Adrenocortical Carcinoma: Clinical Guidelines

List of Abbreviations

¹⁸F-FDG PET/CT – positron emission tomography combined with computed tomography using fluorine-18 fludeoxyglucose (A07.30.043.01 Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement)

AJCC – American Joint Committee on Cancer

ENSAT – European Network for the Study of Adrenal Tumors

HU (Hounsfield units) - densitometric indices during CT scanning

[¹²³I] – Iobenguane [123I] - radiopharmaceutical diagnostic agent

RECIST – Response Evaluation Criteria in Solid Tumors

SUV (standardized uptake value) - uptake criterion in ¹⁸F-FDG PET/CT

TNM – International TNM Classification of Malignant Tumors (abbreviation for Tumor, Nodus, Metastasis)

UICC – Union for International Cancer Control

AH – arterial hypertension

ACC – adrenocortical carcinoma (syn.: adrenocortical cancer)

ACTH – adrenocorticotropic hormone

ALT – alanine aminotransferase

ARR – aldosterone-renin ratio

AST – aspartate aminotransferase

WHO – World Health Organization

EBRT – external beam radiation therapy

GGT – gamma-glutamyl transferase

SHBG – sex hormone-binding globulin

IHC – immunohistochemical study

CE – contrast enhancement

LH – luteinizing hormone

LDH – lactate dehydrogenase

ICD-10 – International Classification of Diseases, 10th Revision

MRI – magnetic resonance imaging

MSCT – multislice computed tomography

MEN – multiple endocrine neoplasia syndrome

NBL – neuroblastoma

IVC – inferior vena cava

AbA – abdominopelvic organs

CT – chest organs

PA – primary aldosteronism

RFA – radiofrequency ablation (A16.14.037)

PCC/PGL – pheochromocytoma/paraganglioma

FSH – follicle-stimulating hormone

CS – Cushing's syndrome

TSH – thyroid-stimulating hormone

Ultrasound – ultrasound examination

Terms and Definitions

Adjuvant chemotherapy – chemotherapy administered after local tumor treatment to eradicate or permanently suppress micrometastases

Germline mutation – an alteration in gene structure (nucleotide sequence, chromosome, genome) compared to the reference sequence, originating in germ cells.

Hypercortisolemia (endogenous) – a complex of clinical symptoms caused by prolonged exposure of the body to corticosteroids due to their excessive endogenous production.

Driver mutation – an alteration in gene structure (nucleotide sequence, chromosome, genome) that initiates the transformation of a normal cell into a cancer cell

Adrenal incidentaloma – a collective term encompassing a morphologically diverse group of tumors greater than 1 cm in diameter, discovered incidentally during radiological imaging.

Carcinogenesis - the complex pathophysiological process of tumor initiation and development.

Mutation – a stable (i.e., heritable by descendants of this cell or organism in the case of a germline mutation) change in the genome.

Neuroblastoma – a malignant tumor developing from precursor cells of the sympathetic nervous system (SNS).

Acute adrenal insufficiency – a symptom complex caused by a sharp decrease or complete cessation of the functional activity of the adrenal cortex.

Orphan disease – a rare disease that affects a small percentage of the general population: in Europe, a disease is considered rare if its prevalence is 1 in 2,000 residents; in the USA, if it affects no more than 2,000 people; in Russia, no more than 10 people per 100,000 population.

Primary aldosteronism – a clinical syndrome developing as a result of excessive aldosterone production by the zona glomerulosa of the adrenal cortex, where aldosterone secretion is fully or partially autonomous relative to the renin-angiotensin system, leading to low-renin hypokalemic arterial hypertension.

Signaling pathway – a sequence of molecules through which information from a cellular receptor is transmitted inside the cell.

«Uncontrolled hemodynamics» syndrome – a pathological condition occurring against the background of a catecholamine-producing adrenal tumor and characterized by a sharp increase in high-amplitude hypertensive crises with worsening untreatable hypotension in the interictal period

Systemic chemotherapy – the administration of drugs orally, subcutaneously, intravenously, or intramuscularly, designed for a general antitumor effect.

Pheochromocytoma – a tumor of chromaffin cells of the sympathoadrenal system of adrenal or extra-adrenal localization, which typically secretes catecholamines.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Adrenocortical carcinoma (syn.: adrenocortical cancer; ACC) is a rare malignant tumor of the adrenal cortex, characterized typically by late detection, an aggressive clinical course, and an unfavorable prognosis.

ACC can be hormonally active, most often causing subclinical or overt Cushing's syndrome (or mixed syndromes), or it can be a hormonally inactive tumor [1].

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

Carcinogenesis in ACC is driven by driver mutations in a number of genes and the activation of corresponding signaling pathways [2]. In most cases, these mutations arise spontaneously in adrenal cortical cells, leading to sporadic cases of the disease. Pathogenesis of ACC may also be based on germline mutations: in this case, the disease will manifest as part of a hereditary syndrome [3].

Several hereditary syndromes that include ACC as a component have been described (Table 1). These syndromes exhibit low phenotypic penetrance of ACC, making it quite difficult to trace the hereditary nature of the disease through anamnesis [1]. The most common hereditary syndrome involving ACC is Li-Fraumeny syndrome, found in the majority of pediatric ACC cases (up to 80% of all patients); it is also the most frequent cause of hereditary ACC in adults (up to 5% of all cases). The prevalence of other ACC-associated syndromes ranges from a fraction of a percent to 3–4% among adult ACC patients [3].

Table 1. Hereditary syndromes associated with ACC [3]

The genesis of Li-Fraumeni syndrome is associated with an inactivating mutation in the tumor suppressor gene TP53. The syndrome is characterized by the development of soft tissue sarcomas, breast cancer, brain tumors, leukemias, and ACC. It is most frequently encountered in the southern regions of Brazil, where 0.3% of the population carries the germline R337H mutation in the TP53 gene.

The pathogenesis of Lynch syndrome is based on germline mutations in one of the DNA mismatch repair genes (MSH2, MSH6, MLH1, PMS2), which leads to the development of proximal colorectal cancer (up to 80% of Lynch syndrome cases). In addition to colorectal cancer and ACC, patients with Lynch syndrome have an increased risk of malignancies in other locations: endometrial cancer (50–71% of Lynch syndrome cases), urinary tract, ovaries, stomach, small intestine, pancreas, as well as brain glioblastomas and sebaceous gland tumors.

Multiple endocrine neoplasia (MEN) type 1 syndrome is caused by germline mutations in the tumor suppressor gene MEN1. The most common adrenal lesions observed in MEN type 1 syndrome are unilateral or bilateral cortical hyperplasia and adenomas. These lesions occur in 45–55% of patients with MEN 1 and can be hormonally active or non-functioning. The prevalence of ACC within MEN type 1 syndrome reaches 22%. Other manifestations of MEN type 1 most frequently include parathyroid hyperplasia or tumors leading to primary hyperparathyroidism, pancreatic neuroendocrine tumors, and pituitary tumors.

ACC may also be detected as part of Gardner syndrome (familial adenomatous polyposis), Beckwith-Wiedemann syndrome, Carney complex, and neurofibromatosis type 1. According to the literature, the share of these syndromes in the structure of ACC does not exceed 1% [3].

1.3 Epidemiology of the Disease or Condition

The annual incidence of ACC is 0.5–2 cases per 1 million population, accounting for 0.04–0.2% of cancer mortality. Regional differences in incidence rates are noted. The incidence rate in southern Brazil is the highest and varies from 3.4 to 4.2 cases per 1 million population, which is approximately 10 times higher than the average in other countries [229]. The disease manifests predominantly in adults and very rarely in children, with a bimodal age distribution. In adults at the time of diagnosis, the average age is 50–60 years, and in children, 3–4 years. Women are affected more frequently, with a female-to-male ratio of 2.5:1 [2, 4, 230]. Epidemiological data for the Russian Federation are extremely difficult to estimate, as cancer reporting for ACC is not generated separately and there is no registry. ACC is included in the list of orphan diseases in the Russian Federation [5].

1.4 Features of Coding the Disease or Condition

C74 Malignant neoplasm of adrenal gland

C74.0 Adrenal cortex

C74.9 Adrenal gland, unspecified part

D44.1 Neoplasm of uncertain or unknown behavior of endocrine glands. Adrenal gland.

1.5 Classification of the disease or condition

1.5.1. International Histological Classification

According to the International Histological Classification (World Health Organization (WHO), 5th edition, 2022), ACC is coded as 8370/3 (Table 2) [2].

Table 2. WHO classification of tumors of the adrenal cortex, 2022

1.5.2. Staging

Staging of ACC in adults is performed according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM classification, 8th edition (2017) and the European Network for the Study of Adrenal Tumors (ENSAT) classification [6, 7]. Staging of ACC in children is carried out according to the TNM classification and the Children's Oncology Group (COG) system [7, 230, 231].

Clinical staging of ACC is performed at the preoperative stage in children and adults based on the results of imaging studies; in children, an additional parameter is the assessment of tumor volume. Following surgical treatment, histological confirmation is required for proper ACC staging (pTnM). In children, an additional parameter is the tumor weight assessed after surgical intervention.

Primary tumor (T/pT). The T criterion reflects the extent of the primary tumor and includes the following categories:

Tx: Primary tumor cannot be assessed

T0: No evidence of primary tumor

T1: Tumor size ≤ 5 cm;

T2: Tumor size > 5 cm;

T3: Tumor of any size with local invasion, without involvement of surrounding organs*;

T4: Tumor of any size with invasion into surrounding organs and/or thrombosis of the inferior vena cava (IVC) and/or renal vein thrombosis.

* Surrounding organs include: kidney, diaphragm, major vessels, pancreas, liver.

Regional lymph nodes (N/pN). The N criterion indicates the presence or absence of metastases in regional lymph nodes

Nx: Regional lymph nodes cannot be assessed;

N0: No regional lymph node metastasis;

N1: Regional lymph node metastasis

Regional lymph nodes are considered to be the renal hilar, para-aortic, and paracaval lymph nodes. The side of the affected adrenal gland is not taken into account.

Distant metastases (M). The M criterion characterizes the presence or absence of distant metastases:

M0: no distant metastases

M1: distant metastases present

The TNM staging classification for ACC according to UICC and ENSAT is presented in Table 3. The criteria for establishing ACC staging are identical for both UICC and ENSAT. ACC staging in children according to the COG system is presented in Table 4.

Table 3. TNM ACC staging according to the 8th edition AJCC/UICC and ENSAT

Table 4. ACC staging in children according to the COG system

1.6 Clinical presentation of the disease or condition

ACC may be hormonally active, most commonly causing subclinical or overt Cushing's syndrome and/or virilizing syndrome, or it may be an incidentally discovered hormonally inactive adrenal tumor

Clinical manifestations of ACC differ somewhat across different age groups.

In adult patients, clinical manifestations of ACC include symptoms of excess hormone secretion (50–60%) and non-specific symptoms associated with tumor growth (30–35%) [2]. In the remaining cases (10–15%), the disease is discovered incidentally during imaging studies: multispiral computed tomography (MSCT) and/or magnetic resonance imaging (MRI) and/or ultrasound (US) as an incidentaloma (Table 5) [8–13].

Table 5. Clinical manifestations of ACC in adult patients [8]

The most common manifestation of hormone hyperproduction is hypercorticism, either isolated (30–50%) or combined with symptoms of virilization (20–30%). Thus, hypercorticism accounts for 50–80% of all cases of hormonally active ACC.

Isolated androgen hyperproduction is the second most common manifestation of hormonal activity in ACC (up to 20% of patients). Hyperandrogenemia in women can lead to hirsutism, virilization, and menstrual irregularities. In men, androgen excess often goes unnoticed due to scarce symptoms. Estrogen hyperproduction in ACC is rare (less than 2%), causes gynecomastia and testicular atrophy in men, and presents with metrorrhagia in postmenopausal women. Excessive secretion of sex hormones when an adrenal tumor is detected is particularly suspicious for ACC.

The rarest variant of endocrinopathy in ACC is associated with manifestations of primary hyperaldosteronism, which presents with severe arterial hypertension and hypokalemia. Increased aldosterone production is noted somewhat more frequently as part of mixed hormone production.

In most cases, ACC is relatively large, on average more than 10 cm. Non-specific symptoms of ACC, such as discomfort or pain, lower back and abdominal pain, and a feeling of gastric fullness, are caused by the increase in tumor size and compression of adjacent organs [14].

Symptoms traditionally associated with malignant disease (marked weight loss, weakness, low-grade fever) are generally not characteristic of ACC [8].

In children, hormonal activity of ACC is detected in 90% of cases. Precocious puberty (PP) or isosexual or heterosexual virilization is frequent and characterized by high testosterone or estrogen levels with low plasma FSH and LH levels [232]. Most tumors secrete cortisol in isolation (65%) or androgens in combination with cortisol (30%). Other variants of hormonal activity in childhood can be considered casuistic. Patients may have a non-specific presentation manifesting as arterial hypertension and seizures. In half of the cases, the presentation of the disease may be associated with a large palpable mass accompanied by pain syndrome and weight loss (Table 6) [232].

Table 6. Clinical manifestations of ACC in children and adolescents [230, 232, 233]

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing a diagnosis of ACC include

1. patient complaints;

2. individual and family medical history data;

3. physical examination results;

4. results of laboratory, instrumental, and other diagnostic studies.

Diagnosis of non-metastatic ACC is performed when an adrenal tumor is detected. From this perspective, the diagnosis of ACC is considered within the framework of differential diagnosis with other adrenal tumors most commonly detected incidentally (incidentalomas). The term "adrenal incidentaloma" is a collective term encompassing a morphologically diverse group of tumors greater than 1 cm in diameter discovered incidentally during radiological examination [15]. The detected formation may

• turn out to be either hormonally inactive or active;

• originate from various zones of the adrenal gland or have a nonspecific organ origin;

• be malignant or benign.

Diagnosis of locally advanced or metastatic cancer generally does not present difficulties; sometimes differential diagnosis is performed with tumors of the liver, kidney, or retroperitoneal non-organ tumors.

In cases of small ACC with massive distant metastatic spread, it may be necessary to perform differential diagnosis with another malignant tumor metastasizing to the adrenal gland (e.g., lung cancer).

In infants under one year of age, ACC without prominent clinical manifestations such as virilization or arterial hypertension and with a normal hormonal profile must be differentiated from neuroblastoma (NBL), which is the most frequent extracranial solid tumor in children and adolescents and the most common adrenal tumor [234]. In older children presenting with arterial hypertension and a normal hormonal profile, differential diagnosis should be performed with pheochromocytoma (PCC), which accounts for 2% of arterial hypertension cases in children and adolescents [235].

2.1 Complaints and Anamnesis

Complaints of patients with hormonally active ACC are determined by the secretory profile of the tumor:

• hypercorticism: general weakness, headaches, dysplastic (centripetal) obesity, arterial hypertension, muscle weakness, matronism, "buffalo hump", prominent wide striae (anterior abdominal wall, thighs, axillary regions, etc.), menstrual irregularities, decreased libido, diabetes mellitus, etc.;

• hyperandrogenemia: hirsutism in women, menstrual irregularities, clitoromegaly; oily and impure skin;

• hyperestrogenemia: impotence, gynecomastia in men, metrorrhagia in postmenopausal women;

• hyperaldosteronism: arterial hypertension unresponsive to multi-drug therapy, muscle weakness.

Hormonally inactive ACCs may manifest as nonspecific complaints of abdominal or back discomfort/pain, a feeling of fullness in the abdomen, or a mass in the abdominal cavity detected independently upon abdominal palpation.

In 10-15% of all cases, patients with ACC have no complaints; in such cases, ACC is initially detected as an incidentaloma.

2.2 Physical Examination

Certain manifestations of ACC caused by symptoms of hormonal hyperproduction can be detected during physical examination (see sections 1.6 and 2.1). In some cases, a large tumor may be detected by palpation. Clinical manifestations may also be caused by ACC metastases in the liver, lungs, and bones.

2.3 Laboratory Diagnostics

• 2.3.1. It is recommended that all patients aged ≥ 18 years with an adrenal tumor larger than 1 cm undergo laboratory testing in the first instance to rule out or confirm the hormonal activity of the mass, which may manifest as hypercatecholaminemia, ACTH-independent hypercorticism, or primary hyperaldosteronism [8, 13, 16, 211].

