List of Abbreviations
HI – histological examination
RT – radiotherapy
MRI – magnetic resonance imaging
LNs – lymph nodes
CT – computed tomography
RII – radioisotope imaging
SG – salivary glands
PSG – parotid salivary gland
MEC – mucoepidermoid carcinoma
TFD – total focal dose
FNA – fine-needle aspiration biopsy
FNAB – fine-needle aspiration biopsy
PET – positron emission tomography
PET/CT – positron emission tomography + computed tomography
US – ultrasound examination
CI – cytological examination
TNM – (stands for tumor, node, and metastasis) international classification of cancer stages
Terms and Definitions
Instrumental diagnostics – diagnostics utilizing various devices, apparatus, and instruments for patient examination.
Laboratory diagnostics – a set of methods aimed at analyzing test material using various specialized equipment.
Medical intervention – a set of medical examinations and/or medical procedures performed by a medical worker or other employee authorized to carry out medical activities in relation to a patient, affecting their physical or mental state, and having a preventive, diagnostic, therapeutic, rehabilitative, or research orientation, as well as artificial termination of pregnancy.
Medical worker – an individual who has a medical or other education, works in a medical organization, and whose job (official) duties include the implementation of medical activities, or an individual who is an individual entrepreneur directly engaged in medical activities.
Working group – two or more people of the same or different professions working together and in coordination to create clinical guidelines and bearing joint responsibility for the results of this work.
Syndrome – a set of symptoms sharing a common etiology and pathogenesis.
Surgical intervention – an invasive procedure that can be used for diagnostic purposes and/or as a method of disease treatment.
Surgical treatment – a method of treating diseases through the division and joining of tissues during a surgical operation.
Survival analysis (from English survival analysis) is a class of statistical models used to estimate the probability of an event occurring.
Recurrence-free survival (RFS) – from the moment of achieving remission to the moment of recurrence.
Event-free survival (EFS) – from the start of treatment to the cessation of remission regardless of the cause leading to it, as well as parental refusal of treatment.
Overall survival (OS) – from the start of treatment to its end or the patient's death.
Major salivary glands: parotid salivary gland, submandibular salivary gland, sublingual salivary gland
Minor salivary glands: salivary glands of the oral cavity and oropharynx
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Salivary gland cancer (carcinoma) is a malignant epithelial tumor of the salivary gland.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Insufficiently studied. Possible predisposing factors for the development of malignant epithelial tumors include exposure to ionizing radiation, prior radiation therapy, and chronic viral infection [1,2]. Data on etiological factors for benign growths are currently lacking.
1.3 Epidemiology of the Disease or Condition
Salivary gland lesions in children and adolescents are a rare pathology and a relevant issue in maxillofacial surgery and oncology. Up to 75–80% of salivary gland lesions are benign in nature [3]. The most common benign lesion in children and adolescents is pleomorphic adenoma. Infantile hemangioma and lymphatic malformations should be highlighted separately; their clinical presentation resembles tumors, but these conditions are vascular malformations and are discussed in detail in the relevant clinical guidelines.
Pleomorphic adenoma is the most common benign salivary gland tumor in both adults and children. It is also called a "mixed tumor" due to the combination of two components: epithelial and myoepithelial. The average age of patients is 16 years, with girls being affected slightly more often in a ratio of 1.43:1. By localization, the parotid salivary gland is involved in 56% of cases, the submandibular salivary gland in 31%, and minor salivary glands in 3.3% [4].
Malignant salivary gland tumors are a rare pathology in children and adolescents, accounting for 1–8% of head and neck growths and ranking 4th after growths of the nasopharynx, skin, and thyroid gland [5,6]. The parotid salivary gland is most frequently affected (up to 72%), followed by the submandibular glands (8%), and minor glands (up to 20%) [7]. The average age is 14 years, with a slight female predominance in a ratio of 1.4:1 [5,7–9]. In terms of frequency, mucoepidermoid carcinoma (MEC) ranks first at up to 53%, followed by acinic cell carcinoma (29%) and adenoid cystic carcinoma (5%) [7].
1.4 Features of Coding the Disease or Condition
C07 - Malignant neoplasm of parotid gland
C08 - Malignant neoplasm of other and unspecified major salivary glands:
C08.0 - Malignant neoplasm of submandibular gland
C08.1 - Malignant neoplasm of sublingual gland
C08.8 - Lesion of major salivary glands overlapping one or more of the above sites
C08.9 - Malignant neoplasm of major salivary gland, unspecified
C06.9 - Malignant neoplasm of mouth, unspecified (Unspecified minor salivary gland localization)
D10.3 Benign neoplasm of other and unspecified parts of mouth
D11 Benign neoplasm of major salivary glands
1.5 Classification of the disease or condition
Table 1. WHO Classification of Salivary Gland Tumors (5th edition, 2022) [10].
Non-neoplastic epithelial lesions | Benign epithelial tumors | Epithelial malignant tumors | Mesenchymal tumors specific to salivary glands |
Nodular oncocytic hyperplasia Lymphoepithelial sialadenitis | Pleomorphic adenoma Basal cell adenoma Canalicular adenoma Warthin tumor. Oncocytoma Myoepithelioma Cystadenoma Sialadenoma Ductal papillomas Lymphadenoma. Sebaceous adenoma Intercalated duct adenoma Striated duct adenoma Sclerosing polycystic adenoma Keratocystoma | Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Secretory carcinoma Microsecretory adenocarcinoma Polymorphous adenocarcinoma Hyalinizing clear cell carcinoma Intraductal carcinoma Salivary duct carcinoma Myoepithelial carcinoma Epithelial-myoepithelial carcinoma Sclerosing microcystic adenocarcinoma Carcinoma ex pleomorphic adenoma Carcinosarcoma Sebaceous adenocarcinoma Lymphoepithelial carcinoma Squamous cell carcinoma Sialoblastoma Salivary gland carcinoma, NOS | Sialolipoma |
Comment: The 5th edition of the WHO classification excludes lesions located in the gland and adjacent tissues, such as hemangiomas, lymphatic malformations, lymphomas, and sarcomas. Currently, 4 groups of nosological entities are distinguished: non-neoplastic epithelial lesions of the salivary glands, benign and malignant epithelial tumors, and mesenchymal tumors specific to the salivary glands. New histological subtypes of malignant tumors have emerged: microsecretory, polymorphous, and sclerosing microcystic adenocarcinomas [10]. Based on a wealth of new data on the molecular and genetic characteristics of tumors, the new WHO international classification of salivary gland tumors accounts for typical gene rearrangements specific to a particular tumor type.
