologists regarding the clarity of the guidelines and their perceived importance as a working tool in daily practice.

Comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultations and expert review: the draft guidelines were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the guidelines.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Procedure for updating clinical guidelines. The mechanism for updating clinical guidelines provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to the previously approved clinical guidelines, but no more frequently than once every 6 months.

The decision to update is made by the Russian Ministry of Health based on proposals submitted by medical non-profit professional organizations. The formulated proposals must take into account the results of comprehensive assessments of medicinal products and medical devices, as well as the results of clinical testing.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care" (Registered with the Russian Ministry of Justice on May 17, 2017, No. 46740)

2. Order of the Ministry of Health of the Russian Federation No. 116n dated February 19, 2021, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncological Diseases." (Registered with the Ministry of Justice of the Russian Federation on April 1, 2021. Registration No. 62964)

3. Federal Law No. 323-FZ of November 21, 2011, "The Fundamentals of Healthcare Protection of Citizens in the Russian Federation"

Current package inserts for medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru.

Appendix B. Physician Action Algorithms

Algorithm for the diagnosis and treatment of early-stage thymic tumors.

Algorithm for postoperative treatment of thymic tumors.

Algorithm for morphological verification of mediastinal tumors

Algorithm for postoperative treatment of resectable stage I-IIIa thymic tumors.

Algorithm for the treatment of unresectable/potentially resectable stage III-IVa thymic tumors, recurrence, and post-progression disease.

Appendix C. Patient Information

Guidelines for post-treatment follow-up

Follow-up after completed treatment is of great importance for maintaining the patient's health. Usually, in the first 1–2 years, follow-up visits with an oncologist are recommended every 1–3 months; in the 2nd year – every 2–6 months; and at 3–5 years – once every 4–8 months. After 5 years from the surgery, visits are conducted annually or upon the appearance of complaints. Nevertheless, the frequency of physician visits may be increased depending on disease characteristics and associated risks and is discussed individually in each specific case. If complaints appear or if symptoms observed before treatment recur, it is necessary to consult a physician immediately without waiting for the scheduled visit date.

The purpose of these visits is to monitor not only the oncological disease but also side effects, including delayed ones (e.g., hypothyroidism after radiation therapy to the neck area, deterioration of nutritional status, assessment of speech and swallowing functions, etc.).

Recommendations regarding lifestyle and nutrition should be individualized taking into account the extent of treatment received, the risks and severity of complications, and the patient's characteristics.

Patients should be informed, depending on indications, about clinical trials conducted in the Russian Federation for patients with the specified disease stage.

Benefits of quitting smoking and alcohol consumption:

1. Higher survival rates.

2. Greater treatment efficacy.

3. Fewer and less severe side effects of antineoplastic treatment (cardiopulmonary complications, fatigue, weight loss, mucositis, loss of taste).

4. Faster recovery of general condition after treatment.

5. Lower risk of recurrence.

6. Lower risk of developing second primary tumors.

7. Lower risk of infections.

8. Higher quality of life.

Recommendations for complications of chemotherapy/chemoradiotherapy/radiotherapy – contact an oncologist (chemotherapy specialist), radiation oncologist!

1) If body temperature rises to 38 °C or higher:

• contact an oncologist (chemotherapy specialist).

2) In case of stomatitis:

• diet with mechanical and thermal sparing of the mucosa;

• frequent mouth rinsing (every hour) – chamomile, oak bark, sage, lubricate the mouth with sea buckthorn (peach) oil;

• treat the oral cavity as prescribed by the oncologist (chemotherapy specialist).

3) For diarrhea:

• diet – exclude fatty, spicy, smoked, sweet, dairy products, and fiber.

  Lean meat, flour products, fermented dairy products, and rice water are permitted. Drink plenty of fluids;

• take medications as prescribed by a clinical oncologist (chemotherapy specialist).

4) For nausea:

• take medications as prescribed by a clinical oncologist (chemotherapy specialist).

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian name: World Health Organization (WHO) / Eastern Cooperative Oncology Group (ECOG) Performance Status Scale.

Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS).

Source (official developer website, validation publication): https://ecogacrin.org/resources/ecog-performance-status;

Oken M.M., Creech R.H., Tormey D.C. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649–55 [70].

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.).

Content (template):

Key (interpretation): Provided within the scale itself.

Appendix G2. Karnofsky Performance Scale

Name in Russian: Karnofsky Scale.

Original name (if any): Karnofsky Performance Status.

Source (official developer website, validation publication):

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 [71].

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.).

Content (template):

Key (interpretation): Provided within the scale itself.

Notes: none.

Appendix G3. Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Russian name: Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Original name (if any): Response evaluation criteria in solid tumors 1.1.

Source (official developer website, validation publication):

Original publication: Eisenhauer E.A., Therasse P., Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–47 [72].

Type: rating scale.

Purpose: assessment of response to chemotherapy.

The content, key, and template in Russian are presented in Methodological Recommendations No. 46 of the Scientific and Practical Center for Medical Radiology of the Moscow Healthcare Department and are available on the website http://medradiology.moscow/d/1364488/d/no46_2018_recist_11.pdf.

Appendix G4. Visual Analog Scale for Pain

Name in Russian: Visual Analog Scale for Pain Assessment.

Original name: Visual Analog Scale for Pain (VAS Pain).

Source (official developer website, validation publication):

Original publication: Hawker G.A., Mian S., Kendzerska T., French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S240–52 [73].

Type: rating scale.

Purpose: designed for the quantitative assessment of pain syndrome taking into account the patient's subjective sensations and the selection of analgesic therapy.

Content (template):

“Rate the severity of pain on a scale, where 0 is no pain and 10 is excruciating pain of maximum severity.”

Instructions: the patient is asked to mark the severity of pain on a 10-centimeter line using a scale from 0 to 10.

Key: 1–3 points – mild pain; 4–7 points – moderate pain; 8 points or more – severe pain.

Appendix G5. Verbal Rating Scale for Pain

Russian name: verbal rating scale for pain.

Original name: Verbal Rating/Descriptor Scale.

Source (official developer website, validation publication):

Original publication: Ohnhaus E.E., Adler R. Methodological problems in the measurement of pain: a comparison between the verbal rating scale and the visual analogue scale. // Pain. 1975. Vol. 1, № 4. P. 379–384. [74]

Type: rating scale.

Purpose: designed for the quantitative assessment of pain syndrome taking into account the patient's subjective sensations and the selection of analgesic therapy.

Content (template):

"Rate the severity of pain on a scale from 0 to 10, where 0 is no pain and 10 is the worst imaginable severe pain."

Instructions: the patient answers the question of how they rate the severity of pain on a scale from 0 to 10.

Key: 1–3 points – mild pain; 4–7 points – moderate pain; 8 points or more – severe pain.