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

Comment. According to autopsy statistics, the prevalence of incidentally discovered adrenal tumors averages 6%. Adrenal incidentalomas are detected in 4% of patients evaluated for other reasons [17]. Under the age of 30, incidentalomas occur in approximately 0.2% of examined individuals, but in the group of patients over 70 years of age, the frequency increases to 7%.

The frequency of ACC among incidentalomas is low. Thus, according to W.F. Young et al. [16], the frequency of ACC was estimated at just over 4%. Another analysis [13] of a large number of patients demonstrated a prevalence of ACC among incidentalomas of no more than 1.9%. The probability of detecting ACC in incidentalomas depends on the size and reaches 25% when the tumor size is greater than 6 cm.

• 2.3.2. Investigation of the hormonal activity of the adrenal tumor is regulated, and it is recommended to take its results into account for every patient for perioperative management and planning of drug therapy [8, 13, 18].

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

Comment. The absence of overt clinical manifestations of hormonal activity does not indicate a hormonally inactive tumor—subclinical hormonal activity is possible.

It is also known that PCC can produce ACTH and cause clinical manifestations of hypercorticism [19-22].

• 2.3.3.1 It is recommended that all adult patients with a detected adrenal tumor and pediatric patients with suspected ACC undergo an assessment of total blood cortisol levels in the early morning hours during a suppression test with 1 mg of oral #dexamethasone** to detect ACTH-independent hypercorticism [8, 19, 23]. Failure to recognize hypercorticism (including subclinical) is associated with a high risk of developing acute adrenal insufficiency in the postoperative period.

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

• 2.3.3.2. In the absence of physiological suppression of cortisol levels in patients ≥ 18 years and pediatric patients with a detected adrenal tumor, it is recommended to use the measurement of morning blood adrenocorticotropic hormone (ACTH) levels (A09.05.067 Measurement of blood adrenocorticotropic hormone level) as a confirmatory test [8, 13, 16, 18].

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

Comment: in healthy individuals, the administration of glucocorticoids leads to the suppression of ACTH and cortisol synthesis. When low doses of the synthetic glucocorticoid dexamethasone** are administered to patients with endogenous hypercorticism syndrome of any origin, this suppression does not occur [24]. The suppression test is performed as follows: 1 mg of oral #dexamethasone** is taken between 23:00 and 24:00, and cortisol is measured in blood samples taken the next morning between 08:00 and 09:00. Higher doses (1.5 or 2 mg) do not improve the accuracy of the test [8, 25].

Suppression of morning cortisol to less than 50 nmol/L is proposed as a diagnostic criterion (sensitivity greater than 95%) [18, 24, 25].

The specificity of the suppression test at a threshold value of less than 50 nmol/L does not exceed 80%. To reduce the number of false-positive results, morning ACTH levels are determined. A suppressed ACTH level confirms the presence of hypercorticism in patients with adrenal tumors [26]. Measurement of ACTH is not a primary diagnostic method, but it can serve as a confirmatory sign of subclinical manifestations of hypercorticism in this patient group.

An adrenocortical tumor autonomously producing cortisol causes atrophy of the cortex of the contralateral adrenal gland. With prolonged hypercorticism, irreversible cortical atrophy is possible, requiring long-term, sometimes lifelong replacement therapy [27].

Diagnosis of subclinical hypercorticism is performed to assess the likelihood of postoperative acute adrenal insufficiency. Clinical manifestations of adrenal insufficiency are nonspecific for the postoperative period and often mimic other complications (bleeding, intoxication, acute myocardial infarction, etc.): loss of appetite, weakness, nausea, moderate hypotension, abdominal distension, evening hectic fever spikes. If recognized untimely and not managed, these clinical manifestations can lead to a fatal outcome [28].

• 2.3.4 It is recommended that all adult patients with a detected adrenal tumor undergo testing for blood or 24-hour urine metanephrine and normetanephrine levels to rule out PCC/PGL (A09.05.133.001 Measurement of blood metanephrines, A09.05.133.002 Measurement of blood normetanephrines) [8, 13, 29 - 31].

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5.

• 2.3.5. It is recommended that all children aged 0-18 years with a detected mass in the adrenal region undergo evaluation of tumor markers: lactate dehydrogenase (LDH), ferritin, and neuron-specific enolase (NSE) in blood plasma to rule out NBL (A09.05.039 Determination of blood lactate dehydrogenase activity, A09.05.076 Measurement of blood ferritin level, A09.05.246 Measurement of blood neuron-specific enolase level) [234, 236];

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Comment: Neuroblastoma (NB) is the most common extracranial solid malignant tumor in childhood and the most common adrenal tumor in children [234]. Given its high incidence, NB should be included in the differential diagnosis of adrenal tumors in children and adolescents [234, 236]. NB is frequently accompanied by elevated plasma levels of NSE, LDH, and ferritin, which therefore need to be assessed, along with urinary catecholamine metabolites (vanillylmandelic acid (VMA), homovanillic acid (HVA)) if possible. The diagnostic and treatment algorithm for suspected NB is detailed in the clinical guidelines for the management of this condition [236]. Pheochromocytoma/paraganglioma is extremely rare in children, with an incidence of 0.2–0.5 cases per million children, while adrenal localization (pheochromocytoma) accounts for 85% of cases [237]. In 80% of pediatric cases, pheochromocytoma is functional or secretory, presenting with arterial hypertension. Catecholamine hyperproduction forms the basis of the clinical presentation and diagnosis of pheochromocytoma via measurement of fractionated metanephrines/normetanephrines in urine (A09.28.034.001, A09.28.034.002) or blood plasma (A09.05.133.001, A09.05.133.002) [235].

• 2.3.6 It is recommended that all adult patients with an adrenal tumor who present with arterial hypertension undergo determination of the aldosterone-to-plasma renin activity ratio to exclude primary aldosteronism (A09.05.069 Blood aldosterone assay, A09.05.121 Blood renin assay) [8, 32, 33].

GCR CLOE 5Grade of Recommendation – C, Level of Evidence – 5

Comment. The diagnostic algorithm for primary aldosteronism is detailed in the clinical guidelines for the diagnosis and treatment of this condition [32, 34].

• 2.3.7 It is recommended that all adult patients with an adrenal tumor and a clinical suspicion of isolated or hypercortisolism-associated sex hormone hyperproduction undergo a comprehensive blood steroid hormone panel: dehydroepiandrosterone sulfate (A09.05.149 Blood dehydroepiandrosterone sulfate assay), 17-hydroxyprogesterone (A09.05.139 Blood 17-hydroxyprogesterone assay), androstenedione (A09.05.146 Blood androstenedione assay), total testosterone in women (A09.05.078 Blood total testosterone assay), total estradiol in men and postmenopausal women (A09.05.154 Blood total estradiol assay), 11-deoxycorticosterone (A09.05.141 Blood 11-deoxycorticosterone assay) [8].

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

Comment. Combined autonomous hyperproduction of androgens and cortisol in patients of either sex, or secretion of steroid precursors or estradiol in men, supports the diagnosis of adrenocortical carcinoma (ACC). Mild, long-standing hirsutism in the setting of hyperandrogenemia in women is more likely due to polycystic ovary syndrome or non-classic congenital adrenal hyperplasia [35].

• 2.3.8. It is recommended that all children aged 0–18 years with suspected ACC undergo blood steroid hormone testing during initial diagnosis and throughout specific treatment: dehydroepiandrosterone sulfate (A09.05.149 Blood dehydroepiandrosterone sulfate assay), 17-hydroxyprogesterone (A09.05.139 Blood 17-hydroxyprogesterone assay), androstenedione (A09.05.146 Blood androstenedione assay), testosterone (A09.05.078 Blood total testosterone assay), total estradiol (A09.05.154 Blood total estradiol assay), 11-deoxycorticosterone (A09.05.141 Blood 11-deoxycorticosterone assay) [233].

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

2.4 Instrumental Diagnostics

• 2.4.1. It is recommended that all patients with an adrenal tumor undergo quantitative densitometric evaluation using three-phase contrast-enhanced abdominal computed tomography with intravenous bolus injection (A06.30.005.003 Abdominal computed tomography with intravenous bolus contrast enhancement) in the absence of absolute contraindications to CT, to assess the malignant potential of the tumor:

• tissue component density before contrast enhancement (non-contrast);

• density in the tissue contrast phase (arterial and venous phases);

• density in the delayed contrast phase (10 minutes after contrast administration, wash-out phase) (for adult patients only). [4, 8, 13, 36, 37].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Comment. If high tumor density is detected on non-contrast CT along with contrast medium retention in the delayed phase, the malignant potential of the tumor should be assessed as high. Tumor size as a sole indicator is not a sign of malignancy. At the same time, it is known that for tumors measuring 4 cm or more, 25% are malignant, and in more than 80% of cases, ACC presents with a size of 6 cm or greater [33].

Lipid-rich tissues (exhibiting low density on CT) are characteristic of benign adrenocortical adenomas. However, about 25% of adenomas may lack low native density—the so-called lipid-poor adenomas. Nevertheless, adenomas exhibit rapid contrast washout from the tissue (greater than 50% at 10 minutes), whereas malignant adrenal tumors tend to retain the contrast medium. The absolute washout percentage calculated by the formula [(HU port. phase) - (HU delay 15m)] / [(HU port. phase) - (HU native phase)] x 100 exceeds 60% for malignant tumors, and the relative washout calculated by the formula [(HU port. phase) - (HU delay 15m)] / (HU port. phase) x 100 exceeds 40%.

Low (less than 10–15 HU) native density of the tissue component on CT or rapid density decrease following intravenous contrast enhancement are not characteristic of ACC, metastases, and PHEO/PGL.

For the differential diagnosis of NBL, PCC/PGL, and ACC, other diagnostic imaging methods are used, such as scintigraphy with [¹²³I] (A07.30.039.001. Whole-body scintigraphy with tumorotropic radiopharmaceuticals), 18F-DOPA PET-CT (A07.30.043.01 Positron emission tomography combined with computed tomography using contrast-enhanced tumorotropic radiopharmaceuticals), or ⁶⁸Ga-DOTA-TATE / ⁶⁸Ga-DOTA-NOC (A07.30.043.01 Positron emission tomography combined with computed tomography using contrast-enhanced tumorotropic radiopharmaceuticals)), alongside laboratory diagnostics.

MRI and ultrasound have high sensitivity in detecting malignant adrenal tumors, but the specificity of these methods is lower due to the lack of universally accepted, clear objective parameters.

Metastatic lesions must be ruled out or confirmed primarily in patients with a history of oncological disease. The probability of metastatic involvement is also considered in bilateral adrenal lesions, especially in the absence of signs of hormonal activity, and in the presence of CT features characteristic of metastases. Patients with such lesions should undergo necessary evaluations to rule out disseminated malignant disease (primarily lung, gastric, and colorectal cancer).

• 2.4.3. It is recommended to perform an MRI of the abdominal cavity and retroperitoneal space as part of primary diagnostics in adult patients with an adrenal tumor of uncertain malignant potential based on CT data (size up to 4 cm, with high native density greater than 10–15 HU or mosaic density) [4, 8, 9].

GCR BLEL 2Grade of Recommendations — B, Level of Evidence — 2.

Comment. MRI has high sensitivity in detecting adrenal tumors and assessing tumor spread, including involvement of adjacent structures. However, the specificity of these methods is significantly lower than that of CT due to the lack of universally accepted objective parameters [9].

• 2.4.3. It is recommended that adult patients with an adrenal tumor of uncertain malignant potential based on CT findings (size up to 4 cm, with a high native density >10–15 HU or mosaic density) undergo (A07.30.043.01 Positron emission tomography combined with computed tomography using contrast-enhanced tumorotropic radiopharmaceuticals) positron emission tomography with Fludeoxyglucose [18F] combined with computed tomography (¹⁸F-FDG-PET/CT). High metabolic activity (SUV >3.5 or 1.5 times greater than liver SUV) is a criterion that strongly suggests the malignant nature of the tumor [37–40].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

• 2.4.3.1. It is recommended that children aged 0–18 years with suspected ACC undergo [18F]-fludeoxyglucose positron emission tomography (A07.30.043.01 Positron emission tomography–computed tomography using tumor-seeking radiopharmaceuticals with contrast enhancement) co-registered with computed tomography (¹⁸F-FDG-PET/CT) and contrast-enhanced intravenous bolus chest computed tomography (A06.09.005.002) [244].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

 Comment. If a neurogenic tumor, including NBL, is suspected in children aged 0–18 years, it is advisable to perform whole-body ¹²³I scintigraphy, including single-photon emission computed tomography (SPECT) or SPECT co-registered with computed tomography (SPECT/CT) protocols (A07.30.041.001 Single-photon emission computed tomography–computed tomography using tumor-seeking radiopharmaceuticals with contrast enhancement) [239]. The diagnostic workup algorithm for NBL is detailed in the clinical practice guidelines for this disease entity.

• 2.4.3.2. It is recommended that adult patients with an adrenal tumor having high malignant potential on CT (size > 4 cm with high unenhanced attenuation, signs of invasion) undergo [18F]-fludeoxyglucose positron emission tomography or contrast-enhanced intravenous bolus chest computed tomography (A06.09.005.002) and contrast-enhanced intravenous bolus abdominal computed tomography (A06.30.005.003) to determine the extent of the neoplastic process [8].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Comment. In cases of suspected ACC or metastases in small, non-functioning, CT-dense lesions (e.g., up to 4 cm), positron emission tomography co-registered with computed tomography using tumor-seeking radiopharmaceuticals is indicated, as this modality assesses the metabolic activity of the lesion. If the maximum standardized uptake value (SUV) determined during this study is > 3.5 (or > 1.5 times the liver SUV), the probability of malignancy exceeds 80% [37–41].

• 2.4.4. It is recommended to perform whole-body bone scintigraphy (A07.03.001.001) (in adult patients only); brain CT or MRI (in adult and pediatric patients) if metastatic involvement of these sites is suspected [4, 8, 13, 244].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

• 2.4.5. Routine needle biopsy (fine-needle aspiration or core needle biopsy) of an adrenal tumor is not recommended for morphological verification. The diagnostic yield of this method is low for the differential diagnosis of adrenal tumors. Adrenal tumor biopsy may be recommended:

• in cases of reasonable suspicion of metastatic (secondary) adrenal involvement;

• in cases of suspected lymphoproliferative disease;

• in cases of inoperable metastatic disease prior to initiating systemic antineoplastic drug therapy [8, 231, 244].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Comment. In pheochromocytoma, biopsy can be potentially dangerous [8, 13, 42]. In many patients, the histological diagnosis of ACC is established only postoperatively based on immunohistochemical (IHC) examination. Therefore, surgical strategy relies on objective imaging data, making their proper prescription and interpretation crucial. In the differential diagnosis of organ-specific adrenal tumors, needle biopsy (core needle biopsy or fine-needle aspiration biopsy) has no proven advantages and is associated with low sensitivity, specificity, and a risk of complications, including needle-track seeding. Needle biopsy is indicated when primary adrenal non-Hodgkin lymphoma is suspected. This entity is extremely rare and characterized by bilateral infiltrative adrenal involvement, rapid tumor growth rate, as well as indirect signs raising suspicion of lymphoma, such as severe constitutional symptoms (B-symptoms), elevated serum LDH, etc. In other types of adrenal tumors in adults, the diagnostic value of preoperative needle biopsy is unsatisfactory (sensitivity does not exceed 65%) [43].

In children with suspected NBL, as the most common adrenal tumor, in the presence of a [¹²³I] -positive locally advanced tumor and/or a tumor with distant metastases, tumor biopsy may be performed to initiate systemic chemotherapy as early as possible [236]. The diagnostic and treatment algorithm for NBL is detailed in the clinical guidelines for this condition. In children with suspected ACC, the principles outlined above regarding needle biopsy must be followed.

2.5 Other Procedures

2.5.1. Pathological diagnosis

• 2.5.1.1. It is recommended to perform a pathological examination of surgical specimens (Table 7), including one of the validated multiparametric scoring systems for malignant potential, using immunohistochemistry (A08.22.002.002 Pathological examination of biopsy (surgical) endocrine gland tumor tissue specimens using immunohistochemical methods) in all patients with an adrenal neoplasm to evaluate the organ origin of the tumor and its malignant potential [2, 44].