Table 2. Malignant epithelial tumors
Malignant epithelial tumors | |
Acinic cell carcinoma 8550/3 | NR4A3 rearrangement/activation 86% MSANTD3 rearrangement/amplification 4% |
Mucoepidermoid carcinoma 8430/3 | CRTC1-MAML2 rearrangement 40–90% CRTC3-MAML2 rearrangement 6% CDKN2A deletion 25% Mutations are included in the subtype definition |
Adenoid cystic carcinoma 8200/3 | MYB rearrangement/activation/amplification ~80%* MYBL1 rearrangement/activation/amplification ~10% NOTCH mutations 14% |
Polymorphous adenocarcinoma 8525/3 Classical subtype Cribriform subtype | PRKD1 mutations 73% PRKD1 rearrangements 38%* PRKD2 rearrangements 14%* PRKD3 rearrangements 19%* |
Epithelial-myoepithelial carcinoma 8562/3 | HRAS mutations 78% |
Hyalinizing clear cell carcinoma 8310/3 | EWSR1-ATF1 rearrangements 93%* EWSR1-CREM rearrangements <5% |
Basal cell adenocarcinoma 8147/3 | CYLD mutations 29% CTNNB1 rearrangement |
Sebaceous adenocarcinoma 8410/3 | MSH2 loss 10% |
Secretory carcinoma 8502/3 | ETV6-NTRK3 rearrangement >90%* ETV6-RET rearrangement 2–5% ETV6-MET rearrangement <1% ETV6-MAML3 rearrangement <1% VIM-RET rearrangement <1% |
Microsecretory adenocarcinoma | MEF2C-SS18 rearrangement >90%* |
Intraductal carcinoma Intercalated duct carcinoma Apocrine subtype | RET rearrangements 47% PIK3CA mutations HRAS mutations |
Salivary duct carcinoma 8500/3 | HER2 amplification 31% FGFR1 amplification 10% TP53 mutation 56% PIK3CA mutation 33% HRAS mutation 33% AR copy number gain 35% PTEN loss 38% CDKN2A loss 10% |
Adenocarcinoma, NOS 8140/3 | |
Myoepithelial carcinoma 8982/3 | PLAG1 rearrangements 38% EWSR1 rearrangements 13% |
Mucinous adenocarcinoma papillary, colloid, signet-ring, and mixed subtypes | AKT1 E17K mutations 100% * TP53 mutations 88% |
Sclerosing microcystic adenocarcinoma | CDK11B mutation (1 case) |
Carcinoma ex pleomorphic adenoma 8941/3 | PLAG1 rearrangements/amplification 73% HMGA2 rearrangements/amplification 14% TP53 mutations 60% |
Carcinosarcoma 8980/3 | |
Squamous cell carcinoma 8070/3 | |
Lymphoepithelial carcinoma 8082/3 | |
Sialoblastoma 8974/1 | |
Salivary gland carcinoma, NOS Undifferentiated carcinoma 8020/3 Oncocytic carcinoma 8290/3 | |
* - mutation is included in the subtype definition
Comment: The biological behavior of tumors within the same subtype is not uniform; they may present with various histological variants of low, intermediate, and high grade. Risk stratification groups have been developed for mucoepidermoid, acinic cell, and adenoid cystic carcinomas, among others [10].
Staging of malignant salivary gland tumors.
To assess the extent of malignant tumor involvement in the salivary glands, the TNM classification (8th edition, 2017) is used. The classification takes into account the size of the primary tumor, the presence/absence of facial nerve palsy, and tumor fixation. The classification was originally developed for parotid gland tumors, but is currently applied to tumors of all major salivary glands.
The T category includes the following grades:
TX – primary tumor cannot be assessed.
T0 – No evidence of primary tumor.
T1 – tumor 2 cm or less in greatest dimension without extraparenchymal extension
T2 – tumor more than 2 cm, but not more than 4 cm in greatest dimension without extraparenchymal extension
T3 – tumor more than 4 cm in greatest dimension and/or with extraparenchymal extension.
T4a – tumor invades skin, mandible, ear canal, and/or facial nerve.
T4b – tumor invades pterygoid plates, skull base, or internal carotid artery.
The N symbol indicates the presence or absence of regional lymph node metastases.
NX – regional lymph nodes cannot be assessed. N0 – no regional lymph node metastasis. N1 – metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2 – metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes not more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes not more than 6 cm in greatest dimension
N2a – metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension.
N2b – metastases in multiple ipsilateral LNs, up to 6 cm in greatest dimension.
N2c – bilateral or contralateral LN metastases, up to 6 cm in greatest dimension
N3 – LN metastases > 6 cm in greatest dimension
The M category describes the presence or absence of distant metastases.
M0 – no distant metastases.
M1 – presence of distant metastases.
Table 3. TNM stage grouping
Stage | T | N | M |
I | 1 | 0 | 0 |
II | 2 | 0 | 0 |
III | 3 | 0 | 0 |
1 | 1 | 0 | |
2 | 1 | 0 | |
3 | 1 | 0 | |
IVA | 4a | 0 | 0 |
4a | 1 | 0 | |
1 | 2 | 0 | |
2 | 2 | 0 | |
3 | 2 | 0 | |
4a | 2 | 0 | |
IVB | any T | 3 | 0 |
4b | any N | 0 | |
IVC | any T | any N | 1 |
1.6 Clinical presentation of the disease or condition
Benign salivary gland tumors are a group of slow-growing masses; it often takes about 5 years to establish a diagnosis, with an average size of 2.6 cm3. The main complaints are a palpable mass in the parotid-masseter region; facial nerve involvement and pain are less common. Trismus and formation of the lateral pharyngeal wall mass are characteristic of deep lobe parotid gland involvement [4].
The clinical course of SG cancer is determined by localization, extent, and morphological structure.
Epithelial malignant tumors are a group of slow-growing masses in the parotid-masseter region or oral cavity with an extremely low metastatic potential, which remain undiagnosed for a long time, on average about 8–12 months [13]. This is due to the anatomical structure of the region, mild clinical manifestations, and the rarity of pain. The main complaints of patients are non-specific: the presence of a palpable, painless, firm-elastic nodular mass in the projection of the affected gland, not fixed to the skin – 99%, soreness in the tumor area – 22%, and facial nerve paresis – 7% [5]. Facial muscle paresis is an extremely unfavorable prognostic sign indicating local spread of the process [4].
