Adenomatous Polyposis Syndrome: Clinical Guidelines

List of Abbreviations

Terms and Definitions

Autosomal dominant inheritance is a type of inheritance characterized by the following features: every affected offspring has an affected parent; the disease occurs in individuals of both sexes; the risk of inheriting the disease for children of an affected parent is 50%; all children of unaffected offspring of an affected individual must be unaffected.

Autosomal recessive inheritance is a type of trait inheritance characterized by the following features: the disease occurs in individuals of both sexes; there are skips in generations; affected children can be born to unaffected parents; if both parents are affected, all their children will also be affected.

Proband is the individual from whom the pedigree is initiated to study the inheritance pattern of a disease among family members.

Pedigree is a graphical representation of family history data that, in addition to the nature of kinship ties among family members, reflects information on the manifestation of a trait, health status, or pathology among relatives, providing visual information on the inheritance pattern of the trait.

Germline (hereditary) variants are any genetic alterations occurring within the precursor cells of germ cells; they are detected in all cells of the organism.

Pathogenic variant (formerly "mutation") is a gene variant that reliably leads to the development of a disease.

Adenoma is a benign tumor originating from glandular epithelium.

Polyp is a collective term used to denote various pathological tissue outgrowths rising above the mucous membrane.

Sessile serrated adenoma is a type of polyp occupying an intermediate position between adenomas and hyperplastic polyps, characterized by prominent basal dilation and horizontal crypt growth along the muscularis mucosae.

Hyperplastic polyp is a polyp formed as a result of focal hyperplasia that morphologically does not belong to benign intestinal tumors.

Desmoid tumor (desmoid, desmoma, aggressive fibromatosis) is a rare, locally invasive, non-metastasizing tumor developing from musculoaponeurotic structures and occupying an intermediate position between benign and malignant neoplasms. The most common locations are the anterior abdominal wall, upper and lower extremities, and the mesentery of the small intestine.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Adenomatous polyposis syndrome (APS) is a rare hereditary disease characterized by the development of multiple (more than 20) colonic adenomas at a young age with their inevitable malignant transformation in the absence of timely surgical treatment [1-2].

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

The etiological cause of APS development is the presence of one germline pathogenic variant in the APC gene or two pathogenic variants in the MUTYH gene.

The APC (adenomatous polyposis coli) gene was identified and mapped by two independent research groups in 1986–1987 [3-5]. It is located on the long arm of chromosome 5 at band 5q22, comprising 16 exons, of which 15 encode a protein containing 2,843 amino acids [6]. The APC gene is responsible for synthesizing a specific protein that functions as a tumor suppressor, ensuring normal proliferation in gastrointestinal mucosal cells. Pathogenic variants (PVs) in the APC gene lead to the synthesis of a "truncated" protein that loses its function of suppressing escalating epithelial dysplasia and cause an autosomal dominant hereditary syndrome—familial adenomatous polyposis, which is characterized by the development of multiple adenomas with subsequent malignant transformation in 100% of cases [7,8]. The most common types of PVs in the APC gene are deletions, frameshift insertions, and nonsense mutations. A deletion is characterized by the loss of one or more nucleotides, the number of which is not a multiple of 3, from the normal DNA strand; an insertion is the addition of one or more nucleotides, the number of which is not a multiple of 3, into the DNA molecule; and a nonsense mutation is a type of PV that results in the immediate formation of a premature stop codon [9]. To date, over 2,000 unique pathogenic hereditary variants have been described in the APC gene, although new PVs are regularly discovered in ongoing studies, driven by both the population background of the probands and the nature of the gene itself [8,9]. The disease is characterized by an autosomal dominant inheritance pattern with several specific features:

• the trait typically appears in every generation, known as vertical transmission;

• males and females are affected with equal frequency;

• affected males and females transmit the trait to offspring—sons and daughters—equally;

• an affected family member typically has an affected parent (less commonly, parents);

• the probability of having an affected child is 75% if both parents are affected, and 50% if one of them is affected.

In 2002, biallelic PVs were first described in the MUTYH gene located on chromosome 1 at band 1p34 [10]. This gene encodes a DNA excision repair protein involved in repairing oxidative guanine damage.