GOL CLOE 5Grade of recommendation – C, level of evidence – 5. 

Table 7. Gross pathology examination protocol for adrenal tumors

Comments: The diagnosis of adrenocortical carcinoma is based on the identification of invasive growth (e.g., vascular invasion, capsular invasion, macroscopic local invasion), increased proliferative activity, and a combination of cytological and architectural features [2]. 

During gross dissection of an adrenal tumor specimen, it is possible in some cases to trace the course of the central adrenal vein when sectioning perpendicular to the long axis. A tissue block containing the vein should be sampled for microscopic examination to detect venous invasion and the presence of a tumor thrombus [45].

Particular attention should be paid to identifying lymph nodes, each of which is sampled (A08.06.002.001 Pathological examination of biopsy (surgical) lymph node specimens using immunohistochemical methods) [45]. It should be noted that during adrenalectomy, lymph nodes are rarely located directly within the periadrenal adipose tissue and may be submitted by the surgeon as separate fragments. 

In endoscopic interventions, adrenal specimens are often fragmented, which can impede morphological evaluation of tumor nodule dimensions, tumor invasion into the adrenal capsule and blood vessels, completeness of tumor resection, etc. Fragmented adrenalectomy requires clinical specialists to provide precise tumor dimensions and characteristics determined during pre-operative workup (MRI, MSCT, ultrasound) as well as intraoperatively. 

When preparing blocks for histological processing, tumors measuring up to 30 mm in diameter should be sampled entirely [45]. For larger lesions, blocks should be prepared at a rate of at least 1 additional block for every additional 10 mm of tumor.

The orientation of tissue blocks must account for the necessity of subsequent microscopic evaluation not only of the tumor parenchyma itself (necrosis, cysts, hemorrhage), but also of the tumor's relationship to major vessels, surrounding adrenal parenchyma, its capsule, and adjacent tissues and organs [45].

Histological features are typically evaluated using one of several accepted multi-factor algorithms/scoring systems [2, 44]. These include the Weiss system, the Lin-Weiss-Bisceglia system, the reticulin algorithm, and the Helsinki scoring system [6, 7, 46, 47]. At this stage, none of the systems has been recognized as sensitive or specific for all clinical situations.

The Weiss system for scoring malignant potential in tumors, developed in 1984 (Weiss score) [46] and modified in 1989 [48], continues to be used for classifying the classic variant of ACC in adults [49, 50] (Table 8).

Each of the 9 criteria is scored as 1 point. A total score of 3 or higher on the Weiss scale confirms high malignant potential of the tumor and establishes the diagnosis of ACC.

Given that oncocytic neoplasms consist of cells with eosinophilic cytoplasm, high nuclear pleomorphism, and almost always a diffuse growth pattern, the Lin-Weiss-Bisceglia system is applied when diagnosing the oncocytic variant of ACC (Table 9) [6].

The oncocytic variant of ACC is diagnosed in the presence of at least one "major criterion"; oncocytic ACA with borderline malignant potential is diagnosed in the presence of at least one "minor criterion"; if all major and minor criteria are absent, the oncocytic tumor is considered benign. It should be taken into account that oncocytic cells must comprise more than 90% of the tumor area for it to be considered a purely ("pure") adrenocortical oncocytic neoplasm. Otherwise, the criteria used for diagnosing the classic variant of ACC must be applied.

The myxoid variant of ACC is characterized by the presence of extracellular mucin comprising more than 20% of the tumor area [2]. Myxoid tumors are also distinguished by the presence of small to medium-sized monomorphic cells with mild to moderate nuclear atypia and a small amount of mildly eosinophilic cytoplasm [51].

The sarcomatoid variant of ACC is characterized by the loss of cortical differentiation or may be mosaic, with areas of typical differentiated tissue [51].

When diagnosing classic, oncocytic, and myxoid adrenocortical neoplasms, the reticulin algorithm [7] and the Helsinki system [47] can also be used. In the former case, the malignant nature of the neoplasm is confirmed when reticulin fiber disorganization, detected by silver impregnation (histochemical study), is combined with one of the following parameters: (1) mitotic rate > 5 per 10 mm2 (50 high-power fields at x400 microscope magnification), (2) presence of tumor necrosis, or (3) vascular invasion (angioinvasion). The Helsinki system is based on the parameters of the Weiss system, utilizes stepwise regression analysis, and proposes the following formula: 3 × (mitotic activity >5/50 HPF) + 5 × (presence of tumor necrosis) + Ki-67 proliferative activity index. A sum of parameters greater than 8.5 is associated with high metastatic potential and an unfavorable prognosis (corresponding to ACC).

Most standard evaluation criteria systems were developed using material exclusively from adult patients. Their use to determine the malignant potential of pediatric adrenocortical tumors leads to overdiagnosis of ACC [52]. To determine the malignant potential of adrenocortical tumors in children, the Wieneke/Armed Forces Institute of Pathology (AFIP) criteria are used (Table 10) [53].

• 2.5.1.2. It is recommended to determine the proliferative activity index via Ki-67 expression using immunohistochemistry and mitotic activity in patients with appropriate histological features and suspected ACC in order to confirm the malignant potential of the tumor and perform prognostic stratification [2, 44].

GOL CLOE 5Grade of recommendation – C, level of evidence – 5. 

Comments: ACC is a proliferation-driven malignant tumor, as confirmed by numerous genomic studies. Therefore, assessing proliferative activity by counting mitoses and determining the Ki-67 labeling index via immunohistochemistry is an important stage of diagnosis and prognosis determination [2, 44, 54, 55].

High mitotic activity, defined as >5 mitoses per 10 mm2 (50 high-power fields at x400 microscope magnification), is part of all diagnostic algorithms. The number of mitoses is counted in areas with the highest density, as proliferative heterogeneity may be observed in ACC. Immunohistochemical staining with phosphohistone H3 can facilitate the identification of mitotic figures in tumors with low mitotic activity [56]. Atypical mitotic figures, which indicate abnormal chromosome content (aneuploidy), are also an important criterion. The classification of adrenocortical carcinomas into low-grade (≤20 mitoses per 10 mm2) and high-grade (>20 mitoses per 10 mm2) has prognostic significance.

According to the results of numerous studies, most adrenocortical carcinomas are characterized by a Ki-67 labeling index of more than 5% [2, 54]. Ki-67 is also a prognostically significant marker [54-57] that necessitates the administration of adjuvant mitotane** therapy [58].

• 2.5.1.3. It is recommended to perform a pathological examination of biopsy (surgical) tissue material from the removed neoplasm of an endocrine gland using immunohistochemical methods in all patients with an adrenal tumor, except for obvious benign adenomas, for the differential diagnosis of adrenocortical tumors versus tumors of another histogenesis, confirmation of tumor malignant potential, and prognostic stratification [2, 44, 58].

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5.

Comments: Adrenocortical neoplasms express markers specific to steroid-producing cells: SF-1 and inhibin-alpha, as well as markers typical of other tumor types: Melan-A, calretinin, synaptophysin [58].

SF-1 has the highest sensitivity and specificity [58]; other markers exhibit a heterogeneous reactivity pattern, are expressed only in a subset of cases, and can be used together in a marker panel. It should be noted that synaptophysin and inhibin-alpha may be expressed in pheochromocytomas. Expression of epithelial markers (cytokeratin, EMA, CEA) is typically absent. Immunohistochemical staining with antimitochondrial antibodies—specifically the presence of strong diffuse staining of the eosinophilic granular cytoplasm—helps identify the oncocytic differentiation of the tumor.

High-grade adrenocortical carcinomas or tumors with invasive growth often present no diagnostic difficulties; however, the differential diagnosis of low-grade tumors confined to the adrenal gland and tumors with adenoma-like areas may require the use of additional biomarkers [55, 58, 59].

Molecular studies are not used as a standard of clinical practice [2].

• 2.5.1.4. It is recommended to perform a pathological examination of biopsy (surgical) tissue material from the removed neoplasm using immunohistochemical methods, including at least the following data: tumor invasion into the capsule, surrounding tissues, and blood vessels; completeness of resection and status of resection margins; lymph node status; score on one of the accepted scoring systems for tumor malignant potential; immunohistochemical staining with antibodies to SF-1, chromogranin A, and Ki-67; and evaluation of the proliferative activity index and mitotic activity (A08.22.002.002 Pathological examination of biopsy (surgical) tissue material of removed endocrine gland neoplasms using immunohistochemical methods) in all patients with an adrenal neoplasm in order to establish the diagnosis of ACC and determine patient prognosis [3].

LoR CGoE 5Level of Recommendation – C, Level of Evidence – 5.

Comments: Establishing a diagnosis of ACC requires morphological and immunohistochemical confirmation of adrenocortical histogenesis and the malignant potential of the tumor, which is usually based on multiparametric algorithms and the results of pathomorphological examination of biopsy (surgical) material from tissues of the removed endocrine gland neoplasm using immunohistochemical methods [2]. In addition to differential diagnosis in ACC pathology, the issue of determining prognostic parameters that can be used to select the most effective therapeutic strategy arises. Currently, there is no single universally accepted system for prognostic stratification of ACC. Advanced tumor stage, identification of tumor growth elements at the resection margins, vascular invasion, high-grade tumors, high Ki-67 proliferation index values, and certain molecular characteristics are considered crucial prognostic factors [2].

It is hypothesized that the prognostic variability in ACC is due to its pronounced morphological, proliferative, and molecular heterogeneity [60].

According to recent data, a Ki-67 value greater than 15% is a reliable predictor of adverse outcomes in patients with ACC [55, 61].

Immunohistochemical markers p53 and beta-catenin can be used for risk stratification in addition to the Ki-67 index and mitotic count [58, 59]. Molecular studies have emphasized the prognostic value of these markers, as the majority of adrenocortical carcinomas belonging to unfavorable molecular clusters typically demonstrate nuclear beta-catenin expression and/or aberrant p53 staining (overexpression or global loss).

The use of the MMR immunohistochemical marker is being considered for screening ACC cases associated with Lynch syndrome [58, 59, 62]. Several potential predictors of response to mitotane** (e.g., RRM1 and CYP2W1) have been proposed [63, 64], but none of them have yet been validated for use in clinical practice.

2.5.2 Genetic testing

• 2.5.2.1. It is recommended that all adult patients with a verified diagnosis of ACC and a positive family history of various malignancies undergo standard genetic counseling (Medical geneticist consultation B01.006.001), including the study of personal history, medical history, and family history, to identify or rule out a hereditary syndrome associated with ACC [2, 8, 44, 212].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Comment. Timely detection of a germline mutation and, consequently, diagnosis of a hereditary syndrome including ACC make it possible to predict the development of other associated diseases in the patient, as well as to purposefully screen their blood relatives.

ACC patients may be prescribed molecular genetic screening to detect Li-Fraumeni and Lynch syndromes, which occur in 3–5% of ACC cases and have well-developed clinical guidelines.

The prevalence of de novo germline mutations in the TP53 gene reaches 20–25% among all adult patients with aberrations in this gene; therefore, such patients will not have a family history of ACC or other tumors. In this regard, molecular genetic testing for mutations in the TP53 gene in blood is performed (A27.05.048).

Lynch syndrome is present in 3–5% of patients with ACC. Its diagnosis can be carried out by direct molecular genetic testing of the MSH2, MLH1, PMS2, MSH6, and EPCAM genes (A27.05.048 Molecular genetic testing for mutations in the MLH1, MSH2, MSH6, PMS2 genes in blood) or by immunohistochemical testing with antibodies against MSH2, MLH1, PMS2, MSH6 and assessment of microsatellite instability (A08.30.040 Determination of mutations in the MLH1, MSH2, MSH6, PMS2 genes by immunohistochemical method; ).

• 2.5.2.2. It is recommended that all children aged 0–18 years with a verified diagnosis of ACC, regardless of family history, undergo standard genetic counseling and molecular genetic analysis to detect pathogenic germline mutations in the TP53 gene (A27.05.048 Molecular genetic testing for mutations in the TP53 gene in blood), since 50–90% of pediatric ACC cases occur within the framework of Li-Fraumeni syndrome [44, 47, 65].

GCR CLOE 5Grade of Recommendation – C, Level of Evidence – 5

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

3.1 Surgical Treatment

• 3.1 It is recommended to perform surgical treatment of patients with ACC in a specialized center that includes the following adult or pediatric specialists: surgeon, oncologist, pathologist, radiologist, radiation oncologist [8, 231, 244].

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5.

Comment. A surgeon performing surgery for ACC in adult patients must have experience of at least 15 adrenal procedures per year. The institution where surgical treatment of an ACC patient is performed must have experience in liver surgery, pancreatic surgery, vascular surgery, or have the ability to include relevant specialists in the surgical team. The surgeon's experience and the volume of care provided by the hospital for this disease have an impact on treatment outcomes in such oncological diseases as liver, esophageal, pancreatic cancer, etc. In adrenocortical carcinoma, the rate of R0 resection is higher among surgeons with extensive experience in adrenal cancer surgery [8, 207].

• 3.1.1 It is recommended that all adult patients with stage I–III ACC according to ENSAT and children aged 0–18 years with stage I–IV ACC according to COG undergo surgical treatment if R0 resection is feasible in a specialized center. The scope of surgery for ACC is total adrenalectomy within healthy tissues, without violating the integrity of the tumor capsule. Performing operations with an attempt to preserve adrenal tissue is unacceptable. All patients must undergo surgical treatment as soon as possible after complete diagnosis and tumor staging [8-10, 231, 244].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Comment. The only possible option for complete cure in ACC at present is radical surgery (A16.22.004.001

Unilateral open adrenalectomy, A16.28.064 Extended adrenalectomy, or adrenalectomy with resection of adjacent organs) (see also Appendix A3 Table 16) [66].

• 3.1.2 It is recommended that all patients with a clinical or morphologically verified diagnosis of ACC undergo surgical treatment adhering to the following principles:

• performing total adrenalectomy within healthy tissues (A16.22.004.001 Unilateral open adrenalectomy, A16.22.015 Unilateral endoscopic adrenalectomy);

• preserving the integrity of the tumor capsule;

• surgical approach for ACC – laparotomy (various types of laparotomy or thoracolaparotomy);

• performing adrenalectomy with resection of adjacent organs in case of tumor invasion into surrounding organs and structures (A16.28.064 Extended adrenalectomy, or adrenalectomy with resection of adjacent organs);

• performing direct thrombectomy from major veins and heart chambers in tumor thrombosis [67];

• performing extended retroperitoneal lymphadenectomy in the aortocaval zone and renal hilum zone [8-10, 68-72].

• Pediatric patients aged 0–18 years with suspected stage I ACC according to COG are recommended to undergo regional lymph node biopsy; for stage II–IV according to COG, regional lymphadenectomy [231, 244];

• Pediatric patients aged 0–18 years with initially unresectable tumor or with residual tumor after initial surgery may be considered candidates for surgery after 2–4 courses of chemotherapy [231, 244];

• For pediatric patients aged 0–18 years with stage IV ACC according to COG, the diagnosis can be confirmed based on a biopsy of metastatic lesions or an open biopsy of the primary tumor if radical tumor removal is impossible [231, 244];

Level of Recommendation CLevel of Evidence 4 Level of recommendation – C, level of evidence – 4.

Comment. The features of tumor growth in ACC and surgical interventions are as follows:

• tumor invasion into surrounding organs and structures: paranephric adipose tissue, kidney, liver, diaphragm, spleen, pancreas, large vessels (inferior vena cava, renal vein, portal vein). Local tumor extent should be assessed preoperatively to plan the extent of surgery. If necessary, liver resections, pancreatectomy, and splenectomy are performed. Nephrectomy is indicated only in case of invasion of the renal hilum structures. Paranephric adipose tissue must be removed up to the level of the renal hilum during adrenalectomy for ACC.

• invasion of the inferior vena cava / renal vein, which according to literature data is observed in 5-7% to 30% of ACC cases and requires vascular resection to varying extents (longitudinal or circular) with or without its subsequent reconstruction.