Neoplasms may be located superficially or in the deep compartments of SGs. Malignant tumors of the pharyngeal process of the parotid gland, despite their slow course, infiltrate the pharyngeal mucosa quite early.
The mean patient age is 14 years, with a slight female predominance of 1.4:1 [2,4,14,15]. MUC in children is represented in 87% of cases by low- and intermediate-grade malignancies. The grade of tumor malignancy plays a significant role in prognosis. The overall 5-year survival rate is 93%, and the disease-free survival rate is 82%, respectively. On average, recurrence is noted 1 year and 1 month after surgical treatment [5].
2. Diagnostics, medical indications and contraindications for diagnostic methods
To diagnose malignant epithelial salivary gland tumors in childhood, it is necessary to use the full range of diagnostic procedures:
1) taking medical history and analyzing patient complaints;
2) thorough clinical examination, palpation of the mass and adjacent tissues, and regional LNs;
3) ultrasound of the salivary glands, soft tissues of the face, and cervical lymph drainage basins;
4) contrast-enhanced CT if skull base or jaw bone involvement or tumor recurrence is suspected;
5) contrast-enhanced MRI to clarify the topography of the process in large tumors (T3-T4), disease recurrence, involvement of the parotid pharyngeal process, or suspicion of intracranial spread;
6) ultrasound-guided FNAB followed by cytological examination of the biopsy material (primary tumor, enlarged or suspicious LNs);
7) chest radiography or MSCT;
8) skeletal scintigraphy during initial staging;
9) pathomorphological examination of surgical material using immunohistochemical methods [5].
Diagnostic algorithm for benign tumors:
1) taking medical history and analyzing patient complaints;
2) thorough clinical examination, palpation of the mass and adjacent tissues, and regional LNs;
3) ultrasound of the salivary glands, soft tissues of the face, and cervical lymph drainage basins;
4) contrast-enhanced MRI to clarify the topography of the process in large tumors, disease recurrence, or involvement of the parotid pharyngeal process;
5) ultrasound-guided FNAB followed by cytological examination of the biopsy material (primary tumor);
6) pathomorphological examination of surgical material using immunohistochemical methods [5].
Differential diagnosis of SG tumors should be carried out within the group itself between benign and malignant, as well as with congenital head and neck anomalies, vascular lesions, lymphatic malformations, inflammatory processes, actinomycosis, tuberculosis, non-specific lymphadenopathies, and autoimmune diseases. One must also not overlook the possibility of metastatic involvement of the parotid, submandibular, and upper jugular lymph nodes in other malignancies, primarily nasopharyngeal carcinoma, retinoblastoma, and lymphoma.
2.1 Complaints and Anamnesis
It is recommended to take a thorough medical history: interview parents and the patient (age permitting); record the child's complaints, place of residence before the onset of symptoms, cases of cancer in the child and relatives, harmful exposures to the mother during pregnancy and to the child, and indications of a congenital nature of the disease. When interviewing parents and the patient, it is recommended to pay attention to the time of appearance of facial or submandibular deformity, the rate of external changes, presence of complaints, facial muscle function, and trismus [1, 2]. Main patient complaints: presence of a slowly growing mass in the parotid-masseter region – 99%, soreness in the tumor area – 22%, and facial nerve paresis – 7% [7].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
2.2 Physical Examination
If a pediatrician (or other specialist) suspects a nodular SG lesion based on external examination and palpation, the patient must be referred to a specialized clinic (oral and maxillofacial surgery clinic or pediatric oncology center).
It is recommended to perform an external examination, measure height, body weight, and physical development level in all patients with suspected or verified SG tumor [1, 2].
LoE 5Grade of recommendation – C (Level of evidence – 5)
It is recommended to palpate the parotid or submandibular SG, assess node mobility, identify the presence or absence of infiltration in the SG tumor area, and evaluate the size and mobility of cervical lymph nodes in all patients with suspected or verified SG tumor [1, 2].
LoE 5Grade of recommendation – C (Level of evidence – 5)
It is recommended to pay attention to the presence and severity of facial nerve dysfunction (paresis, paralysis), mouth-opening degree (trismus), and swallowing difficulties in all patients with suspected or verified SG tumor [1, 2].
LoE 5Grade of recommendation – C (Level of evidence – 5)
2.3 Laboratory Diagnostics
It is recommended upon hospitalization to perform a complete blood count (CBC) with mandatory differential leukocyte count (leukocyte formula) to assess the patient's condition and determine management tactics [54].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that all patients undergo a general biochemical blood test (urea, creatinine, total protein, total and conjugated bilirubin, glucose, lactate dehydrogenase (LDH), amylase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), sodium, potassium, calcium) upon hospitalization to clarify the extent of the disease and assess the patient's condition, including individual organs and systems [53].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that all patients undergo a coagulogram (exploratory hemostasis study) to assess the patient's condition and diagnose/determine the likelihood of severe hemorrhagic/thrombotic complications [53].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that all patients undergo a urinalysis to diagnose possible comorbid conditions and determine supportive care tactics [53].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that all patients undergo ABO blood typing, Rhesus antigen D (Rh factor) testing, and C, c, E, e, Cw, K, k antigen phenotyping for subsequent blood component replacement therapy if necessary [53].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
2.4 Instrumental Diagnostics
It is STRICTLY recommended that all patients undergo ultrasound of the salivary glands and ultrasound of one anatomical zone of cervical lymph nodes with fine-needle aspiration biopsy of the parotid gland mass (and fine-needle aspiration biopsy of lymph nodes if metastatic involvement is suspected) followed by cytological examination of FNAB smears to verify the nature of the neoplasm and identify possible specific lymph node involvement [11–17].
Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)
It is recommended that all patients with suspected malignant salivary gland tumors undergo magnetic resonance imaging of the soft tissues of the head and magnetic resonance imaging of the neck with intravenous contrast, which is strictly recommended in case of suspected skull base involvement, perineural spread (cranial nerve involvement), intracranial extension, recurrence, or continued growth [18–21].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
It is recommended to perform computed tomography of the facial skeleton with intravenous bolus contrast enhancement in all patients with suspected involvement of bone structures (upper/lower jaw, skull base) [22].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
All patients with malignant tumors are recommended to undergo computed tomography of the chest organs to search for possible secondary specific lung involvement [9-15].
Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)
It is recommended to perform bone scintigraphy in all patients with malignant salivary gland tumors when metastatic bone lesions are suspected [21-23].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
It is recommended to perform whole-body positron emission tomography with tumorotropic radiopharmaceuticals only in patients with late-stage disease to clarify regional and distant metastasis [23,24]. Positron emission tomography (PET/CT) with fluorodeoxyglucose (FDG) in the early stages of salivary gland tumors is not indicated [25].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
It is recommended to perform an ultrasound examination of the abdominal organs (complex) and an ultrasound examination of the retroperitoneal space in all patients with malignant salivary gland tumors with a high malignant potential, such as adenocarcinoma [4, 17, 20].
Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)
2.5 Other Procedures
It is recommended to perform cytological examination of the salivary gland tissue micropreparation in all patients undergoing fine-needle aspiration biopsy of a salivary gland mass to verify the nature of the neoplasm. It is recognized as a minimally invasive and effective diagnostic method [11–16].
Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)
It is recommended to perform core needle biopsy (CNB) in patients with minor salivary gland tumors or a non-diagnostic preceding fine-needle aspiration biopsy of a parotid gland mass to verify the nature of the mass [26–28].
GCR ALEL 2Grade of Recommendation – A (Level of Evidence – 2)
Comment: it is optional not to perform FNA followed by cytological examination in previously operated patients with a previously established histologically verified diagnosis.
It is recommended to indicate the risk of malignancy (ROM) in the cytological report according to the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) [29–32]: non-diagnostic, non-neoplastic, atypia of undetermined significance, suspicious for malignancy, and malignant. If possible, determine the grade of malignancy: low grade or high grade [30].
GCR ALEL 2Grade of Recommendation – A (Level of Evidence – 2)
It is recommended to perform an open biopsy in cases of a non-diagnostic preceding FNA and/or core needle biopsy (CNB), suspicion of non-epithelial malignant salivary gland tumors (rapid growth of the mass, involvement of adjacent tissues, localization of the lesion outside the glandular tissue, metastatic involvement), or the need to obtain material for molecular genetic testing in inoperable tumors [4, 25].
Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)
Comment: In case of extensive lesions of the parotid salivary gland involving the superficial and deep lobes, with suspected involvement of the facial nerve after double verification of the absence of malignant cells based on cytological examination results, additional histological verification via open biopsy of the neoplasm is indicated.
It is recommended for all patients to undergo pathomorphological examination of the biopsy (surgical) material of the salivary gland tissue using immunohistochemical methods of the removed tumor specimen, reflecting the following parameters [4]:
Tumor dimensions;
Depth of tumor invasion;
Histological structure of the tumor;
Tumor differentiation grade;
Assessment of resection margins;
Presence of lymphovascular or perineural invasion (a negative result must also be stated);
pT;
рN (indicating the total number of examined and affected lymph nodes, and signs of extranodal tumor extension);
Comment: items 6-8 are applicable to malignant tumors and are not required to be specified for benign tumor processes.
It is recommended to perform a cytogenetic study of the biopsy (surgical) material in patients with metastatic forms, inoperable cases, or secretory carcinoma, in order to search for molecular targets for subsequent targeted therapy, as well as in complex diagnostic cases to search for mutations as a criterion for the tumor subtype [10].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Surgical Treatment
It is recommended to consider surgical intervention as the main method of radical treatment for patients with epithelial malignant neoplasms of the salivary glands [16,17]. Tumor enucleation leads to continued growth and cannot be considered a treatment method [33]. The procedure must be performed in a specialized cancer center [16, 17, 33].
GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)
It is recommended to choose surgery as the main treatment method for benign tumors, in the scope of partial resection, parotidectomy, or subtotal resection with identification and preservation of the facial nerve. The procedure must be performed in a specialized center by an oncologist, maxillofacial, or plastic surgeon; the indications for neurophysiological monitoring remain relevant [3, 4].
GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)
It is recommended to use intraoperative neurophysiological monitoring of the facial nerve, which is strictly indicated for large tumors (T3-T4), tumor recurrence, re-operation, extended resections involving the skull base bones, as well as when planning simultaneous reconstruction of the facial nerve and its branches [48, 52].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
Applicable in the treatment of malignant tumors:
For T1–T2, N0:
It is recommended to remove parotid gland masses with identification and preservation of the facial nerve branches using intraoperative neurophysiological monitoring of the facial nerve [39, 40, 52].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
Patients with detected affected lymph nodes within the gland are recommended to undergo cervical lymphadenectomy (IA, IIA, IIB, and III collectors) [39, 40].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
Prophylactic cervical lymphadenectomy on the affected side is recommended for patients whose routine histological examination reveals a tumor with high malignant potential [39, 40].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
If routine pathomorphological examination of the surgical material reveals tumors with high malignant potential (high-grade), positive resection margins, or perineural invasion, it is recommended to consider postoperative external beam radiotherapy (EBRT) [25].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
It is not recommended to perform prophylactic lymph node dissection in patients with low- and intermediate-grade malignant tumors (except for patients with detected intra-glandular affected lymph nodes) [39, 40].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
For T1–2, N+M0:
It is recommended to completely remove parotid gland masses with identification and preservation of the facial nerve branches using intraoperative neurophysiological monitoring of the facial nerve [39, 40, 52].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
If affected lymph nodes are detected within the gland, it is recommended to perform cervical lymphadenectomy (IA, IIA, IIB, and III collectors) [39, 40].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
If routine pathomorphological examination of the surgical material reveals tumors with high malignant potential (high-grade), positive resection margins, or perineural invasion, it is recommended to consider postoperative external beam radiotherapy (EBRT) [25].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
For T3–4a, N0 M0:
It is recommended to completely remove parotid gland masses with identification and preservation of the facial nerve branches, mandatory intraoperative use of facial nerve neurophysiological monitoring, combined with ipsilateral cervical lymphadenectomy of IA, IIA, IIB, III, and IV collectors [39, 40, 52].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
If routine pathomorphological examination of the surgical material reveals adverse histological features (moderately or poorly differentiated tumor, positive margins, perineural invasion, vascular embolization), it is recommended to consider concurrent chemoradiotherapy (CCRT) [7].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4).