MUTYH-associated polyposis (MAP) is an autosomal recessive hereditary disease characterized by the development of multiple colonic adenomas and a risk of CRC reaching 80% in cases of delayed diagnosis and treatment. A characteristic feature of APS caused by PVs in the MUTYH gene is the presence in the colon of adenomatous polyps as well as sessile serrated adenomas, hyperplastic polyps, and mixed polyps (hyperplastic and adenomatous) [11,12]. The disease is characterized by an autosomal recessive inheritance pattern with several specific features:

• the trait is rare and does not appear in every generation;

• affected children are typically born to unaffected parents;

• primarily siblings (brothers, sisters) are affected;

• an affected parent may have unaffected children;

• males and females are affected with equal frequency;

• the probability of having an affected child from a union of two heterozygotes is 25% for each subsequent child, regardless of the number of already affected children.

At birth, clinical signs of APS are not manifested. Subsequently, as the body grows, small polyps appear on the colonic mucosa [13,14].

1.3 Epidemiology of the Disease or Condition

In 2023, more than 80,700 new cases of CRC were detected in the Russian Federation [15]. Approximately 5–10% are attributed to cancer cases with a known molecular genetic cause, with up to 1% caused by APS [16], which is the second most common genetically determined syndrome after Lynch syndrome [17,18]. The prevalence of PVs in the APC gene among Europeans is estimated to range from 1:6,850 to 1:31,250 [19,20].

The frequency of biallelic PVs in the MUTYH gene is estimated to range from 1:20,000 to 1:60,000 [19,21].

1.4 Features of Coding the Disease or Condition

ICD-10 Codes

Class — Neoplasms (C00-D48) (II).

Block — Benign neoplasms (D10-D36).

Code — D12 — Benign neoplasm of colon, rectum, anus and anal canal:

D12.0 — Cecum

D12.1 — Appendix

D12.2 — Ascending colon

D12.3 - Transverse colon

D12.4 - Descending colon

D12.5 - Sigmoid colon

D12.6 - Colon, unspecified part, including

• Colonic adenomatosis

• Colon, unspecified

• Polyposis (congenital) of colon

D12.7 - Rectosigmoid junction

D12.8 - Rectum

D12.9 - Anus and anal canal

1.5 Classification of the disease or condition

Polyposis syndromes refer to conditions where examination reveals 20 or more polyps of the colon. All of these are encompassed by the term "adenomatous polyposis syndrome".

APS is classified according to the clinical course and the localization of pathogenic variants (PVs). This classification is used to determine disease severity and select management tactics [1,2]. The following clinical forms of the disease are distinguished:

1. Classic form - the most common form, characterized by the presence of hundreds or thousands (i.e., more than 100) of polyps in the colon, with malignant transformation occurring at 18-40 years of age. The initial symptoms of the disease may appear already in childhood. In addition, patients with the classic form may develop severe metabolic disorders and anemia, which frequently cause delayed physical development in children [2,23]. In the classic form of APS, PVs in the APC gene are detected in approximately 80% of cases. In remaining cases, the presence of wild-type APC gene is established.

Additionally, Gardner syndrome and Turcot syndrome are distinguished in the classic form of APS.

• Gardner syndrome - a combination of APS with soft tissue tumors and cranial osteomas. Desmoids are the most common—well-differentiated connective tissue tumors localized in the anterior abdominal wall, small or large bowel mesentery, and occasionally in the intermuscular layers of the back and shoulder girdle. Structurally, these tumors are not malignant and do not metastasize, but they are prone to aggressive locally destructive growth and frequent recurrence.

• Turcot syndrome - APS combined with malignant tumors of the central nervous system, specifically medulloblastomas.

2. Attenuated form, characterized by the presence of 20 to 100 polyps in the colon, localized predominantly in the proximal segments. Clinical manifestations appear at 40-45 years of age, and polyp malignization occurs after 50 years of age. The attenuated form occurs in approximately 8% of patients with APS. In the attenuated form of APS, PVs in the APC gene are identified in approximately 20% of cases. In remaining cases, when 20-99 polyps are detected, the presence of the wild-type APC gene is established.