• tumor thrombosis of the inferior vena cava or renal vein (in left-sided lesions), the proximal border of which can reach the right heart chambers. In patients without distant metastases, direct thrombectomy from the main veins is indicated; the feasibility of thrombectomy should also be considered in patients with distant metastases due to the lack of effective conservative treatment methods and the high risk of fatal complications of the disease, primarily PE and tumor embolism of the pulmonary artery branches. Direct thrombectomy from the great veins (A16.12.035) or the atrium is performed both with and without cardiopulmonary bypass, depending on the level of thrombosis. Measures must be taken to prevent pulmonary embolism by tumor masses. The necessity of reconstructing the inferior vena cava with a vascular prosthesis after thrombectomy, which is often accompanied by its resection (vessel resection), including circular resection, is determined based on the degree of blood flow impairment and the development of collateral circulation, based on preoperative evaluation;

• Breach of the tumor capsule significantly increases the risk of local recurrence or dissemination of ACC. Precision of manipulation during tumor removal is one of the key tasks for the surgeon, as violation of the capsule integrity leads to local tumor dissemination even after a formally "R0" resection [8, 73, 74].

• In ACC, removal of regional lymph nodes is indicated in case of their metastatic involvement or suspected involvement according to clinical and instrumental data [43, 75]. The benefits of lymphadenectomy in ACC were demonstrated in a study by J. Reibetanz et al. [76], which proved on a sufficiently large sample of patients a statistically significant improvement in disease-free survival and ACC-associated mortality in patients with R0 resection. As an additional argument, the fact is cited that in the lymphadenectomy group, the average tumor size was significantly larger and combined resections were performed more frequently, yet despite this, better results were achieved. The study by Gaujoux S. et al. [69] indicates that lymph node involvement in the tumor process in ACC patients, without stratification by stage, is 20%, which, according to the authors, is an indication for broader performance of lymphadenectomy. The boundaries of prophylactic lymphadenectomy are not precisely defined; according to available data, the renal hilum lymph nodes, right paracaval and left para-aortic lymph nodes should be removed.

• In the absence of overt signs of adrenal tumor invasion into the renal parenchyma or structures of the renal hilum, there is no need for "prophylactic" nephrectomy (nephroadrenalectomy) to increase the radicality of resection. Resection of the renal adipose capsule down to the level of its hilum is sufficient.

• 3.1.3. Adult patients with a clinical diagnosis of ACC may be recommended to undergo endoscopic (laparoscopic, retroperitoneoscopic) adrenalectomy with the mandatory combination of all the following factors: tumor size less than 6 cm, ENSAT stage I and II disease (no signs of tumor invasion into surrounding structures), sufficient experience of the surgeon and medical institution in treating ACC patients and video-endoscopic interventions. With greater disease extent, endoscopic surgery is contraindicated, as the possibility of performing lymphadenectomy and adequate inspection and resection of adjacent organs is limited, and the radicality of the intervention is questionable [8, 13, 77, 78]. Pediatric patients aged 0-18 years with suspected ACC should preferably undergo open surgery, as endoscopic procedures are associated with a high risk of tumor capsule rupture and peritoneal carcinomatosis [230, 231, 238, 244].

Level of Recommendation CLevel of Evidence 4 Level of recommendation – C, level of evidence – 4.

Commentary. Due to the widespread adoption of endoscopic procedures, there is an increasing number of patients with adrenocortical carcinoma (ACC) who undergo laparoscopic surgery, including in institutions that do not specialize in ACC treatment. The main issue with endoscopic adrenalectomy is the high incidence of postoperative peritoneal tumor dissemination due to intraoperative tumor capsule violation. Most experts agree that when tumor size exceeds 5 cm and/or malignancy is suspected based on preoperative evaluation, the likelihood of tumor dissemination following capsular violation is significantly higher than with open surgery [8, 43, 68, 70, 73, 77].

The specialized nature of the institution and the experience of the operating surgeon are indisputable points in this recommendation.

• 3.1.4. It is recommended that patients with resectable forms of local recurrence or with solitary/single metastases occurring after surgery undergo repeat R0 resection as the most effective and preferred treatment option, providing the longest disease-free interval or survival (see also Appendix B, Fig. 1). A disease-free interval of more than 1 year after the initial surgery is a favorable prognostic factor in the surgical treatment of ACC recurrences or metastases. Patients with early recurrence (less than 6 months) following R0 resection are generally not candidates for reoperation. The feasibility of repeat surgery for recurrences or metastases is determined individually by a multidisciplinary team, taking into account the extent of the disease, the possibility of achieving complete cytoreduction, tumor biological features, and the availability of medical treatment [70, 80, 81, 82]. Laparoscopic surgery is also contraindicated in recurrent ACC. Surgical treatment for metastatic ACC rarely leads to a cure, but may be associated with increased survival. In metastatic ACC, selecting patients for surgical treatment requires considering prognostic factors: the number of metastatic sites and a high mitotic index [8].

LoE CGoE 4Level of Evidence – C, Grade of Recommendation – 4.

Commentary. The 5-year progression rate of ACC following surgical treatment in stage III disease ranges from 40% to 80–85%. The only method ensuring long-term survival in cases of recurrence or metastasis remains repeat "radical," i.e., R0 resection. Its feasibility should be considered for every patient, taking into account the extent of the disease, the specifics of prior surgical treatment, and the biological features of the tumor, such as grade and growth rate.

The feasibility of surgical treatment for ACC recurrences and metastases was evaluated in a classic study from the Memorial Sloan-Kettering Cancer Center, USA [80]. Repeat resections were performed in 47 patients with local recurrence or distant ACC metastases, of whom four underwent surgery 5 and 6 times, and one patient underwent 7 procedures. In 62 cases, the surgery was radical, and in 21, it was palliative. Among the radical operations, 43 (69%) were performed for distant metastasis, 14 (23%) for local recurrence, and 5 (8%) for both recurrence and metastasis. The most frequent distant metastasis sites were the liver (28), lungs (17), and peritoneum (8). The median survival of patients who underwent repeat radical resection was 74 months, with a 5-year survival rate of 57%; for patients after palliative repeat resection, it was 16 months and 0%, respectively, with the differences being statistically significant. This study was the first to perform a multivariate survival analysis in such a patient group, demonstrating that disease stage and the radicality of the first operation are independent prognostic factors.

The German ACC Study Group compared the treatment outcomes of 101 patients who underwent repeat surgery and 99 patients who received medical therapy for ACC recurrence. Multivariate analysis showed that two factors had significant prognostic value for both overall survival and progression-free survival: a time to first recurrence of more than 12 months and the radicality of the initial surgery. The median progression-free survival (PFS) in patients with two favorable factors was 24 months, and overall survival was 60 months. The median PFS in patients undergoing repeat R0 resection was 19 months, after R2 resection – 6 months, after palliative resections (debulking) – 5 months, and in non-operated patients – 4 months. The median overall survival in patients undergoing repeat R0 resection was 88 months, after R2 resection – 30 months, after palliative resections (debulking) – 22 months, and in non-operated patients – 16 months [69].

The University of Turin [81] retrospectively analyzed comparative treatment outcomes for ACC recurrence: Group A consisted of 22 patients who underwent surgery (17 underwent recurrence resection, 5 underwent distant metastasis resection; median Weiss score 6, mean time to progression 22 months, mean Ki-67 18%). Group B consisted of 17 patients who received chemotherapy with #doxorubicin**, #etoposide**, #cisplatin**, and #mitotane** (median Weiss score 7, mean time to progression 9.5 months, mean Ki-67 28%). In Group A, 5 patients had no recurrence, 17 experienced recurrence at a mean of 23 months, and 8 underwent repeat surgery; the mean overall survival was 86 months. In Group B, 88% of patients died from disease progression during follow-up; the mean overall survival was 33.5 months, which was significantly lower.

Repeat surgery leads to increased life expectancy if performed with an R0 resection margin.

Individualization of indications for repeat surgery remains an unresolved issue and requires further studies, taking into account the biological characteristics of the tumor [82]. In cases of ACC, the hormonal activity of the tumor can have a major impact on treatment strategy. It should also be borne in mind that repeat surgeries lead to symptom reduction in many patients [82].

• 3.1.5. Routine palliative R2 adrenalectomy (A16.22.004.001 Unilateral open adrenalectomy, A16.28.064 Extended adrenalectomy, or adrenalectomy with resection of adjacent organs) (Table 18, Appendix G5) is not recommended for metastatic ACC. In hormonally active tumors accompanied by severe somatic manifestations of hypercortisolism, a strategy aimed at maximal cytoreduction may be justified [8,9].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Progression-free survival is similar in patients with metastatic ACC who did not undergo surgical treatment and those who underwent palliative (R2) surgery. However, palliative adrenalectomy may be considered as an option in patients with bulky, symptomatic, or hormonally active tumors.

• 3.1.6.All patients with ACC and hypercortisolism (manifest or subclinical) are recommended to receive replacement therapy for adrenal insufficiency in the postoperative period [13, 18, 19].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Commentary. Manifest hypercortisolism and functionally autonomous cortisol overproduction generally lead to the development of adrenal insufficiency following adrenalectomy for the tumor. Therefore, all patients with ACC and verified/highly probable hypercortisolism are indicated for intraoperative and postoperative replacement therapy for adrenal insufficiency in accordance with clinical guidelines [9].

3.2 Medical Treatment.

• 3.2.1 It is not recommended to administer adjuvant therapy to patients with adrenocortical tumors of uncertain malignant potential [8, 83-86].

GCR CLOE 5Grade of Recommendation – C, Level of Evidence – 5

• 3.2.2. It is not recommended to administer adjuvant mitotane** therapy to adult patients with a low risk of recurrence (T1-2N0 and Ki-67 ≤10%) following R0 resection, according to the results of the randomized ADIUVO trial, nor to children aged 0–18 years with stage I–II disease according to the COG protocol ARAR0332 [87, 231, 240, 244].

For adult patients, the Grade of Recommendation is B, and the Level of Evidence is 2.

For children, the level of recommendation validity is C, and the level of evidence reliability is 4.

Comment. The only prospective randomized trial, ADIUVO, investigated the efficacy of adjuvant mitotane** therapy in a subgroup of patients with a low risk of disease recurrence (Ki-67 ≤10%) after R0 resection for stage I–III adrenocortical carcinoma (ACC) [87]. The study included 91 patients randomized 1:1 to observation versus mitotane**. No significant differences in recurrence-free and overall survival were observed. It should be noted that only 13% of patients (N=6) with stage III in the mitotane** group and 11% (N=5) in the observation group were included in the study, which precludes making a definitive conclusion about the inefficacy of mitotane** administration in the subgroup of patients with stage III and Ki-67 ≤10%.

According to the prospective interventional study ARAR0332 the outcomes of pediatric patients with stage I–IV ACC according to COG were evaluated. The analysis demonstrated high 5-year overall survival (OS) rates in patients with stage I COG (95.2%) and stage II COG (78.8%) [231]. Nevertheless, the 5-year relapse-free survival (RFS) in patients with stage II is only 53.3%. The feasibility of prescribing mitotane** to children with stage II COG has not been sufficiently studied, and this patient subgroup requires an individual case discussion with specialists from federal centers [231, 240, 244].

• 3.2.3 It is recommended that adult patients be prescribed adjuvant mitotane** therapy when the Ki-67 level is >10% for a duration of 2–5 years [8, 87, 91–94, 213] (Table 12).

GIB CLoE 2Level of recommendation validity – C, level of evidence reliability – 2.

Comment. In February 2018, mitotane** was registered in Russia for the first time and approved for medical use. The drug is included in the list of vital and essential drugs (VED) [88].

Mitotane** therapy should be initiated as soon as possible after surgical treatment. Blood drug levels require ongoing laboratory monitoring, and provided it is tolerated, the recommended therapeutic concentration range is 14 to 20 µg/mL. The dose of mitotane** required to achieve and/or maintain its blood concentration within the therapeutic range is individual and typically ranges from 4 to 8 g/day. In the absence of ACC recurrence, adjuvant treatment is administered for 2 to 5 years (see also Appendix A3). There are no prospective studies comparing different durations of adjuvant mitotane** therapy. A small retrospective analysis including 154 patients who received adjuvant mitotane** therapy after R0 resection for ACC showed no significant differences in recurrence-free and overall survival when adjuvant mitotane** therapy was continued for more than 2 years [89]. However, it should be noted that the majority of patients included in this analysis belonged to the low recurrence risk group (T1-2N0 – 80%, Ki-67 ≤10% – 60%), and these data may not be reproducible in the high recurrence risk patient group.

A small Italian retrospective study involving 152 patients after R0 resection for stage I–III ACC, of whom 100 received adjuvant mitotane** therapy, demonstrated a significant increase in recurrence-free survival with mitotane** administration [90]. A key predictor of recurrence and death was a Ki-67 level >10%. According to multivariate analysis, mitotane** administration significantly improved recurrence-free and overall survival in the subgroup of patients with Ki-67 >10%, as well as overall survival in the stage III subgroup.

A multicenter study and meta-analysis of the German-Italian ACC patient registry analyzed the treatment outcomes of 177 patients and demonstrated an extended recurrence-free period with adjuvant therapy – 42 months versus 10 and 25 months in the two control groups, and a reduction in recurrence rates to 49% versus 73% and 91%, respectively [91].

Along with its antitumor effect, mitotane** possesses adrenolytic

effect, damaging intracellular enzymes involved in steroid synthesis, thereby reducing the intensity of adrenal steroidogenesis [92,93]. Due to the blockade of steroidogenesis, patients receiving mitotane** require glucocorticoid replacement therapy. The decrease in blood glucocorticoid levels is associated not only with the adrenolytic activity of mitotane**, but also with its induction of hepatic steroid clearance [94], which necessitates at least a twofold increase in the standard replacement dose for adrenal insufficiency. An inadequate replacement dose impairs the tolerability of mitotane** and exacerbates its adverse effects.

• 3.2.4 It is recommended for adult patients to consider adjuvant mitotane therapy for a duration of 2 years in cases of intermediate risk of recurrence/progression (T3-4 with a Ki-67 level ≤ 10%) [8, 87, 90, 214] (Table 12).

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Comment. A small Italian retrospective study that included 152 patients following R0 resection for stage I–III ACC, of whom 100 received adjuvant therapy with mitotane**, showed a significant increase in recurrence-free survival with mitotane** administration. A Ki-67 index >10% was the most important predictor of recurrence and death [90]. According to multivariate analysis, mitotane** significantly improved recurrence-free and overall survival in the subgroup of patients with Ki-67 >10%, as well as overall survival in the stage III subgroup.

The only prospective randomized trial, ADIUVO, evaluated the efficacy of adjuvant therapy with mitotane** in a subgroup of patients at low risk of recurrence (Ki-67 ≤10%) after R0 resection for stage I–III ACC [87]. A total of 91 patients were randomized 1:1 into two groups: surveillance and mitotane**. No significant differences in recurrence-free and overall survival were observed. Notably, only 13% of patients (N=6) in the mitotane** group and 11% (N=5) in the surveillance group had stage III disease, precluding definitive conclusions regarding the inefficacy of mitotane** in the subgroup of patients with stage III disease and Ki-67 ≤10%.

• 3.2.5 It is recommended that all patients indicated for therapy with #mitotane** start treatment with low doses with gradual escalation under monitoring of the patient's condition, tolerability, and plasma mitotane** concentration (see also Appendix A3) [8, 87, 95-100, 215].

LoR CLoE 5Level of recommendation credibility – C, level of evidence – 5.

Comment. Various dosing regimens exist for mitotane** therapy; none has demonstrated proven superiority to date. The most widely used regimen involves starting therapy at a dose of 2 g/day with gradual dose escalation by 0.5–1 g/day every 3–7 days up to a total dose of 4 g/day [87]. According to results of the ADIUVO study, a starting dose of #mitotane** of 1 g per day with gradual titration by 0.5–1 g/day every 3–7 days to a total dose of 4 g/day achieves therapeutic levels in 56% of patients and can be used in routine clinical practice [87].

International experts recommend that children and adolescents with ACC start #mitotane** therapy at a dose of 50 mg/kg/day or 1500 mg/m2/day with gradual dose escalation by 20 mg/kg/day or by 500 mg/m2 every 1–2 weeks up to a total dose of 4000 mg/m2/day under monitoring of serum mitotane** concentration (target range 14–20 µg/mL) [240].