For T3–4a N+ M0:
It is recommended to completely remove parotid gland masses with identification and preservation of the facial nerve branches, mandatory intraoperative use of facial nerve neurophysiological monitoring, combined with extended ipsilateral cervical lymphadenectomy [39, 40, 52].
LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)
In the postoperative period, it is recommended to administer postoperative radiotherapy [24, 25].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
For stage T4b:
If radical surgery cannot be performed at the first stage, it is recommended to perform a cytogenetic study of the biopsy (surgical) material to search for molecular targets for targeted therapy or to perform EBRT, as well as other combinations, according to the decision of a federal oncological multidisciplinary team [10].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
Locoregional recurrence:
Recommended radical parotidectomy with a reconstructive-plastic component with mandatory intraoperative use of facial nerve neurophysiological monitoring [39, 40, 52].
GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)
If radical surgical intervention cannot be performed, it is recommended to perform a cytogenetic study of the biopsy (surgical) material to search for molecular targets and subsequent administration of targeted therapy; it is possible to consider concurrent chemoradiotherapy based on the decision of an oncological multidisciplinary team at a federal center [7].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
In case of primary non-radical surgical treatment
It is recommended to obtain consultation from an oncology tumor board at a federal center to decide on repeat second-look revision surgery (second-look operation) or prescribing RT [39].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Comment: For low- and intermediate-malignancy tumors in children and adolescents, a resection margin of 2 mm or more leads to good disease control [43, 45]. For high-malignancy tumors (adenoid cystic carcinoma), a sufficient resection margin is considered to be 5 mm or more. Simultaneous biopsy of suspicious lymph nodes based on preoperative examination results is indicated. If facial nerve branches are transected during parotidectomy, perform simultaneous nerve repair by suturing and/or using autografts from the great auricular or sural nerves or other types of plastics [45].
3.2 Principles of radiotherapy (this section applies to malignant epithelial neoplasms).
It is recommended to consider RT as an important tool in the treatment of malignant epithelial tumors of the salivary glands [37].
LoR CLoE 5Level of Recommendations – C (Level of Evidence – 5)
Approaches to radiotherapy in children are recommended to be based on the same principles as RT in adults [52, 53].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
RT is recommended in the following conditions [52, 53]:
poorly differentiated nature of the primary tumor;
tumor invasion into surrounding tissues (skull base, facial soft tissues);
presence of metastases in the neck region;
presence of tumor cells at the resection margin;
tumor rupture during surgery;
large tumor residue after surgery when its removal is impossible;
presence of histological signs of an aggressive tumor nature, for example, perineural invasion typical of adenoid cystic carcinoma;
tumor invasion into blood vessels or lymph nodes;
local extraglandular extension into soft tissues;
inoperability
Comment: technical requirements for EBRT equipment.
1) Medical linear electron accelerator with a photon energy of 6-10 MeV, equipped with a multileaf collimator and, highly desirably, image-guided radiation therapy (IGRT) system/systems: cone-beam computed tomography (CBCT), portal imaging. Scanning-beam proton therapy is possible using patient position verification methods before the irradiation session.
2) Head and body fixation devices (thermoplastic masks, vacuum mattresses, etc.).
3) X-ray computed tomography scanner for topography, featuring a flat tabletop with the ability to attach and index fixation systems.
4) 3D radiation planning system and, highly desirably, with the ability to calculate irradiation using intensity-modulated radiation therapy (IMRT/VMAT) techniques in static and dynamic modes.
Pre-radiotherapy preparation should be carried out in the following scope:
- CT-topometry should be performed on an X-ray computed tomography scanner adapted for radiotherapy needs.
- Marking is performed using individual fixation means: thermoplastic masks and, possibly, a vacuum mattress.
- The scan area must include the entire head, neck, and mediastinum down to the level of the tracheal bifurcation. Scanning is performed with a slice thickness of 1-3 mm,
- The field of view (FOV) must be adequate to include all body parts and fixation systems.
- It should be taken into account that general anesthesia may be required during topometry and radiation therapy in patients under 5 years of age.
- Planning is performed on a non-contrast CT topometry series.
- The use of IMRT [2] or scanning-beam proton therapy [3] techniques is preferable
It is recommended to take into account the following RT principles [52, 54]:
In case of standalone RT prescription
High-risk zone: primary tumor, as well as involved lymph nodes
Fractionation: 66 Gy (2.0 Gy/fraction) daily [52, 54]
Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)
Intermediate- and low-risk zones: areas of suspected subclinical spread
Fractionation: 44–50 Gy (2.0 Gy/fraction) daily [52, 54]
Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)
As postoperative RT
The preferred interval between resection and postoperative RT is less than 6 weeks.
High-risk zone: positive resection margins
Fractionation: from 66 Gy (2.0 Gy/fraction) daily [52, 54]
Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)
Intermediate- and low-risk zones: areas of suspected subclinical spread
Fractionation: from 44–50 Gy (2.0 Gy/fraction) daily [52, 54]
Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)
Volume | Definition and description |
GTV66 | Parotid or submandibular salivary gland: residual tumor or tumor bed. Cervical lymph nodes: all lymph nodes greater than 1 cm in the axial plane or with a necrotic center |
CTV66 | GTV66 + 5 mm = CTV66 |
PTV66 | Typically, CTV66 + 3–5 mm = PTV66. |
Table 4. High-risk zone
Table 5. Intermediate- and low-risk zones
Volume | Definition and description |
CTV50 | CTV50 must encompass the entire GTV or tumor bed. Boundaries of the postoperative parotid bed field: Anterior – masseter muscle Lateral – soft tissues of the neck Medial – styloid process Posterior – mastoid bone Parotid tumors: include the facial nerve, glossopharyngeal nerve, and trigeminal nerve; extension to Meckel's cave may be required Submandibular and sublingual tumors: extension to Meckel's cave is required, especially in adenoid cystic carcinoma. |
CTVLN | Electively irradiate the remaining neck (levels Ib–V) to 50 Gy; consider omitting levels V and IVb |
PTVLN | Usually CTVLN + 5 mm = PTVLN |
Doses: D95 = 95% of volume.