3. MUTYH-associated polyposis, caused by the presence of 2 biallelic PVs in the MUTYH gene, in contrast to the classic and attenuated forms where PVs occur in the APC gene [24-27]. Despite the localization of PVs in different genes, MAP can manifest either as the classic form of APS (100 or more polyps) or the attenuated form (20-99 polyps). Unlike the classic and attenuated forms of APS, MAP always reveals 2 PVs in the MUTYH gene.

4. Preclinical form. This variant refers to clinical situations where a relative of an APS patient is found to have a PV, but colonoscopy reveals no colonic polyps.

1.6 Clinical presentation of the disease or condition

The most common manifestations of the disease in the classic form of APS are changes in stool frequency and consistency (diarrheal syndrome), metabolic disorders, presence of blood and mucus impurities in the stool, and abdominal pain. In addition, characteristic symptoms include general weakness and dizziness developing secondary to anemia. The first symptoms appear at 14-16 years of age, and malignant transformation of polyps occurs at 18-40 years of age. In late presentations, signs of bowel obstruction may occur.

In the attenuated form of APS, the main patient complaints are discharge of blood and mucus from the anus. The initial symptoms of the disease appear at 20-45 years of age, and malignant transformation of polyps frequently occurs after 40 years of age. Most commonly, the diagnosis of the attenuated form of APS is established as a result of evaluation for clinical symptoms characteristic of colonic malignancy.

MUTYH-associated polyposis is clinically similar to the attenuated form of APS.

Furthermore, patients with APS have a high risk of developing extraintestinal malignancies: cancer of the duodenum, stomach, thyroid gland, brain, hepatoblastomas (can occur in children), and hepatobiliary system tumors [23].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of APS is based on the clinical presentation, family history data, endoscopic findings, and molecular genetic testing.

When establishing a diagnosis of APS, it is necessary to perform differential diagnosis with other diseases and hereditary syndromes:

• colorectal cancer

• Lynch syndrome

• Peutz-Jeghers syndrome

• juvenile polyposis

• serrated polyposis

• mixed polyposis

Criteria for establishing the diagnosis/condition:

The diagnosis of APS is established based on the clinical presentation (presence of 20 or more colonic polyps) and the results of genetic testing, indicating the presence and localization of PVs in the APC/MUTYH genes. The last two criteria are particularly important for a clinical geneticist, whose participation in APS cases is required as part of a multidisciplinary team.

When 100 or more colonic polyps are present, a diagnosis of the classic form of APS is established. If a PV is identified in the APC gene, it must be specified. For example:

"Adenomatous polyposis syndrome, classic form. Pathogenic variant in the APC gene c.2730-2737del8."

If no PV is detected in the patient's APC gene, the presence of the APC wild-type gene is stated. In this case, the diagnosis is formulated as follows:

"Adenomatous polyposis syndrome, classic form. APC wild-type gene."

In the classic form of APS with detection of a soft tissue tumor, a diagnosis of Gardner syndrome is established, and the nature, localization, and size of the soft tissue tumor are indicated, for example:

"Adenomatous polyposis syndrome, classic form. Pathogenic variant in the APC gene c.2730-2737del8. Gardner syndrome, desmoid tumor of the anterior abdominal wall 6x13 cm."

In the classic form of APS with detection of a posterior cranial fossa tumor, a diagnosis of Turcot syndrome is established. This part of the diagnosis is formulated by a neurosurgeon, for example:

"Adenomatous polyposis syndrome, classic form. Pathogenic variant in the APC gene c.2730-2737del8. Turcot syndrome, cerebellar medulloblastoma."

Upon detection of 20-99 colonic polyps, a diagnosis of the attenuated form of APS is established. In the attenuated form, the number and size of detected polyps, as well as the localization of the PV in the APC gene, must be indicated, for example:

"Adenomatous polyposis syndrome, attenuated form (52 colonic polyps, 3-28 mm). Pathogenic variant in the APC gene p.Arg405Ter."