Dose adjustment of mitotane** is guided by its blood concentration (measurement is required 4 weeks after reaching a dose of 4 or 6 g/day; during a high-dose regimen, monitoring of mitotane** levels (A09.05.035 Therapeutic drug monitoring in blood) should be performed every 2–3 weeks) and tolerability [95-97]. Mitotane** has a narrow therapeutic window, limited on the one hand by the need to achieve a target therapeutic concentration >14 mg/L as quickly as possible, and on the other hand by drug tolerability. The intensity and severity of adverse clinical manifestations increase with cumulative effects and resolve upon drug discontinuation (Table 11) [98].

Achieving the target blood concentration of mitotane** does not always depend on the administered dose, but relies heavily on dose accumulation related to the prolonged half-life of the drug, underscoring the need for careful therapeutic drug monitoring of mitotane** levels and ongoing dose titration [99, 100]. In a comparative pharmacokinetic study, a regimen with high starting doses allowed a higher proportion of patients to achieve therapeutic levels above 14 µg/mL. However, these results were not statistically significant due to inadequate study power. Beyond these two regimens, numerous other variations exist; the choice depends on the physician's experience, the clinical course of ACC, and the patient's performance status. For recommendations on the use of mitotane** as adjuvant therapy, see also Appendix A3.

Mitotane** is a lipophilic drug and is believed to have improved intestinal absorption when co-administered with fat-containing foods, such as milk or chocolate. In cases of limited gastrointestinal tolerance, symptomatic treatment for nausea/vomiting and/or diarrhea should be offered.

All patients receiving mitotane** therapy must be evaluated for drug interactions (particularly due to mitotane**-mediated induction of cytochrome CYP3A4). All concomitant medications should be checked for CYP3A4 metabolism and switched to alternatives if possible. The molecular mechanisms of mitotane** action remain insufficiently understood. However, mitotane** is known to upregulate hepatic CYP3A4 monooxygenase, which metabolizes numerous therapeutic agents. Therefore, all drugs administered concurrently with mitotane** and/or while it remains detectable in the bloodstream must be checked for CYP3A4 metabolism and replaced with alternatives whenever possible [85].

The prescription of mitotane** requires hormone replacement therapy with hydrocortisone** or prednisolone** in most patients; it is typically initiated from the first day of treatment and maintained after its completion [101]. In a small observational study, hypothalamic-pituitary-adrenal (HPA) axis function fully recovered after mitotane** withdrawal in 78.3% (18/23) of patients, 13% (3/23) could not be weaned off glucocorticoids (ATC H02AB Glucocorticoids) despite normal hormone test values, and 8.7% (2/23) had no recovery of HPA axis function. The median time to HPA axis recovery was 2.5 years, an important consideration when completing adjuvant therapy with mitotane**.

Table 11. Mitotane** adverse effects

Frequency definitions of adverse effects: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the currently available data).

• 3.2.6 It is recommended to consider platinum-based combination chemotherapy (EDP, EP, or EC) combined with #mitotane** in the adjuvant setting in adult patients with a very high risk of recurrence/progression (Ki-67 ≥20% and T3-4, see also Appendix B, Fig. 1) and in pediatric patients (0–18 years) with COG stage III–IV disease [85, 102-104, 231, 244] (Table 12).

LoE CGoE 4Level of Evidence – C, Grade of Recommendation – 4.

Comment. The use of adjuvant chemotherapy in adrenocortical carcinoma remains a subject of debate and is not recommended for routine clinical practice. Prospective trials evaluating the efficacy of adjuvant therapy after radical resection of stage I–III ACC have not been conducted. Nevertheless, most experts from the European Society of Endocrinology and ENSAT endorse an individualized approach to polychemotherapy in the adjuvant setting for patients at very high risk of recurrence/progression (T3-4 and Ki-67 ≥20%) [103].

A small retrospective case-control study investigated the efficacy of 2–8 cycles of platinum-based chemotherapy following surgical resection for stage I–IV ACC [104]. The study included 62 patients, 64.5% of whom had stage III–IV disease; R1 and Rx resections were performed in 6.5% and 13% of patients, respectively, and 75% had a Ki-67 index ≥20%. The majority of patients (77.4%) received chemotherapy with #etoposide** + #cisplatin**/#carboplatin**. In this cohort of patients with a very high risk of recurrence, adjuvant chemotherapy was associated with a significant improvement in median recurrence-free survival from 7.3 to 17.7 months (p=0.021) and overall survival (p=0.01).

Thus, in patients with a very high risk of recurrence (Ki-67 ≥ 20% and stage III–IV), the addition of combination chemotherapy including #etoposide** and #cisplatin** / #carboplatin** for 4–6 cycles to mitotane** should be considered on an individual basis. [104].

All patients aged 0–18 years with morphologically verified stage III and IV adrenocortical carcinoma (ACC) according to COG are indicated to receive adjuvant chemotherapy according to the #etoposide** + #cisplatin** + #doxorubicin** regimen with the addition of #mitotane** to improve survival rates [231, 240]. The number of chemotherapy cycles depends on the patient's individual tolerance and can range from 6 to 8 cycles. According to the ARAR0332 protocol, the duration of #mitotane** administration is 8 months [231, 240]. However, the current duration of #mitotane** therapy in the pediatric ACC population remains controversial. One study demonstrated that a #mitotane** therapy duration of less than 9 months and low mitotane levels (below 14 mg/L) had a statistically significant negative impact on survival rates [241]. Considering that achieving therapeutic mitotane concentrations can take several months, authors of international studies have proposed increasing the duration of #mitotane** administration in children and adolescents with ACC from 2 to 5 years [240]. Thus, the duration of #mitotane** therapy in patients aged 0 to 18 years with ACC may be discussed on a case-by-case basis with specialists from federal centers.

• 3.2.7 It is recommended that adult patients consider all cases with an R2 resection as advanced ACC (see sections 5.3.1 and Appendix B, Fig. 2) [8].

CRALEL 5Level of recommendation evidence – C, level of data reliability – 5.

Table 12. Adjuvant therapy regimens for ACC

Systemic therapy for metastatic and unresectable ACC

• 3.2.8 It is recommended that adult patients with low tumor burden, slow disease progression, and a low Ki-67 index (< 10%) be considered for mitotane** monotherapy in combination with potential cytoreductive interventions or other local treatment modalities (e.g., radiological or interventional) as first-line treatment (see also Appendix B, Fig. 2) [85, 102, 105–108].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Comment. A prospective study involving 127 patients evaluated the efficacy of single-agent mitotane** in the treatment of metastatic ACC [107]. The objective response rate (ORR) was 20.5%, and disease stabilization for more than 6 months was observed in 18.1% of patients. Median progression-free survival and overall survival were 4.1 and 18.5 months, respectively. Achieving a therapeutic concentration was associated with a statistically significant improvement in the objective response rate (31.9% vs. 11.1%) and overall survival. The group of patients with a low Ki-67 index ≤ 10% showed the highest rate of long-term disease control (54% vs. 24% for Ki-67 > 20%). According to a multiparametric analysis, fewer than 10 metastatic lesions were significantly associated with a reduced risk of disease progression and death. The data above indicate that in patients with an indolent disease course, a low Ki-67 index, and a low tumor burden, mitotane** monotherapy can be prescribed as first-line treatment. When analyzing the efficacy of mitotane** in 246 patients with advanced forms of ACC (ENSAT stage IV), an objective response according to RECIST criteria was noted in 26% of cases (11 patients with complete response, 52 with partial response) [108].

• 3.2.9 It is recommended that adult and pediatric patients with unresectable ACC, widespread metastatic disease, and rapid disease progression undergo chemotherapy according to the #etoposide**, #doxorubicin**, #cisplatin** regimen (the regimen is provided in Table 13) with continued #mitotane** administration daily at a dose ensuring a serum concentration of 14–20 mcg/mL without intervals between chemotherapy cycles (EDP-M regimen for adult patients, EDP-M regimen of the ARAR0332 protocol for children) [105, 231, 244]. The duration of therapy is 6–8 cycles, followed by maintenance therapy with #mitotane** at a dose ensuring a serum concentration of 14–20 mcg/mL.

For adults: Level of recommendation evidence – A, level of data reliability – 2.

For children, the level of recommendation validity is C, and the level of evidence reliability is 4.

Comment. According to the randomized FIRM-ACT trial, the most effective therapeutic regimen is the combination of #etoposide**, #doxorubicin**, and #cisplatin** administered alongside continuous mitotane** therapy (EDP-M regimen). The study included 304 patients with advanced ACC. The administration of the EDP + m combination achieved an objective response rate of 23.2% and a median progression-free survival of 5 months [105].

Therapeutic options for the pediatric ACC population are also very limited and generally overlap with those for adults [109]. The evidence base is primarily derived from studies involving adult studies; pediatric studies are isolated and characterized by small sample sizes. In a study of 11 children with advanced ACC, a complete or partial response was achieved in 81% of cases (9 patients) when using the EDP-M protocol combined with achieving therapeutic blood concentrations of mitotane** [110]. The EDP-M protocol is used as first-line polychemotherapy regardless of the patient's age (see Table 13). In clinical practice for adult ACC patients, the first dosing schedule is most frequently used, while in the pediatric population, the second and fourth schedules are preferred.

In patients with mitotane** intolerance (development of severe unmanageable adverse events while mitotane** concentrations are within reference ranges), chemotherapy with the omission of mitotane** from the regimen is permitted.

• 3.2.10 It is recommended that adult patients with unresectable ACC, widespread metastatic disease, and rapid disease progression who have contraindications to anthracyclines (L01DB: Anthracyclines and related substances) undergo cytotoxic therapy according to the #etoposide**, #cisplatin** / #carboplatin** regimen (the regimen is provided in Table 13) with continued mitotane** administration daily at a dose ensuring a serum concentration of 14–20 mcg/mL without intervals between chemotherapy cycles [111, 117, 216, 226, 249]. The duration of therapy is 6–8 cycles, followed by maintenance therapy with mitotane** at a dose ensuring a serum concentration of 14–20 mcg/mL.

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Comment. A small retrospective study evaluated the efficacy of the #etoposide** and #carboplatin** combination in the treatment of metastatic or locally advanced ACC in patients with contraindications to #cisplatin** [111]. The study included 12 patients, 7 of whom received chemotherapy with mitotane** and 5 without mitotane**. An ORR was observed in 33% of patients (n=4), all treatment responses were partial, and disease stabilization was also observed in 33% (n=4). Median overall survival was 17.2 months. Thus, it can be concluded that the combination of #etoposide**, #carboplatin**, and mitotane** is a viable option in patients with contraindications to #cisplatin**.

In patients with mitotane** intolerance (development of severe unmanageable adverse events while mitotane** concentrations are within reference ranges), chemotherapy with the omission of mitotane** from the regimen is permitted.

• 3.2.11 It is recommended to consider adding local control modalities (surgical treatment, stereotactic radiation therapy/surgery (conformal external beam radiation therapy, including IMRT, IGRT, VMAT, stereotactic radiation therapy), interventional procedures) in adult patients with oligometastatic disease who have achieved disease control on systemic therapy for at least 6 months [8, 112, 217].

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5.

Comment: About 20% of patients achieve long-term disease control following treatment; these patients may be candidates for surgical treatment after completing platinum-based chemotherapy [112]. In a small retrospective study of 58 patients, residual tumor resection in the setting of disease control after 6–8 cycles of first-line EDP-M chemotherapy was performed in 26 patients and was significantly associated with an increased median PFS compared to the observation group: 13.1 vs. 7.4 months (p = 0.053), and a median OS of 29.8 months vs. 10.8 months (p = 0.0001), respectively. The efficacy of this approach has not been evaluated in children with ACC; consultation with specialists at federal centers is advisable for pediatric patients with oligometastatic disease [244].

• 3.2.12 It is recommended to perform immunohistochemistry with antibodies against MSH2, MLH1, PMS2, and MSH6 (A08.30.040 Immunohistochemical detection of mutations in MLH1, MSH2, MSH6, and PMS2 genes) [preferred method] or PCR for microsatellite instability testing (A27.30.001 PCR-based detection of microsatellite instability in biopsy (surgical) specimens) in all patients with metastatic ACC if Lynch syndrome is suspected (8, 113).

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Comment: A high level of microsatellite instability (MSI-high) is detected in 3–6% of patients, which serves as an indication for #pembrolizumab** as second- and subsequent-line therapy [114].

Table 13. Regimens used as first-line therapy

• 3.2.13 It is recommended to administer pembrolizumab** to adult patients with high microsatellite instability (MSI-H) at 200 mg IV every 3 weeks or 400 mg IV every 6 weeks as an IV infusion, or #pembrolizumab** + mitotane** as second- and subsequent-line therapy for metastatic ACC. The duration of therapy should continue until disease progression or unacceptable toxicity, but no longer than 2 years [114-115, 246]. The dosage regimen of #pembrolizumab** in children is 2 mg/kg IV every 3 weeks [242].

LoE CGoE 4Level of Evidence – C, Grade of Recommendation – 4.

Comment: A Phase II study evaluated the efficacy of pembrolizumab** as second- and subsequent-line therapy for metastatic MSI-H tumors, excluding colorectal cancer [114]. Pembrolizumab** 200 mg every 3 weeks was administered until disease progression or unacceptable toxicity, for up to 2 years. A total of 233 patients were enrolled in the study, including 5 with ACC. The objective response rate was 34.3%, and the median progression-free survival was 4.1 months. One- and two-year progression-free survival rates were 33.9% and 29.3%, respectively.

The efficacy of pembrolizumab** has been investigated in advanced ACC following progression on prior chemotherapy regimens regardless of MSI status. One Phase II study included 39 patients with progressive ACC. Patients received pembrolizumab** 200 mg IV every 21 days until disease progression or unacceptable toxicity, for up to 24 months [115]. Concomitant mitotane** was not permitted. The objective response rate to pembrolizumab** was 23%, the disease control rate was 52%, median progression-free survival was 2.1 months, and median overall survival was 24.9 months. Six patients (16%) had genetic alterations in the DNA mismatch repair system (dMMR/MSI-H). Of these, two achieved a partial response, two had stable disease, and two progressed on pembrolizumab** therapy. Notably, dMMR/MSI-H status was not a significant predictor of response to pembrolizumab** (P = 0.61).

It should be noted that the efficacy of pembrolizumab** in adrenocortical carcinoma has been evaluated only as monotherapy. Combining mitotane** with another immune checkpoint inhibitor, avelumab**, led to an increase in the incidence of grade 3–4 adverse events from 8% to 24%, including grade 3–4 transaminase elevations, which were observed exclusively in the combination arm with mitotane** (8% vs. 0%) [116].

However, in adult patients with hypercortisolism, the combination of #pembrolizumab** and mitotane** is advisable [246].

• 3.2.14 It is recommended to consider #pembrolizumab** +/- mitotane** for adult patients as second- and subsequent-line therapy for metastatic ACC in patients with mismatch repair-proficient (MSS) tumors and an ECOG performance status of 0–1. Therapy should continue until disease progression or unacceptable toxicity, but no longer than 2 years [115, 246].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Comment: The efficacy of pembrolizumab** was studied in advanced ACC following progression on prior chemotherapy regimens regardless of MSI status. One Phase II study included 39 patients with progressive ACC. Patients received pembrolizumab** 200 mg IV every 21 days until progression or unacceptable toxicity, for up to 24 months [115]. Concomitant mitotane** was not permitted. The objective response rate to pembrolizumab** was 23%, the disease control rate was 52%, median progression-free survival was 2.1 months, and median overall survival was 24.9 months. Six patients (16%) had genetic alterations in the DNA mismatch repair system (dMMR/MSI-H). Of these, two achieved a partial response, two had stable disease, and two progressed on pembrolizumab** therapy. Notably, dMMR/MSI-H status was not a significant predictor of response to pembrolizumab** (P = 0.61). In the KEYNOTE-051 trial, 2/4 pediatric patients with progressive/recurrent ACC achieved a partial response on #pembrolizumab** [242]. However, in adult patients with hypercortisolism, the combination of #pembrolizumab** and mitotane** is advisable [246].