Dmax = maximum dose to 0.03 cc of volume
Table 6. Dose constraints
Structures | Dose constraint |
Bones | Max <70 Gy |
mandible | D 0.03 cc <70 Gy |
TMJ | D 0.03 cc 66–70 Gy |
Brachial plexus | D 0.03 cc 54–58 Gy |
Spinal cord | Max 45 Gy Max_PRV (Cord + 5 mm) 48 Gy |
Parotid | Mean dose <26 Gy |
Submandibular glands | Mean dose <39 Gy or 40 Gy |
Oral cavity, excluding PTV | Mean dose of <32 Gy |
Esophagus | Mean dose <30 Gy |
Cochlea | Mean <35 Gy Max <55 Gy |
Lips | Mean <20 Gy |
Larynx | Mean <35 Gy |
Chiasm | <55 Gy D0.03 cc (Gy) |
Optic nerves | Max 55 Gy D0.03 cc (Gy) |
Lenses | <Max 55 Gy D0.03 cc (Gy) |
Comment: Evidence suggests that proton therapy may offer advantages regarding acute toxicity and dose characteristics [38].
3.3. Chemotherapy (this section applies to malignant tumors).
Chemotherapy for salivary gland tumors may be recommended based on the results of a federal multidisciplinary board following molecular genetic testing to identify molecular targets for subsequent targeted therapy in cases of:
secretory carcinomas
in the presence of an unresectable tumor
and/or distant metastases [27, 28], when surgical and radiation therapy options are exhausted [6, 39, 40].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
4. Medical Rehabilitation and Sanatorium-Resort Treatment
It is recommended to include social and pedagogical support for the patient, as well as psychosocial support for the family, in the rehabilitation plan throughout specialized treatment [1, 4, 38].
LoE 5Grade of recommendation – C (Level of evidence – 5)
It is recommended that follow-up care for patients with malignant salivary gland tumors be provided by a pediatric oncologist, and for benign tumors, by a maxillofacial surgeon or pediatric surgeon (until the patient reaches 18 years of age), as well as by a neurologist, ophthalmologist, rehabilitation specialist (physiotherapist), and clinical psychologist in the presence of facial nerve palsy [1, 4].
LoE 5Grade of recommendation – C (Level of evidence – 5)
Comments: An important aspect of patient rehabilitation after salivary gland tumor surgery is the restoration of facial nerve function. In case of facial nerve branch palsy, exercise therapy and stimulation therapy for facial muscles are indicated, which the patient can perform under the supervision of a speech-language pathologist, physical therapist, and neurologist. Facial nerve plastic surgery techniques may be used in cases of facial nerve paralysis.
It is recommended to consider the duration of facial muscle paresis and paralysis when choosing treatment methods [4]:
when performing parotidectomy and transection of facial nerve branches, perform immediate nerve repair by suturing, as well as using autografts from the great auricular or sural nerves;
in the treatment of facial muscle paralysis of up to 2 years duration, perform neuroplasty using the masseteric branch of the trigeminal nerve, the descending branch of the hypoglossal nerve, cross-nerve grafting, or combinations thereof;
when facial paralysis has lasted for more than 2 years with no neuromuscular activity on electromyography, perform: temporalis muscle transposition, vascularized muscle flap transfer (e.g., gracilis muscle), static correction methods, and botulinum toxin therapy.
LoE 5Grade of recommendation – C (Level of evidence – 5)
5. Prevention and Dispensary Observation
Monitoring of "at-risk" groups is necessary, including children and adolescents living in regions with a developed woodworking industry, if the child has a history of head and neck radiotherapy, received radioiodine therapy for thyroid cancer, or underwent combination chemotherapy.
5.1 Follow-up care
All patients are recommended to undergo routine follow-up examinations: every three months in the first year; at least once every six months for five years; and at least annually thereafter (lifelong for patients with malignant tumors) [53].
LoE 5Grade of recommendation – C (Level of evidence – 5)
Comment: The scope of diagnostic procedures during follow-up examinations includes:
1. General clinical examination;
2. Ultrasound examination of the salivary glands and ultrasound of the cervical lymph nodes (one anatomical region);
3. Ultrasound of the abdominal organs and retroperitoneum;
4. Computed tomography of the lungs at least once a year (for patients with malignant tumors);
5. Magnetic resonance imaging of the soft tissues of the head with intravenous contrast;
6. Three-phase bone and soft tissue scintigraphy at least once a year (for patients with malignant tumors);
7. Bilateral electromyography of the facial muscles in the presence of facial nerve paresis at 3 months, 6 months, and 1 year.
Further management: follow-up by an oncologist or maxillofacial surgeon (for benign tumors).
6. Organization of Medical Care
Indications for emergency inpatient admission:
Bleeding phenomena with signs of life-threatening condition for the patient.
Upper airway obstruction with indications for tracheostomy.
Acute loss of consciousness, coma.
Symptoms of compression with the development of superior vena cava syndrome.
Symptoms of acute facial nerve palsy on the affected side.
Indications for planned admission to a medical organization:
Performing confirmatory diagnostics.
Performing stages of specialized treatment (surgical, radiation, medical).
Symptomatic therapy.
Performing surgical rehabilitation methods, botulinum toxin therapy for facial nerve palsy
Comment: the specifics of organizing specialized medical care are described in section A3.
7. Additional Information
Vaccination is not performed during treatment (except for hepatitis B vaccination)
The possibility of attending organized groups is not restricted, except in cases of severe somatic condition
Physical exertion is excluded during treatment, as well as for 1 month after surgical treatment or longer if there are complications limiting the child's physical activity.
Transfer of the child to home schooling is possible if persistent signs of facial nerve palsy, communication problems with peers, as well as swallowing and chewing difficulties persist, at the request of the patient/legal representative.
Insolation and electromyostimulation of the parotid-masseteric region are not recommended in patients with malignant salivary gland tumors during the first 5 years.