If, in the presence of 20-99 colonic polyps, no PV is detected in the APC gene, the wild type of the APC gene is stated, for example:

"Adenomatous polyposis syndrome, attenuated form (34 colonic polyps, 8-34 mm), APC wild-type gene."

If a PV in the APC gene is detected in patient relatives, a diagnosis of APS must be made even in the absence of colonic polyps, and the localization of the PV must be indicated, for example:

"Adenomatous polyposis syndrome, preclinical form. Pathogenic variant in the APC gene c.2730-2737del8."

Upon detection of 2 biallelic PVs in the MUTYH gene in a patient, a diagnosis of MAP is established, indicating the number and size of polyps as well as the localization of PVs in the MUTYH gene, for example:

"Adenomatous polyposis syndrome. MUTYH-associated polyposis (14 polyps, 6-25 mm). Pathogenic variants in the MUTYH gene p.Arg231His and p.Gly382Asp."

In MAP, if the number of polyps exceeds 100, the exact number and sizes of the polyps are not specified, for example:

"Adenomatous polyposis syndrome. MUTYH-associated polyposis (more than 100 polyps). Pathogenic variants in the MutYH gene p.Arg231His and p.Gly382Asp."

Upon discovery of 2 PVs in the MUTYH gene in patient relatives, even in the absence of polyps on colonoscopy, a diagnosis of APS is established, for example:

"Adenomatous polyposis syndrome. MUTYH-associated polyposis. Pathogenic variants in the MUTYH gene p.Arg231His and p.Gly382Asp. Preclinical stage."

When a malignant colonic tumor is discovered in APS, the cancer diagnosis should be placed first in the diagnostic formulation, for example:

"Ascending colon cancer T4N0M0. Adenomatous polyposis syndrome, classic form. Pathogenic variant in the APC gene c.2730-2737del8."

2.1 Complaints and Anamnesis

Patients with APS most typically complain of frequent, loose stools, abdominal pain, and abnormal impurities in the stool (blood, mucus). Some patients may present with complaints of general weakness, weight loss, abdominal distension, and nausea.

• For all patients who, according to anamnesis and instrumental examination, have a total of more than 20 colorectal polyps (including adenomas, serrated lesions, hyperplastic polyps), as well as those with a family history of FAP or a history of extraintestinal manifestations of FAP in the presence of any number of colorectal polyps (multiple duodenal/gastric adenomas, desmoid tumors, papillary thyroid cancer, epidermal cysts, osteomas), it is recommended to construct a pedigree followed by an analysis of the inheritance pattern characteristic of the family (autosomal dominant, autosomal recessive) [24,28-30].

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

2.2 Physical Examination

All patients with suspected FAP require a physical examination:

• general physical examination;

• inspection and palpation of the abdomen;

• external inspection of the perineal and perianal region;

• digital rectal examination.

During the general examination of the patient, attention is paid to the body mass index, pallor and dryness of the skin, and the presence/absence of extraintestinal manifestations (soft tissue and sebaceous gland tumors). Inspection and palpation of the abdomen are performed to identify abdominal cavity tumors and desmoid tumors, and to assess the state of the inguinal lymph nodes.

Inspection of the perianal area is performed in a gynecological chair with the patient lying on their back with their legs brought as close to the abdomen as possible, or, if not possible, in the lateral position. During the external inspection of the perineal and perianal region, attention is paid to changes in the perianal skin, the shape of the anus, its gaping, and the presence of any changes or deformations. Digital rectal examination assesses the presence or absence of polyps in the lower ampullary rectum and their size, as well as the presence or absence of malignancies arising from them. Attention should be paid to the tone and voluntary contractions of the anal sphincter to assess the functional state of the anal sphincter apparatus.

2.3 Laboratory Diagnostics

• All patients with suspected FAP are recommended to undergo molecular genetic testing for mutations in the APC/MUTYH genes in blood samples [30-36].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: this method makes it possible not only to establish the presence of the disease in the patient, but also to determine the probability of its development in a currently healthy child. All patients with more than 20 adenomatous polyps in the colon should undergo DNA diagnostics of the entire coding sequence of the APC/MUTYH genes. Moreover, if a patient has more than 100 polyps, it is advisable to start testing with the APC gene to save time, whereas if the number ranges from 20 to 100, testing should start with the MUTYH gene [19,21,22,34]. Given the number of already known pathogenic variants (PVs) in the APC gene (over 2,000) as well as in the MUTYH gene (over 220), it is necessary to study the complete coding sequence of these genes.