• 3.2.15 It is recommended that adult patients with metastatic ACC who experience disease progression no earlier than 6 months after completing platinum-based chemotherapy be considered for re-induction of platinum-based chemotherapy while continuing mitotane**. Upon reaching the maximum permissible cumulative dose of #doxorubicin** (450 mg/m2), it is recommended to continue chemotherapy using the EP/EC regimen for up to 6–8 cycles [117].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Comment: In a small retrospective study of 17 patients, re-induction of platinum-based chemotherapy with a platinum-free interval of at least 6 months achieved disease control ≥ 6 months in 52.9% of patients [117]. Median PFS was 6.17 months. Currently, given the scarce international literature describing the use of adult salvage regimens in very limited cohorts of pediatric patients with progressive/recurrent ACC, standards for second-line cytotoxic therapy in children aged 0–18 years with ACC remain insufficiently studied [244]. In the event of disease recurrence/progression in children and adolescents with ACC, consultation with specialists at federal centers is required [251].

• 3.2.16 It is recommended for adult patients with advanced ACC who have progressed on platinum-based chemotherapy to administer a combination of #gemcitabine** and #capecitabine** until disease progression or unacceptable toxicity, while continuing mitotane** daily at a dose maintaining target serum levels of 14–20 mcg/mL without interruption between chemotherapy cycles [8, 118-120, 214, 215, 226].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Commentary. The objective response rate to #gemcitabine**-containing chemotherapy is 4–7%, with disease control achieved for at least 4 months in approximately half of patients. In the largest retrospective study evaluating the efficacy of #gemcitabine**-containing chemotherapy regimens in metastatic ACC (n=145), including #gemcitabine**+#capecitabine** (n=132), the objective response rate was 4.9%, and the median PFS was 12 weeks [119]. Notably, 6 of 7 objective responses were observed in patients who achieved therapeutic concentrations of mitotane**. Thus, the combination of #gemcitabine** and #capecitabine** without mitotane** or with low serum concentrations of the drug has minimal clinical efficacy, highlighting the need to continue mitotane** therapy and maintain its therapeutic concentration even after disease progression on mitotane**.

• 3.2.17 It is recommended that adult patients consider discontinuation of mitotane** in third- and subsequent-line therapy in cases with a platinum-free interval of less than 6 months in the absence of signs of hypercortisolism. If well tolerated, mitotane** is recommended to be continued throughout all subsequent lines of therapy [120, 121, 214].

CRALEL 5Level of recommendation evidence – C, level of data reliability – 5.

Commentary. Patients with progression on 2 or more lines of therapy and platinum-resistant disease (L01XA) (platinum-free interval less than 6 months) have an extremely poor prognosis; median overall survival in various studies, both with and without mitotane, is 6–7 months (155, 218), so mitotane** may be discontinued in case of poor tolerability.

• 3.2.18 It is recommended that adult patients with advanced ACC progressing on platinum-containing and #gemcitabine**-containing chemotherapy consider #temozolomide** +/- mitotane** daily at a dose that maintains its serum concentration at 14–20 µg/mL without interruption between chemotherapy cycles [155, 226].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Commentary. In a retrospective study evaluating the efficacy of #temozolomide** as second- and subsequent-line chemotherapy for metastatic ACC, the objective response rate was 21.5% (N=6/28), and the median progression-free survival and overall survival were 3.5 months and 7.2 months, respectively [155, 226].

Chemotherapy regimens used in second- and subsequent-line treatment of advanced adrenocortical carcinoma are presented in Table 14.

Table 14. Polychemotherapy regimens used as second-line therapy

3.3 Other Treatment

3.3.1 External beam radiation therapy

• 3.3.1.1 It is recommended that adult patients with ACC bone metastases and pain syndrome be evaluated for palliative external beam radiation therapy (A07.22.001 External beam radiation therapy for neoplasms of endocrine glands) to relieve pain. Radiation therapy can be delivered using various fractionation regimens: 24 Gy in 6 fractions over 2 weeks, 30 Gy in 10 fractions over 2 weeks, or 8 Gy in 1 fraction [219, 247-250].

GCR CLEL 5Grade of Recommendations — C, Level of Evidence — 5.

Commentary. For a long time, ACC was considered a radioresistant tumor. It is now recognized that EBRT is the method of choice for palliative treatment of ACC metastases to the bones and central nervous system (30–40 Gy). The possibilities of conformal 3D external beam radiation therapy are being investigated both in unresectable disease and as an adjunctive local modality after non-radical surgery. The use of radiation therapy in children and adolescents with ACC is limited [244]. Given the high frequency of TP53 gene mutations in children and adolescents with ACC, radiation therapy may increase the risk of secondary malignancies [243, 244].

• 3.3.1.2 It is recommended to consider delivering EBRT (A07.22.001 External beam radiation therapy for neoplasms of endocrine glands) in adult patients in addition to mitotane** therapy on an individual basis following R1 resection in the early postoperative period (within one month) when repeat surgery is not feasible. It should be taken into account that EBRT may complicate repeat surgical interventions. Therefore, EBRT should not be routinely prescribed; the decision should be made on an individual basis [121-125, 228].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Commentary. For a long time, ACC was considered a radioresistant tumor. According to the literature, EBRT (A07.22.001 External beam radiation therapy for neoplasms of endocrine glands) can prevent local recurrence, but does not significantly affect the risk of distant metastasis and overall survival [121-123].

It is known that distant metastases account for recurrence in 40–60% of ACC cases and have a significant impact on patient prognosis, while being more difficult to treat effectively. Nonetheless, preventing complications caused by local recurrences indicates a potential benefit of radiation therapy. Adjuvant EBRT may be reasonable in patients after R1 resection. It should be emphasized that repeat surgery is the treatment of choice in these patients. Delivery of EBRT may complicate subsequent surgical interventions and increase their risk; therefore, EBRT should be used when repeat surgery is reasonably declined. The feasibility of repeat surgery must be evaluated at specialized centers.

For a long time, ACC was considered a radioresistant tumor. According to the literature, EBRT can prevent local recurrence, but does not significantly affect the risk of distant metastasis and overall survival [121-123].

Delaying mitotane** therapy and/or systemic chemotherapy due to EBRT is unacceptable.

A high risk of intraoperative tumor dissemination is not an indication for EBRT.

3.3.2 Hormone replacement therapy for adrenal insufficiency during mitotane** treatment.

• 3.3.2.1 It is recommended that all patients receiving mitotane** therapy undergo hormone replacement therapy for adrenal insufficiency. In the presence of hypercortisolism, the need for replacement therapy should be discussed individually. The drug of choice is hydrocortisone**. Mitotane** intake induces hepatic steroid clearance and increases serum levels of corticosteroid-binding globulin; therefore, at least a twofold increase in the standard replacement dose for adrenal insufficiency is required [37, 126 - 129].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Commentary. Replacement therapy for mitotane**-induced adrenal insufficiency is typically initiated from the first day of its administration. The most common strategy is to start therapy using a full replacement dose of glucocorticoids, which should be at least twice the standard dose (see also Section 3.2.2). An alternative strategy is to start replacement therapy at a reduced dose—hydrocortisone** 20 mg/day with gradual escalation over several weeks. The total daily dose of hydrocortisone** is usually 50 mg/day; however, some patients require daily doses up to 100 mg. Given the high risk of postoperative adrenal insufficiency in children and adolescents, intravenous hydrocortisone** at a dose of 50–100 mg/m2 with gradual dose tapering may be prescribed [244, 245]. According to the ARAR0332 protocol, replacement therapy is initiated one or two weeks after starting mitotane**: hydrocortisone** at a dose of 30 mg/m2 (divided into 2 or 3 doses per day), fludrocortisone** 0.15–0.2 mg/day [240, 244, 251]. In consultation with a pediatric endocrinologist, the dose of hydrocortisone** and fludrocortisone** during mitotane** therapy may be adjusted based on plasma ACTH and cortisol levels [240, 244].

There is no reliable laboratory marker for determining the optimal dose of hydrocortisone**. The adequacy of replacement therapy for adrenal insufficiency during mitotane** therapy should be based on clinical presentation parameters such as blood pressure, pulse rate, appetite, nausea/vomiting, and body weight dynamics. In addition to the clinical presentation, plasma ACTH and potassium concentrations may be considered as auxiliary biomarkers.

In the event of intercurrent illnesses or stress (psychological or severe physical exertion), the glucocorticoid dose should be increased by 1.5–3 times for the duration of the acute phase of the illness or the period of stress exposure. Subsequently, returning to the usual replacement dose taken by the patient before the illness is appropriate. If oral administration of glucocorticoids is impossible for any reason, or if any acute conditions arise, switching to parenteral administration is required. Hydrocortisone** is also the drug of choice.

Some patients receiving mitotane** may experience symptoms of mineralocorticoid deficiency (hyperkalemia, hyponatremia, hypotension, weakness) despite the use of glucocorticoids at a full replacement dose. In this case, adding fludrocortisone** to therapy should be considered, taking into account the clinical presentation, electrolyte levels, and renin level/plasma renin activity [9].

3.3.3 Antiresorptive therapy

• 3.3.3.1 Antiresorptive therapy is recommended for adult patients with ACC and bone metastases [8, 13].

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5.

Commentary. Bone metastases in patients with ACC are associated with poor quality of life due to pain syndrome, as well as the occurrence of pathological fractures, spinal cord compression, and hypercalcemia. Several phase III randomized trials have shown that bone resorption inhibitors (M05B: Drugs affecting bone structure and mineralization), such as bisphosphonates (M05BA) and denosumab** (M05BX04), are effective in patients with bone metastases from primary breast, prostate, and lung malignancies. There are currently insufficient data specifically for patients with ACC. However, based on these results, treating patients with bone metastases from any cancer with antiresorptive therapy has become standard practice. Therefore, in patients with ACC and bone metastases, it is advisable to prescribe bisphosphonates (M05BA) at therapeutic doses combined with calcium supplementation (A12AA Calcium preparations) and vitamin D (A11CC05 colecalciferol**).

Patients with ACC and hypercortisolemia are at increased risk for glucocorticoid-induced osteoporosis and osteoporotic fractures. This group of patients should be considered for antiresorptive therapy using "anti-osteoporotic doses" of bisphosphonates (M05BA) or denosumab** (M05BX04). Because fracture risk declines rapidly after blood cortisol levels normalize, continuation of anti-osteoporotic therapy is usually not required once hypercortisolemia has been controlled.

3.3.4 Contraception

• 3.3.4.1 Effective contraception methods are recommended for female patients of reproductive age receiving cytotoxic chemotherapy and/or mitotane** therapy [130].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Commentary. Cytotoxic chemotherapy and mitotane** therapy are associated with potential teratogenic effects; therefore, pregnancy during these treatments is contraindicated. To prevent unintended pregnancy, female patients of reproductive age should use effective methods of contraception (see also Section 5.4).

It is currently known that ACC cells can express estrogen receptors. Furthermore, preclinical studies have shown that estrogens may stimulate ACC progression via crosstalk with insulin-like growth factor (IGF) signaling pathways. Therefore, preference should be given to estrogen-free contraceptives (G03A Hormonal contraceptives for systemic use) and barrier methods of contraception [220].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

5.1 Prevention of ACC

There is no primary prevention for ACC.

Secondary prevention of ACC progression consists of appropriate management and comprehensive regular follow-up monitoring of patients (see Sections 3 and 5.2).

5.2 Postoperative follow-up of patients with ACC

• 5.2.1 Regular follow-up is recommended for all patients with ACC, including (1) imaging of the abdomen, pelvis, and chest, and (2) laboratory assessment of tumor hormonal secretion. During the first 2 years after radical surgical treatment, follow-up examinations are performed at least once every 2–3 months, then at least once every 3–6 months for the subsequent 3 years. After 5 years of recurrence-free follow-up for ACC, the intervals may be extended to 6–12 months. In advanced/progressive ACC, the decision regarding the optimal surveillance interval is made individually; as a rule, it is conducted at least once every 2–3 months [1, 8, 9] (see also Appendix B, Fig. 1 and Fig. 2).

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5.

Commentary. Regular restaging of the tumor process over time is necessary for timely adjustment of management strategy and for disease prognostication. Determination of tumor extent—detecting locoregional recurrence or distant metastasis—is based on chest CT (A06.09.005.002) and intravenous contrast-enhanced abdominal CT (A06.30.005.003) or 18F-FDG PET/CT (A07.30.043 Positron emission tomography combined with computed tomography using tumor-seeking radiopharmaceuticals). To date, no published studies have evaluated the optimal surveillance schedule in ACC. Therefore, recommendations are based on expert consensus from the European Society of Endocrinology and ENSAT.

All patients with ACC are indicated for regular laboratory testing to assess tumor hormonal secretion, which facilitates early detection of disease recurrence/progression. Clearly, biochemical evaluation should primarily target the steroid hormones and/or metabolites that were present at the initial tumor diagnosis [9].

• 5.2.2 In all patients with ACC receiving mitotane** therapy, regular monitoring of blood mitotane** concentration (A09.05.035 Therapeutic drug monitoring in blood) is recommended. The target blood mitotane** concentration range is 14–20 mcg/mL [8, 126, 131, 132, 215] (see also Appendix A3).

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5.

Commentary. The narrow therapeutic range of mitotane** necessitates regular monitoring of its plasma concentration. Measurement of plasma mitotane** levels (A09.05.035 Therapeutic drug monitoring in blood) is best performed in the morning, at least 12 hours after the last dose.

At the initiation or resumption of mitotane** therapy, until its concentration reaches the target level of > 14 mcg/mL, monitoring should be performed at least once every 3–4 weeks; subsequently, once a therapeutic blood concentration is reached and stably maintained, measuring the plasma mitotane** level (A09.05.035 Therapeutic drug monitoring in blood) every 4–12 weeks is sufficient.

At the initiation or resumption of mitotane** therapy, while its concentration is <14 mcg/mL, it is advisable to gradually escalate the daily dose, provided tolerance is acceptable, until the therapeutic range is achieved. When selecting the optimal dose of mitotane**, its pharmacokinetic properties must be considered, particularly its high lipophilicity, which leads to accumulation in adipose tissue and subsequent slow release into the bloodstream.

Most patients experience various side effects of mitotane**, the severity of which usually correlates with its blood concentration (see also Section 3.2.2 and Table 9). Nevertheless, some gastrointestinal side effects (such as diarrhea) appear to correlate more strongly with oral dosage than with plasma levels, occurring more frequently at the beginning of treatment [8, 126, 131, 132]. Neurological adverse events occur more frequently when concentrations exceed 20 mcg/mL [134-135]. Therefore, many experts recommend maintaining plasma concentrations below 20 mcg/mL. However, there is evidence that higher plasma mitotane** levels may also be associated with higher efficacy. In addition, some patients do not experience corresponding adverse events even at plasma levels well above 20 mcg/mL.

• 5.2.3 In all patients with ACC receiving mitotane** therapy, regular screening for adverse events and their timely management are recommended [36, 133-135].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Commentary. In addition to adrenal insufficiency, mitotane** treatment may be accompanied by numerous potential adverse events (see also Section 3.2.2 and Table 11). All patients with ACC receiving mitotane** therapy require regular screening for adverse events (Table 15). The importance of their early detection and management is evident [9].

Table 15. Scope of routine surveillance during mitotane** therapy

Gastrointestinal side effects are common, especially during the initial months of mitotane** therapy. Supportive therapy should include antiemetics (A04A) and antidiarrheal medications (A07X), if needed (215, 227). It should be kept in mind that nausea/vomiting may also be signs of adrenal insufficiency, which requires prompt treatment. Importantly, treatment tolerability is the key factor determining the achievement of the therapeutic plasma range of mitotane**.

If moderate central nervous system or GI side effects occur, the dose of mitotane** should be reduced by 0.5–1 g/day and appropriate symptomatic treatment administered. In the event of serious but non-life-threatening CNS side effects, any life-threatening side effects, and/or an elevation of liver enzymes > 5× ULN (excluding GGT), mitotane** must be temporarily discontinued and appropriate symptomatic therapy provided. Resuming mitotane** at a reduced dose (50–75% of the previous dose) is possible after the resolution of side effects under close patient monitoring.