Criteria for Evaluating the Quality of Medical Care
No. | Quality criteria | Evaluation of compliance | ||
|---|---|---|---|---|
1. | Fine-needle/core-needle aspiration biopsy of the tumor and/or altered regional lymph nodes was performed followed by cytological examination (at diagnosis) or histological material review in case of progressive growth/disease recurrence | Yes/No | ||
2. | Ultrasound of the salivary glands and/or computed tomography of the facial skeleton and/or magnetic resonance imaging of the skull base were performed initially (at diagnosis) | Yes/No | ||
3. | Neck ultrasound was performed (at the diagnosis of a malignant tumor) | Yes/No | ||
4. | Chest computed tomography was performed (at the diagnosis of a malignant tumor) | Yes/No | ||
5. | Morphological and/or immunohistochemical examination of the removed tissue specimen was performed (in case of surgery) | Yes/No | ||
6. | Surgical treatment corresponding to the stage of the disease was performed (exception: hospitalization cases involving radiation therapy — select "not applicable") | Yes/No/Not applicable | ||
7. | An oncological multidisciplinary team meeting was held if radiation therapy or chemotherapy was indicated | Yes/No/Not applicable | ||
8. | A follow-up monitoring plan was specified upon patient discharge, indicating the schedule and methods of control examinations | Yes/No | ||
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E.C. Fortune IV 1, D.J. Indelicato 1, R.Mailhot Vega 1, S. Bradfield 2, J.A. Bradley 1 Outcomes Following Proton Radiotherapy for Pediatric Salivary Gland Tumors
Appendix A1. Working Group Composition
Grachev Nikolai Sergeevich, 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, Head of the Department of Pediatric Surgery with a Course of Oncology and Reconstructive Plastic Surgery at the Dmitry Rogachev NMRCPHOI of the Russian Ministry of Health, member of the Federation of Head and Neck Oncologists, member of the Russian Society of Pediatric Oncologists (RSPO).
Vorozhtsov Igor Nikolaevich, Candidate of Medical Sciences, Head of the Department of Pediatric Oncology, Head and Neck Surgery, and Neurosurgery at the Dmitry Rogachev NMRCPHOI of the Russian Ministry of Health, member of the Federation of Head and Neck Oncologists.
Kalinina Margarita Pavlovna, Maxillofacial Surgeon at the Department of Pediatric Oncology, Head and Neck Surgery, and Neurosurgery of the Dmitry Rogachev NMRCPHOI of the Russian Ministry of Health, Head of the Day Hospital at the Federal Scientific and Clinical Center of Children and Adolescents of the Federal Medical-Biological Agency (FMBA) of Russia.
Oganesyan Raisa Surenovna, Pediatric Surgeon at the Department of Pediatric Oncology, Head and Neck Surgery, and Neurosurgery of the Dmitry Rogachev NMRCPHOI of the Russian Ministry of Health
Zhukov Nikolai Vladimirovich, Doctor of Medical Sciences, Head of the Department of Interdisciplinary Oncology at the Dmitry Rogachev NMRCPHOI of the Russian Ministry of Health
Nechesnyuk Aleksei Vladimirovich, Candidate of Medical Sciences, Head of the Radiotherapy Department at the Dmitry Rogachev NMRCPHOI of the Russian Ministry of Health
Rabaeva Lilia Leonidovna, Candidate of Medical Sciences, Pediatric Oncologist at the Department of Older Children Hematology/Oncology and Neuro-oncology at the Dmitry Rogachev NMRCPHOI of the Russian Ministry of Health
Gornostaev Vladimir Vasilyevich, Radiotherapist at the Radiotherapy Department of the Dmitry Rogachev NMRCPHOI of the Russian Ministry of Health.
Polyakov Vladimir Georgievich, Academician of the RAS, Doctor of Medical Sciences, Professor, Head of the Head and Neck Tumors Department at the Research Institute of Pediatric Oncology and Hematology of the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Head of the Department of Pediatric Oncology at the Russian Medical Academy of Continuous Professional Education (RMACPE) of the Russian Ministry of Health, member of the Society of Head and Neck Tumors Specialists, member of the Federation of Head and Neck Oncologists, member of the Russian Society of Pediatric Oncologists (RSPO), Chief freelance pediatric oncologist of the Russian Ministry of Health.
Ivanova Natalia Vladimirovna, Candidate of Medical Sciences, Surgeon at Surgical Department No. 1 of the Research Institute of Pediatric Oncology and Hematology of the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, member of the Society of Head and Neck Tumors Specialists, member of the Federation of Head and Neck Oncologists, member of the Russian Society of Pediatric Oncologists (RSPO).
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
Pediatric oncologists/hematologists
Hematologists
Pediatric oncologists.
Oncologists
Pediatricians
Radiologists
Clinical laboratory diagnostics physicians
Table 7. Levels of Evidence (LE) rating scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 8. Levels of Evidence (LE) rating scale for prevention and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
LoE | Definitions |
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 9. Grades of Recommendation (GR) rating scale for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
GoR | Definition |
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
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
1. General principles of surgical treatment
The main treatment method for malignant epithelial salivary gland tumors in both children and adults is surgery [31]. As early as 1986, Spiro RH formulated the main principles of successful treatment: radical tumor removal with negative resection margins and no distant metastases [32]. According to M. Zamani et al., 95% of patients undergo surgical treatment, and postoperative radiation therapy is required in 24% of cases [7]. According to Ullah A. (2023), in a cohort of over two thousand patients with mucoepidermoid carcinoma, isolated surgical treatment was administered in 63.6% of pediatric patients and 53.3% of adults. Combined treatment was performed in 26.1% and 29.6%, respectively [37]. Despite the simplicity and logic of Spiro R.H.'s statement, which has remained relevant for over 35 years, many questions remain: resectability, radicality and adequacy of resection margins, and preservation of the facial nerve.
The level of development of head and neck microsurgery classifies T4b tumors or the presence of distant metastases as unresectable [33]. Tumor enucleation leads to progressive growth or recurrence and cannot be considered a treatment method [34]. ASCO published recommendations stating that partial superficial resection of parotid gland tumors up to 4 cm (T1/T2 according to WHO) is possible if the tumor is of low grade, albeit with a low level of certainty [22]. There are no randomized trials accounting for the extent of resection in low-grade epithelial tumors, but there are a number of retrospective studies. Clinically, the course of these tumors is similar to pleomorphic adenomas. The authors believe that complete excision of the tumor must be ensured, while resection of additional parotid gland tissue is not required due to the low rate of metastasis.
The choice of the optimal extent of resection is based not only on the primary tumor size, but also on the histological type and risk stratification.
Morse E demonstrated in his work how the risk of recurrence/progressive growth changes depending on the resection margin for head and neck squamous cell carcinoma. At a distance of greater than 1 mm, there is no statistically significant difference between the resection margin and the development of recurrence [50] (Table 2)
Table 10. Risk of recurrence depending on the resection margin according to Morse E. [50]
Resection margin | Probability of recurrence/progressive growth, % |
Tumor at the margin | 44 |
Margin less than 1 mm | 28 |
1 mm | 17 |
2 mm | 13 |
3 mm | 13 |
4 mm | 14,4 |
5 mm | 11 |
The minimal yet sufficient resection margin has not been defined. Difficulties in this matter are associated with the lack of randomized trials, the anatomical features of the parotid-masseteric region and the skull base, as well as various histological variants of tumors.