Methods: blood is drawn from the FAP patient, and the coding regions of the APC/MUTYH genes are analyzed. If a pathogenic variant (PV) is detected, blood is drawn from blood relatives. Since the identified PV in blood relatives is localized in the same gene regions as in the patient, targeted analysis of only a single gene region is performed. If the presence of the PV is confirmed, the individual is diagnosed with FAP and scheduled for an endoscopic examination.

• All patients with suspected FAP in whom sequencing reveals no pathogenic variants (PVs) in the APC/MUTYH genes are recommended to continue molecular genetic testing to search for large rearrangements in the APC gene [30].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: according to studies, large rearrangements in the APC gene account for up to 10% of all diagnosed pathogenic variants leading to the development of classic FAP. The sequential use of traditional Sanger sequencing and methods for detecting large rearrangements (MLPA — multiplex ligation-dependent probe amplification) increases the total detection rate of pathogenic variants in the APC gene to over 90%. At the same time, the need to search for large deletions/duplications in the MUTYH gene is not indicated [30].

• All blood relatives of a patient with a confirmed pathogenic variant (PV) in the APC/MUTYH genes (children, siblings, nephews/nieces) are recommended to undergo molecular genetic testing to search for the same PV; if detected, they are indicated for lifelong clinical monitoring and timely surgical intervention to prevent malignant transformation of polyps [31-33].

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

Comment: if no pathogenic variants (PVs) are found in the APC and MUTYH genes in patients with the clinical presentation of FAP, genetic testing of all their blood relatives loses its clinical utility. However, all these relatives remain potentially at risk for colorectal cancer and require lifelong monitoring.

In addition, patients with suspected FAP may be diagnosed with iron deficiency anemia based on a complete blood count, while blood biochemistry can reveal electrolyte and metabolic disorders, and hypoproteinemia (specifically hypoalbuminemia).

2.4 Instrumental Diagnostics

Comment: colonoscopy is the primary and most accurate diagnostic method for FAP. This examination determines the extent of polyp involvement across different sections of the colon, which directly influences the choice of treatment strategy. Biopsies provide data on the malignant transformation of polyps in various segments of the colon [28].

• To increase the detection rate of adenomas, all patients with suspected FAP are recommended to additionally use software during colonoscopy (artificial intelligence) that has demonstrated a reproducible level of accuracy in the automated detection/identification of benign epithelial neoplasms of the colon [91-95].

GRG BLEL 1Level of Recommendation Evidence – B (Level of Evidence – 1)

Comments: a systematic review analyzed 6 randomized controlled trials to compare the adenoma detection rate (ADR) during colonoscopy with and without the use of a CADe system (2480 individuals in the CADe group, 2482 in the control group) [91]. Meta-analysis results showed a statistically significant increase in the adenoma detection rate when using computer-aided polyp detection systems and an increase in colonoscope withdrawal time. Another systematic review and meta-analysis of seven randomized clinical trials (2595 colonoscopies using CADe systems, 2622 standard colonoscopies) showed an 80% increase in the mean number of small adenomas detected per patient when using computer-aided detection tools compared to standard colonoscopy [92]. However, the studies included in the review were predominantly conducted in a single country (PRC); furthermore, the expertise level of the endoscopists performing the colonoscopies was not specified. A meta-analysis of six randomized controlled trials (4996 cases) showed a higher detection rate of flat adenomas and sessile serrated lesions during colonoscopy using artificial intelligence, although standard colonoscopy showed better results for pedunculated polyps [93]. A large multicenter randomized controlled trial (3059 patients, 1519 in the CADe colonoscopy group, 1540 in the standard colonoscopy control group) demonstrated an increase in the detection rate of adenomas among both endoscopists with over 5,000 prior colonoscopies and less experienced endoscopists [94]. Similar results were obtained in studies evaluating domestically developed software [95].