Mitotane** therapy may lead to the development of clinical hypothyroidism, typically of central origin (hence, an elevated TSH is not an obligatory finding); therefore, regular monitoring of TSH and free T4, as well as replacement therapy with levothyroxine sodium** as indicated, is required (224).

Serial evaluation of testosterone and SHBG levels, as well as upon the onset of clinical symptoms of hypogonadism, is warranted in men receiving mitotane** therapy. If symptoms of hypogonadism occur in combination with decreased testosterone levels, hormone replacement therapy should be considered.

Ovarian steroidogenesis, as well as female reproductive function in general, is less affected by mitotane**. However, women of reproductive age receiving mitotane** may develop multiple ovarian cysts.

Hypercholesterolemia and/or dyslipidemia are common adverse events of mitotane** therapy. Lipid-lowering therapy using statins (C10AA) NOT metabolized by CYP3A4 (pravastatin, rosuvastatin, and other non-CYP3A4-metabolized agents) is indicated in patients receiving mitotane**, taking into account prognosis, cardiovascular risks, etc. (with an atherogenic index > 3.5).

For replacement therapy recommendations, see also Appendix A3.

5.3 Prognosis

• 5.3.1 To evaluate prognosis and determine the optimal treatment strategy at the time of diagnosis, it is recommended to consider the following factors: disease stage, resection status, Ki-67 index, autonomous cortisol secretion, and the patient's performance status [136-143].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Commentary. The prognosis of ACC depends mainly on the ENSAT stage, as it reflects the extent of the tumor process: 5-year overall survival for stage I is 70–80%, for stage II – 60–70%, for stage III – 20–40%, and for stage IV – 0–10%, respectively. Overall, non-stage-stratified 5-year survival ranges from 16% to 38%. The median overall survival for stage IV is less than 12 months. [144–146].

Based on the results of several studies [136–141], resection margin status and the Ki-67 proliferation index have been recognized as important prognostic factors. In advanced disease (over 40% of patients at initial diagnosis), Cushing's syndrome has a significant negative impact on survival time. Finally, the patient's performance status is an obvious prognostic factor, particularly in elderly patients [141].

In 2015, the ENSAT group conducted a retrospective analysis of the prognostic value of the Ki-67 index in ACC [142]. The German cohort was analyzed separately from the rest of the cohort as being more homogeneous. The cutoff values for the Ki-67 index were set at 5 to 10%, 10–20%, and greater than 20%. Both overall and recurrence-free survival differed significantly in both the German and the overall cohorts in univariate and multivariate analyses. In this study, other significant prognostic factors were tumor size and invasion of venous structures. Based on this, risk groups were established: a Ki-67 index greater than 10% and greater than 20%, the presence of venous invasion, or a tumor size of 15–20 cm corresponded to the third risk group.

An international study of the Ki-67 index in 101 cases of ACC using the conventional counting method, including review by multiple observers, as well as digital image analysis, demonstrated interobserver variability that was method-dependent. The authors concluded that when assessing the Ki-67 index using digital image analysis, patient groups stratified by cutoff values of either 0–10–20% or 0–15–30% differed significantly in prognosis when analyzing overall survival [143].

In advanced ACC (ENSAT stage IV, defined by the presence of distant metastases, and/or disease recurrence not amenable to R0 surgical resection, and/or R2 resection status), the main prognostic factors associated with worse outcomes are disease extent, high Ki-67 proliferation index, and poorly controlled tumor-related symptoms.

The COG study enrolled 78 children and adolescents with ACC between 2006 and 2013. Data analysis showed that 5-year event-free survival in patients with COG stages I (n=24), II (n=15), III (n=24), and IV (n=14) was 86.2%, 53.3%, 81%, and 7.1%, respectively; whereas 5-year overall survival was 95.2% for COG stage I, 78.8% for COG stage II, 94.7% for COG stage III, and 15.6% for COG stage IV, respectively. Univariate analysis revealed that older age, advanced stage, virilization, Cushing's syndrome, arterial hypertension, TP53 mutation, and the presence of somatic ATRX mutation were associated with worse survival rates [231].

• 5.3.2 During follow-up, it is recommended to re-evaluate the prognosis at each follow-up visit to determine the optimal management strategy. [1, 8, 9]

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5.

Following radical surgical treatment, the primary prognostic factor is the occurrence of tumor recurrence. If recurrence occurs, the time to progression, the extent of the tumor process, and resectability play a prognostic role.

In metastatic ACC, the spectrum of prognostic factors includes the Ki-67 proliferation index, the extent of the tumor process, the patient's performance status, progression dynamics, and response to treatment.

It is important to note that assessing these factors in combination allows only preliminary conclusions to be drawn; multivariate prognostic systems have not yet been developed.

5.4 ACC and Pregnancy

• 5.4.1 When a tumor with high malignant potential is identified during pregnancy, it is recommended to perform surgical treatment as soon as possible, regardless of the gestational trimester [147, 148].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Commentary. Given the importance of prompt and radical surgical treatment for the future prognosis in ACC, surgery must be performed as soon as possible after diagnosis, regardless of gestational age. However, preterm birth (especially in the third trimester) and pregnancy loss represent evident surgical risks. The decision regarding the optimal treatment strategy for a pregnant patient with highly suspected ACC must be collegial, involving a multidisciplinary team. It must consider the prognosis of the disease and the risks to both mother and fetus associated with the underlying condition and interventional procedures. The patient must be informed of the potential risks and benefits of surgical treatment during pregnancy and must participate in shared decision-making.

To date, there is no convincing evidence regarding the safety and optimal timing of pregnancy following ACC. Importantly, the primary concern is the generally poor prognosis of ACC, as well as the possibility that pregnancy could increase the risk of recurrence. Limited data suggest that ACC diagnosed during pregnancy or in the postpartum period carries a worse prognosis than in non-pregnant women [149]. It has been hypothesized that pregnancy may promote a more aggressive variant of ACC. At the same time, Pauline de Corbière et al. [147, 148, 150–153] found no adverse impact of pregnancy on the clinical course and prognosis of ACC in patients who had previously received appropriate treatment for ACC. The limitations of the study include the small sample size (17 patients, 21 pregnancies) and its retrospective design, which limits its statistical power.

Given the extreme paucity of evidence regarding pregnancy and ACC, patients must be informed about the significant risk of ACC recurrence in the first years after diagnosis, as well as the potential for ACC progression during pregnancy.

• 5.4.2 Pregnancy while receiving mitotane** therapy is not recommended [9, 225].

GCR CLEL 4Grade of Recommendation – C, Level of Evidence – 4.

Commentary. The concern regarding the use of mitotane** during pregnancy is related to potential teratogenic effects, which may be caused by its transplacental passage and adrenolytic effects on the fetus. To date, only isolated case reports of pregnancy during mitotane** treatment have been published. The virtual absence of an evidence base precludes definitive conclusions about the safety of mitotane** treatment during pregnancy or its associated risks. A patient receiving mitotane** must be informed of these risks and use effective contraception.

Planning a pregnancy can only be considered after discontinuing mitotane** therapy and once its blood concentrations drop to undetectable levels (which may take 3–12 months).

If pregnancy occurs during mitotane** therapy, the patient must be informed about the potential risks to the fetus associated with mitotane** exposure and the potential risks of ACC progression upon mitotane** discontinuation. If the patient wishes to continue the pregnancy, mitotane** treatment should be discontinued [9].

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, which is approved by the authorized federal executive body;

2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of 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 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.

The oncologist of the ambulatory cancer care center (primary oncology office) refers the patient to an oncological dispensary (cancer hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive authority (hereinafter referred to as a federal medical organization), to clarify the diagnosis (in case of the impossibility of establishing a diagnosis, including the extent of the oncological process and the stage of the disease), 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 corresponding International Classification of Diseases for Oncology (ICD-O) 3rd edition codes 8936, 906–909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, the oncologist of an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall, in order to determine treatment tactics, 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 for the purposes of this Procedure as national medical research centers).

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 a pathologo-anatomical bureau (department) of the fourth group (reference center) via information interaction, including the use of telemedical technologies for remote interaction between medical workers;

digital images obtained from radiation imaging results to the remote diagnostic consultation center for radiation diagnostics through information interaction, including via telemedicine technologies for remote interaction between medical workers;

biopsy (surgical) material for repeated pathomorphological, immunohistochemical, and molecular genetic studies: to the pathoanatomical bureau (department) of the fourth group (reference center), as well as to molecular genetic laboratories for molecular genetic testing.

Treatment tactics are determined by a medical board (consilium) of physicians, including oncologists, a radiation oncologist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for the treatment of malignant neoplasms, systemic antineoplastic therapy, and radiation therapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians if necessary.

Dispanserization (follow-up) by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for follow-up 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 with oncological diseases is provided on the basis of medical indications stipulated by the regulations on the organization of specialized, including high-tech, medical care.

Specialized medical care, with the exception of high-tech medical care, in medical organizations subordinate to federal executive authorities is provided based on the medical indications provided for in 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, provided in the appendix to the provision on organizing the provision of specialized, including high-tech, medical care.

Waiting times for the provision of specialized (excluding high-tech) medical care must not exceed the timeframes established in the program of state guarantees of free medical care for 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 provision on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, 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. presence of oncological disease complications requiring emergency and urgent specialized medical care;

2. presence of complications from cancer treatment (surgical intervention, radiation therapy, drug therapy, etc.).

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

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

2. presence of indications for specialized antitumor treatment (surgical intervention, radiation therapy including brachytherapy, external beam radiation therapy, and other types of radiation therapy, drug therapy, etc.) requiring inpatient or day-hospital monitoring.

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 a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

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

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

4. need to transfer the patient to another medical organization in the relevant medical specialty.

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

Factors influencing the course and outcome of ACC include the following:

1. Extent of the tumor process;

2. Localization of metastatic sites;

3. Biological characteristics of the tumor;

4. Development of adverse events during antineoplastic therapy.

Criteria for Evaluating the Quality of Medical Care

Table 16. Quality of Care Assessment Criteria

References

Appendix A1. Working Group Composition

Melnichenko Galina Afanasyevna, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Deputy Director for Research, Head of the Department of Clinical Endocrinology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Alekseev Boris Yakovlevich, MD, PhD, Professor, Deputy Director General for Science, National Medical Research Center for Radiology of the Russian Ministry of Health.

Beltsevich Dmitry Germanovich, MD, PhD, Professor, Chief Researcher, Head of Surgical Department No. 1, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Stylidi Ivan Sokratovich, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Director of the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

Gorbunova Vera Andreevna, MD, PhD, Professor, Chief Scientific Consultant of the Department of Antitumor Drug Therapy No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

Artamonova Elena Vladimirovna, MD, PhD, Professor, Head of the Department of Antitumor Drug Therapy No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health. Professor at the Department of Oncology and Radiotherapy, Therapeutic Faculty, Pirogov Russian National Research Medical University.

Bokhyan Vagan Yurikovich, MD, PhD, Head of the Department of Abdominal Oncology No. 4 (Endocrine Surgery), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health. Professor at the Department of Oncology and Radiotherapy, Therapeutic Faculty, Pirogov Russian National Research Medical University.

Kolomeytseva Alina Andreevna, Cand. Sci. (Med.), Head of the Day Hospital for Tumour Drug Treatment, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Goryainov Dmitry Alexandrovich, Cand. Sci. (Med.), Oncologist, Head of the Oncological Department of the Extrabudgetary Medical Services Division, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

Kalpinsky Alexey Sergeevich, Cand. Sci. (Med.), Board Member of the RSETO, Head of the Surgical Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Zhulikov Yaroslav Andreevich, Oncologist at the Department of Antitumor Drug Therapy No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

Kovalenko Elena Igorevna, Cand. Sci. (Med.), Senior Researcher, Oncologist at the Department of Antitumor Drug Therapy No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

Orlova Rashida Vakhidovna, MD, PhD, Professor, Head of the Department of Oncology, Faculty of Medicine, Saint Petersburg State University, Chief Specialist in Clinical Oncology and Rehabilitation, City Clinical Oncology Dispensary.

Nesterova Alfiya Irekovna, Cand. Sci. (Med.), Associate Professor at the Department of Oncology, Radiology and Palliative Medicine, Kazan State Medical Academy; Associate Professor at the Department of Surgery, Institute of Fundamental Medicine and Biology, Kazan Federal University; Head of the Department of Translational Oncology and Telemedicine Technologies, M.Z. Sigal Republican Clinical Oncological Dispensary.

Delektorskaya Vera Vladimirovna, MD, PhD, Professor, Leading Researcher, Pathologist at the Department of Pathology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Melanoma Association.

Kletskaya Irina Semenovna, Pathologist, Russian Children's Clinical Hospital of the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

Urusova Liliya Sergeevna, MD, PhD, Associate Professor, Leading Researcher, Head of the Department of Fundamental Pathomorphology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Romashenko Pavel Nikolaevich, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department and Clinic of Faculty Surgery named after S.P. Fedorov, S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation.

Maystrenko Nikolay Anatolyevich, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Professor at the Department of Faculty Surgery named after S.P. Fedorov, S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation.

Roslyakova Anna Alexandrovna, Endocrinologist at the Department of Surgery, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Shamanskaya Tatyana Viktorovna, MD, PhD, Member of the Russian Association of Pediatric Oncologists (RODOG), Head of the Department of Embryonal Tumors, Institute of Oncology, Radiology and Nuclear Medicine, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

Kachanov Denis Yurievich, MD, PhD, Member of RODOG, Head of the Department of Clinical Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health; Deputy Director of the Institute of Oncology, Radiology and Nuclear Medicine, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology.

Utalieva Dinara Timorkanovna, Member of RODOG, Pediatric Oncologist at the Department of Clinical Oncology, Research Laboratory Assistant at the Department of Catamnesis of Children after Oncological Diseases, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

Rubanskaya Marina Vladimirovna, Cand. Sci. (Med.), Pediatric Oncologist, Head of Pediatric Oncology Department No. 1 (Thoracoabdominal Tumor Chemotherapy), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

Belokhvostova Anna Sergeevna, Cand. Sci. (Med.), Head of the Department of Antitumor Drug Therapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Associate Professor at the Department of Radionuclide Medicine, Institute of Engineering Physics for Biomedicine, National Research Nuclear University MEPhI.

Dmitriev Vadim Nikolaevich, MD, PhD, Head of the Day Hospital Department of Antitumor Drug Therapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Professor at the Department of Faculty Surgery, Medical Institute, Belgorod State National Research University.

Medical Care Organization Section

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

Ivanov Sergey Anatolyevich, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Honored Doctor of the Russian Federation, Director of the A.F. Tsyb Medical Radiological Research Center — branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Chief Freelance Oncologist of the Central Federal District of the Russian Ministry of Health.

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

Gevorkyan Tigran Gagikovich, Deputy Director for Federal Project Implementation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

Komarov Yury Igorevich, PhD, Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

Conflict of interest:

The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Currently, these clinical guidelines serve as the primary consensus document governing the practical activities of physicians in the management of ACC.

These clinical guidelines are aimed at improving the outcomes of diagnosis and treatment in patients with adrenocortical carcinoma.

These clinical guidelines do not address absolutely all aspects of the problem and potential exceptions to the rules.

These clinical guidelines cannot guarantee a specific outcome and do not establish standards of patient care.

These clinical guidelines are not intended for the treatment of any individual patient. Decisions on the optimal management strategy for each patient must be based on examination results, taking into account individual circumstances.

The rarity of ACC poses objective difficulties due to the lack of adequately powered prospective studies and sufficient experience in treating this disease outside of specialized centers that concentrate such patients. Over the past 30–40 years, large-scale prospective and retrospective studies have been conducted abroad, some of which include up to 500 patients. Unfortunately, studies with such sample sizes have not been conducted in Russia. Therefore, these clinical guidelines rely primarily on foreign evidence and take into account the expert opinions of foreign researchers.

The clinical guidelines are based on existing consensuses and clinical guidelines: (1) World Health Organization (WHO) Classification of Tumours of Endocrine Organs, 4th edition, 2017; (2) European Society of Endocrinology Clinical Practice Guidelines for the Management of Adrenocortical Carcinoma, in collaboration with the European Network for the Study of Adrenal Tumors, 2018; (3) Clinical guidelines for the diagnosis and treatment of adrenocortical carcinoma, 2015 – as well as domestic and international scientific papers on this subject.