In the early stages of the disease, disease control can also be achieved with a narrow margin of resection (less than 5 mm) in the absence of perineural or lymphovascular invasion [43,45]. The dependence of resection margins on the histological type of the tumor is discussed in the works of Zenga et al. A 2 mm resection margin demonstrated the absence of locoregional recurrence in 90% of cases over 6 years in patients with low- or intermediate-grade mucoepidermoid carcinoma with T1 and T2 tumors. In the group of acinic cell carcinomas, only 1 out of 18 patients developed a recurrence with this type of removal within 64 months [44]. Similar results among low- and intermediate-grade tumors were shown by Stodulski et al. The recurrence-free survival of 32 patients was 90.6% with a margin greater than 1 but less than 5 mm [45]. For any type of high-grade cancer or advanced T3-T4 stages, the recommended scope of intervention is superficial parotidectomy, with a potential extension to subtotal or total parotidectomy. In advanced T3-T4 forms, not only the size of the primary lesion is evaluated, but also lymph node involvement [40]. When choosing the extent of resection in patients with advanced tumors (T4), data are available from the group with skin involvement.
Neck dissection remains controversial; according to Aro K. et al., only 17% of patients have regional metastases [47]. Its performance is recommended for T3 and T4 tumors among high-grade neoplasms. In the National Cancer Database, 26% of patients had lymph node involvement [50]. Using multivariate analysis, Wang Y. L. et al. established that lymph node involvement was a predictor of major nerve involvement, high grade, lymphovascular, and extracapsular invasion [39].
To date, there are no data on the impact of prophylactic neck dissection on disease control in the event of postoperative radiotherapy.
The necessity and level of neck dissection for the treatment of various salivary gland cancers largely depend on the histological type and risk stratification. According to ASCO guidelines, with low level of evidence, surgeons should include neck levels II-V depending on the location of the primary tumor. Dissection up to levels I-5 may be performed for high-grade tumors [22].
Ali S. et al. found that levels II-III (upper and middle jugular lymph nodes) are most frequently involved in clinically N0 necks, level 4 (lower jugular lymph nodes) in 11%, level 1 (submental and submandibular lymph nodes) in 5%, and level 5 (posterior triangle of the neck) in 7%. In the case of initial lymph node involvement (N+), their distribution across groups is as follows: level 1 – 52%, level 2 – 77%, level 3 – 73%, level 4 – 53%, and level 5 – 40%, respectively [51]. Lim et al. published data on a high incidence of level 5 lymph node involvement in patients with initial node-positive disease, reaching up to 82% [52].
The scope of neck dissection for high-grade T3 and T4 tumors in the absence of initial lymph node involvement is levels II-V. When performing therapeutic neck dissection for T3-T4 N+ disease, it will encompass levels I-V for high-grade tumors.
2. Organization of specialized medical care
Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Public Health Protection 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 body;
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 body.
Primary specialized health care is provided by an oncologist and other medical specialists at an outpatient oncological center, primary oncological office, primary oncological department, or the outpatient department of an oncological dispensary. If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practitioners (family physicians), medical specialists, and mid-level medical staff shall refer the patient in the established manner for a consultation at the outpatient oncological center, primary oncological office, or primary oncological department of a medical organization to receive primary specialized health care. The consultation at the outpatient oncological center, primary oncological office, or primary oncological department of the medical organization must be conducted no later than 5 working days from the date of issuing the referral for consultation. The oncologist of the outpatient oncological center (or, in the absence of such a center, the oncologist of the primary oncological office or primary oncological department) shall arrange for the collection of biopsy (surgical) material, as well as the performance of other diagnostic tests necessary to establish the diagnosis, including the extent of the tumor process and the stage of the disease. If it is impossible to obtain biopsy (surgical) material or perform other diagnostic tests within the medical organization that incorporates the outpatient oncological center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases. The timeframe for performing pathomorphological examinations necessary for the histological verification of a malignant neoplasm (MN) of the salivary glands must not exceed 15 working days from the date the biopsy (surgical) material arrives at the pathoanatomical bureau (department). If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, such patients are transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine the management tactics and the need for additional specialized antitumor treatment methods. The oncologist of the outpatient oncological center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases to clarify the diagnosis (if it is impossible for the oncologist of the outpatient oncological center, primary oncological office, or primary oncological department to establish the diagnosis, including the extent of the tumor process and the stage of the disease) and to provide specialized, including high-tech, medical care.
The timeframe for initiating specialized, except for high-tech, medical care for patients with oncological diseases in a medical organization providing medical care to cancer patients must not exceed 14 calendar days from the date of pathomorphological verification of a malignant neoplasm (MN) of the salivary glands or 14 calendar days from the date of establishing a preliminary diagnosis of an MN of the salivary glands (in the absence of medical indications for outpatient pathomorphological studies). Specialized, including high-tech, medical care is provided by oncologists and radiotherapists in an oncological dispensary or in medical organizations providing medical care to cancer patients, holding the necessary license, material and technical base, certified specialists, in inpatient and day-hospital settings, and includes prevention, diagnosis, and treatment of oncological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation. In a medical organization providing medical care to cancer patients, the strategy of medical examination and treatment is determined by a concilium of oncologists and radiotherapists, involving other medical specialists if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the medical concilium, and entered into the patient's medical documentation. Indications for hospitalization in an inpatient or day-hospital unit of a medical organization providing specialized, including high-tech, medical care in the profile of "oncology" are determined by a concilium of oncologists and radiotherapists, involving other medical specialists if necessary.
The conclusion regarding the feasibility of transferring a patient to a specialized medical organization is made after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by medical specialists of the medical organization to which the transfer is planned.
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
Frequency of visits to the oncologist after completion of special treatment: every 3 months during the 1st year after treatment, every 6 months for 5 years, once a year for life.
It is necessary to completely avoid visiting solariums, not to sunbathe on the beach during holidays; physical therapy procedures and vaccinations must be approved by the oncologist.
Upon reaching the age of 18, patients are transferred to dispensary follow-up in the adult department.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not applicable