Methods used for collecting/selecting evidence: a search of electronic databases was conducted using keywords related to adrenocortical carcinoma (ACC) and the relevant sections of clinical guidelines; the quality and relevance of the retrieved sources were assessed.

Description of methods used for collecting/selecting evidence: the evidence base for the guidelines includes publications from the Cochrane Library, EMBASE, MEDLINE, and eLIBRARY databases. The search depth was up to 40 years.

Methods used for determining the levels of evidence:

• Expert consensus;

• Assessment of significance in accordance with levels of evidence.

Due to the orphan nature of the disease and the lack of prospective studies of sufficient statistical power, a number of recommendations are formally characterized by a low level of evidence.

Table 17. Scale for assessing levels of evidence (LoE) for diagnostic methods (diagnostic interventions)

Table 18. Scale for assessing levels of evidence (LoE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 19. Scale for assessing grades of recommendation (GoR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

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 peer review

· Internal peer review

Description of the guideline validation method

The draft of these recommendations 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.

The comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and the resulting changes to the recommendations were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

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.

Target audience for these clinical guidelines:

1. Oncologists (surgeons, urologists).

2. Pediatric oncologists.

3. Pediatric surgeons

4. Endocrinologists.

5. Pediatric endocrinologists;

6. Pediatricians

7. Radiation oncologists.

8. Pathologists.

9. General practitioners.

10. General practitioners (family physicians).

Diagnostic and therapeutic options for patients with ACC require a multidisciplinary approach.

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

Recommendations for hormone replacement therapy during mitotane treatment**

1. Absolute glucocorticoid deficiency

• Glucocorticoids: from the start of mitotane** treatment, doses exceed standard regimens:

  - Hydrocortisone** 50–75 mg/day

  - In children and adolescents with ACC, the dose of hydrocortisone** will depend on plasma cortisol and ACTH levels, under the supervision of a pediatric endocrinologist

• The adequacy of replacement therapy is assessed based on clinical criteria, including blood pressure, heart rate, presence/absence of appetite, and body weight dynamics. Blood electrolyte levels must also be taken into account.

2. Mineralocorticoid deficiency is regularly assessed via blood electrolyte levels; correction is performed with fludrocortisone**

3. Hypogonadism in men is assessed based on clinical manifestations (erectile dysfunction and gynecomastia), confirmed by hormonal assay results, and requires replacement therapy.

4. Secondary hypothyroidism is regularly assessed via TSH and free T4 levels (TSH within normal range, decreased free T4) and requires replacement therapy.

Recommendations for the use of mitotane** as adjuvant therapy

• The initial dose of #mitotane** is 1–2 g/day (2–4 tabl./day). The dose is increased every 3–7 days by 0.5–2 g/day (tolerability permitting) up to 4–8 g/day (8–16 tabl./day), or up to the maximum tolerated dose; the drug is taken 2–5 times/day with meals [215, 225]. In children and adolescents, the initial dose of mitotane is 1.5 g/m² (50 mg/kg/day). The dose is increased every 1–2 weeks by 20 mg/kg/day or 500 mg/m² up to a maximum dose of 4 g/m²/day, monitored by serum mitotane** concentrations (normal range 14–20 µg/mL) [231, 240, 244].

• Dose titration is adjusted based on:

- drug tolerability;

- achieved therapeutic concentration (14–20 µg/mL)

• Blood mitotane** levels must be assessed:

- every 4–8 weeks until the target range is reached;

- upon reaching the target range, every 2–3 months for 2 years; thereafter, evaluation at longer intervals is possible.

• Clinical and imaging evaluations are performed at least once every 2–3 months.

• Determination of blood mitotane** levels (A09.05.035) is required if side effects occur.

• In case of side effects:

- mild/moderate – continue mitotane**, administer symptomatic therapy;

- significant – revert to the last tolerated dose, administer symptomatic therapy;

- severe – discontinue mitotane**, provide specific treatment for symptoms, then resume mitotane** starting with low doses.

Appendix B. Physician Action Algorithms

Figure 2. Treatment algorithm for unresectable or progressive ACC

Appendix C. Patient Information

Adrenocortical carcinoma (ACC) is a rare (orphan) neoplastic disease characterized typically by late detection and, in the case of untimely and incomplete treatment, an unfavorable prognosis. In about half of cases, ACC may be accompanied by elevated secretion of adrenal hormones into the blood [148].

ACC is one of the rarest human tumors. It has an incidence of 0.5–2 cases per million population per year. Women are affected 2.5 times more frequently than men, and the mean patient age is 46 years. In Russia, ACC is included in the List of Rare (Orphan) Diseases of the Russian Ministry of Health.

Causes of ACC development

The causes of the onset and progression of ACC undoubtedly lie in genetic defects. These may exclusively affect the cells of the adrenal cortex from which the tumor arises. In this case, the disease affects only the patient and is not inherited by their children. Much less frequently (3–5% of all adult ACC cases), ACC develops due to congenital genetic defects present in all cells of the body. In such cases, ACC develops as part of a hereditary syndrome. To date, ACC has been described as a component of the following syndromes: Li-Fraumeni, Lynch, multiple endocrine neoplasia type 1, Gardner (familial adenomatous polyposis), Carney complex, Beckwith-Wiedemann, and neurofibromatosis type 1. If a patient is diagnosed with ACC as part of a hereditary syndrome, their blood relatives, primarily their children, must be screened.

It is important to note that among all pediatric ACC cases, 80% are due to congenital genetic defects leading to Li-Fraumeni syndrome.

No clear link between the occurrence of ACC and lifestyle or external factors has been established to date.

Manifestations of ACC

In 50–60% of cases, ACC is accompanied by increased production of adrenocortical hormones, namely:

1. glucocorticoids (cortisol and cortisone);

2. mineralocorticoids (aldosterone, corticosterone, and deoxycorticosterone);

3. sex hormones (androgens and estrogens).

Most tumors secrete cortisol in isolation (up to 60%) or androgens combined with cortisol (30%).

Symptoms in patients with hormonally active ACC are determined by the excess production of the respective hormones:

• cortisol (general weakness, headaches, obesity with typical fat deposition in the face, neck, chest, and abdomen. The face appears rounded and moon-shaped, with a plethoric flush on the cheeks. Conversely, arms and legs become thin due to muscle wasting. Acne appears on the skin. Wounds and cuts heal slowly. Bone pain and predisposition to fractures, infertility, elevated blood pressure, etc. occur);

• aldosterone (elevated blood pressure, muscle weakness due to potassium loss);

• testosterone (unwanted body hair growth, deepening of the voice, clitoromegaly in women, oily and unclean skin);

• estrogens (impotence, gynecomastia in men, uterine bleeding in postmenopausal women).

Hormonally inactive tumors occur in 40% of cases and are insidious because they may remain asymptomatic for a long time and later manifest, as the tumor enlarges, with general non-specific symptoms: abdominal or back discomfort or pain, a feeling of abdominal fullness, or an abdominal mass detected by a physician or by the patient during abdominal palpation.

Detection (Diagnosis) of ACC

The widespread adoption in clinical practice of diagnostic imaging methods, such as ultrasound (US) of the kidneys and adrenal glands (A04.28.001), computed tomography (CT) of the abdomen (A06.30.005.003), and magnetic resonance imaging (MRI) of the abdomen (A05.30.005.001), has led to a sharp increase in the number of incidentally detected adrenal tumors. An incidental adrenal tumor can be either hormonally inactive or actively produce various hormones (see above); it may originate from different parts of the adrenal gland and can be malignant or benign. Among all incidentally discovered adrenal tumors, ACC accounts for approximately 4% of cases.

If ACC is suspected, laboratory diagnostics are performed to identify hormonal abnormalities characteristic of hormonally active ACC. To confirm or rule out the hormonal activity of the tumor, the following laboratory diagnostic methods are recommended:

• determination of cortisol in the early morning hours during the #dexamethasone suppression test**;

• in the absence of physiological suppression of cortisol levels, determination of adrenocorticotropic hormone in the morning hours;

• for all patients with a detected adrenal tumor, to exclude another dangerous tumor, pheochromocytoma, determination of normetanephrine and metanephrine in 24-hour urine (A09.28.034.001, A09.28.034.002) or plasma (A09.05.133.001, A09.05.133.002) is indicated;

• if a patient with an adrenal tumor presents with arterial hypertension, determination of the aldosterone-to-plasma renin activity ratio is indicated to rule out primary hyperaldosteronism;

• if isolated or combined (with hypercortisolism) tumor hyperproduction of sex hormones is suspected, determination of serum steroid hormones (dehydroepiandrosterone sulfate [A09.05.149], 17-hydroxyprogesterone [A09.05.139], androstenedione [A09.05.146], testosterone [A09.05.078], estradiol [A09.05.153] in men and postmenopausal women) is indicated.

At the present stage, diagnostic imaging methods are of paramount importance for the preoperative confirmation of an ACC diagnosis. While the presence of direct signs of tumor malignancy, such as invasion into surrounding organs, metastatic lesions of lymph nodes, liver, or lungs, makes the diagnosis of ACC virtually obvious, their absence sets the task of identifying features specifically characteristic of this tumor.

Computed tomography (CT) of the abdomen with intravenous bolus contrast enhancement [A06.30.005.003] is the "gold standard" of diagnostic imaging for adrenal tumors.

Ultrasound (US) [A04.28.001] is quite frequently used as a primary diagnostic method. Ultrasound detects the tumor very well, but, unfortunately, it cannot always accurately determine the origin of this tumor. Ultrasound can be used for the primary diagnosis of adrenal tumors if computed tomography cannot be performed.

Magnetic resonance imaging (MRI) of the brain (A05.23.009.001) is recommended for the primary diagnosis of adrenal tumors, as well as to rule out brain metastases. MRI has high sensitivity in detecting adrenal tumors and assessing tumor status, including involvement of adjacent organs. However, the accuracy of this method is still lower than that of CT.

Osteoscintigraphy (whole-body bone scan) is indicated when skeletal bone metastases are suspected.

Positron emission tomography (PET) with fludeoxyglucose [18F] (FDG) (A07.30.043 Positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals, A07.30.043.001 Positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals with contrast enhancement) is indicated to determine the stage and extent of the process, as well as a diagnostic method to determine malignant potential in small tumors (up to 4 cm).

Puncture biopsy in the case of ACC has no proven advantages, has low sensitivity, insufficient informativeness, and a high probability of complications; therefore, its performance is not indicated.

Treatment of ACC

Diagnosis and treatment of ACC should be carried out with the participation of an oncologist, endocrinologist, surgeon, clinical laboratory diagnostician, and radiologist in a specialized institution/department.

The most effective treatment method is surgical. When ACC is detected at early stages of the disease, when there is no tumor invasion into vital organs and/or multiple metastases, surgery is the first stage of complex therapy. Furthermore, in the absence of metastases, surgical treatment can be supplemented with adjuvant drug therapy. The decision on treatment is made based on the characteristics of the tumor (primarily the Ki-67 index) and the course of ACC in the given patient.

In the case of metastases at the time of ACC detection or their subsequent development, complex treatment must also include chemotherapy.

Multiple metastases and/or tumor invasion into vital organs at the time of ACC diagnosis generally preclude adequate surgical treatment or may lead to serious complications during surgery. Therefore, in such situations, treatment is initiated with chemotherapy, which in most cases leads to a reduction in the size of tumor foci; surgery is then performed.

External beam radiation therapy (EBRT) is indicated as palliative therapy for painful bone metastases of ACC (External beam radiation therapy for bone lesions) and central nervous system metastases (External beam radiation therapy for central nervous system and brain lesions).

Prognosis

In general, the prognosis of ACC is determined by the timeliness of disease detection, the effectiveness of the treatment administered, and patient adherence to therapy.

The treatment of ACC is a long and laborious process, requiring the efforts not only of the medical team but also of the patient. Adherence to treatment and compliance with recommendations for timely examination and treatment generally help achieve improvement or stabilization of ACC. The most unfavorable prognosis is observed in patients who deny their illness and fail to follow the attending physician's recommendations.

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

Russian title: Weiss system for histological grading of adrenocortical carcinoma malignancy

Original title: Weiss scale

Source (validation publication):

Lau SK, Weiss LM. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum Pathol. 2009;40(6):757-768.

Type: Rating scale

Purpose: histological assessment of adrenocortical tumor malignancy

Table 8. Weiss scoring system for the malignant potential of adrenocortical tumors

Notes. Each of the 9 criteria is scored 1 point. A score of 3 or more on the Weiss scale confirms a high malignant potential of the tumor and establishes the diagnosis of ACC.

Appendix G2. Scoring scale for the malignant potential of adrenocortical oncocytic tumors

Russian title: Lin-Weiss-Bisceglia scale for histological grading of adrenocortical oncocytic tumor malignancy

Original title: Lin-Weiss-Bisceglia scale

Source (validation publication):

Bisceglia M. et al. Adrenocortical oncocytic tumors: Report of 10 cases and review of the literature // Int. J. Surg. Pathol. 2004. Vol. 12, № 3. P. 231–243.

Type: Rating scale

Purpose: histological assessment of adrenocortical oncocytic tumor malignancy

Table 9. Lin-Weiss-Bisceglia scoring system for the malignant potential of oncocytic adrenocortical tumors

Note: Oncocytic ACC is diagnosed in the presence of at least one "major criterion"; oncocytic ACA of borderline malignant potential is diagnosed in the presence of at least one "minor criterion"; in the absence of all major and minor criteria, the oncocytic tumor is considered benign. It should be noted that oncocytic cells must account for more than 90% of the tumor area to be classified as a pure oncocytic adrenocortical neoplasm. Otherwise, criteria used for diagnosing conventional ACC should be applied.

Appendix G3. Scoring system for assessing the malignant potential of pediatric adrenocortical tumors

Russian title: Wieneke criteria for histological evaluation of pediatric adrenocortical tumor malignancy

Original name: Wieneke/Armed Forces Institute of Pathology criteria

Source (validation publication):

Wieneke J.A. et al. Adrenal cortical neoplasms in the pediatric population: A clinicopathologic and immunophenotype analysis of 83 patients // Am J Surg Pathol. 2003. №27. P. 867-881.

Type: Rating scale

Purpose: histological assessment of malignancy in pediatric adrenocortical tumors

Table 10. Wieneke criteria for determining malignancy in pediatric adrenocortical tumors (age <20 years) [53]

1. Tumor weight >400 g

2. Tumor size >10.5 cm

3. Local invasion and/or extension into adjacent organs

4. Vena cava invasion

5. Venous invasion

6. Capsular invasion

7. Presence of tumor necrosis

8. >15 mitoses per 20 high-power fields at ×400 magnification

9. Presence of atypical mitoses

Key:

0–2 criteria: benign tumor, favorable prognosis.

3 criteria: undetermined malignant potential.

>3 criteria: malignant tumor, unfavorable prognosis.

Appendix G4. Tumor response evaluation criteria (RECIST 1.1)

Russian name: Criteria for evaluating tumor response to chemotherapy (RECIST 1.1)

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

Source (validation publication):

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228-247

Source (in Russian):

Gombolevsky VA, Laypan ASh, Shapiev AN, Vladzymyrskyy AV, Morozov SP (eds.): Guidelines on the application of solid tumor response criteria to chemotherapy (RECIST 1.1). Clinical Guidelines No. 46; 2018. http://medradiology.moscow/d/1364488/d/no46_2018_recist_11.pdf

Type: Rating scale

Purpose: assessment of response to chemotherapy

Table 20. Target lesion evaluation

Table 21. Non-target lesion evaluation

Table 22. Overall disease response evaluation

Appendix G5. Criteria for surgical adequacy

Title in Russian: Residual Tumour Classification (R Classification)

Original title: Residual Tumour (R) Classification

Source (validation publication):

Brierley J, Gospodarowicz MK, Wittekind Ch (eds). TNM classification of malignant tumours. Oxford, UK; Hoboken, NJ: John Wiley & Sons, Inc., 2017.

Type: Rating scale

Purpose: assessment of the adequacy of surgical treatment based on the presence/absence of residual tumor

Table 23. Residual Tumour Classification (R Classification)