Comment: in the presence of malignant tumors associated with FAP, chest CT is additionally performed to determine the extent of the malignant process and diagnose distant metastases.

• When planning surgery with the formation of an ileal pouch for a patient with FAP, it is recommended to perform a physiological assessment of the anal sphincter apparatus function to rule out baseline anal sphincter insufficiency, which could negatively impact the functional outcomes of the surgery [44,45].

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

• In the presence of malignant rectal tumors in patients with FAP, pelvic MRI is recommended to assess the presence of malignant transformation and depth of invasion [35,51,59].

Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)

Comment: if a neoplasm with suspected malignancy or a malignant colorectal tumor is detected in a patient with FAP, additional diagnostic methods provided by the Clinical Guidelines for the Diagnosis and Treatment of Colon and Rectosigmoid Cancer and Rectal Cancer must be performed [58,59].

2.5 Other Procedures

No.

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

3.1 Conservative Treatment

There are no non-surgical treatment methods for FAP [1,2,35,47].

3.2 Surgical Treatment

Currently, the main treatment method for FAP is surgery. Furthermore, FAP treatment should be performed in specialized centers, since the complication rate and functional outcome significantly depend on the qualifications of the coloproctologist and surgeon (specifically, on the number of similar procedures performed) [48].

• When performing surgical interventions in patients with FAP, the use of laparoscopic techniques is recommended whenever technically feasible [49,50,83,84].

GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)

Comments: the use of laparoscopic techniques helps reduce surgical trauma, decreases the rate of periopharmaceutical complications, enables early patient mobilization, and shortens the rehabilitation period [50]. In addition, in female patients with FAP, laparoscopic techniques reduce the risk of infertility by 90% [83].

3.2.1 Classical form of APS

Given the genetically determined nature of the disease (and consequently the lack of conservative treatment options), as well as the obligate precancerous status of the condition, the only possible method of surgical treatment is the removal of the target organ—the large intestine.

• In confirmed classical FAP, all patients are recommended to undergo proctocolectomy with ileal pouch-anal anastomosis (IPAA) and a diverting ileostomy [52,53,86].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: taking into account the young age of the patients (manifestation occurs in the 2nd-3rd decade of life in the classical form of the disease), with the potential goal of social adaptation after colectomy, a reconstructive stage of the operation is performed: formation of a pouch from the distal ileal loop, pull-through of the constructed pouch into the pelvic cavity with creation of an ileoanal pouch anastomosis and a diverting loop ileostomy [53].

To improve patients' quality of life during surgery, it is possible to preserve 1–2 cm of the rectal wall in the supranal area for stapled anastomosis creation. If stapled anastomosis is not feasible, handsewn anastomosis should be performed. Although a small mucosal remnant is preserved when using a stapler, the risk of cancer development in this area is low and comparable to that of a handsewn anastomosis [54].

Reconstructive surgery to restore intestinal continuity—ileostomy closure—is performed no earlier than 2–3 months after the initial surgery, provided that the ileal pouch and ileoanal anastomosis are airtight and competent (based on retrograde contrast X-ray examination, i.e., pouchography) [2].

• For patients with classical FAP who have contraindications to the formation of an ileal pouch and ileoanal anastomosis, proctocolectomy with end ileostomy is recommended [35].

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

Comment: contraindications to proctocolectomy with ileal pouch and ileoanal anastomosis include: the presence of a desmoid tumor involving the small bowel mesentery, anatomical features of the small bowel mesentery that preclude its pull-through into the pelvic cavity, low rectal cancer with extension into surrounding tissues and infiltration of pelvic floor elements, as well as patient refusal of the reconstructive component of the surgery in favor of a permanent ileostomy (due to personal preferences or impaired anal sphincter function) [35].

3.2.2 Attenuated form of APS

The choice of surgical treatment for attenuated FAP depends on the age at disease manifestation, the number, type, size, and location of detected colorectal polyps, as well as the results of genetic testing.

• For patients with attenuated FAP who are candidates for complete endoscopic clearance of the colon and have no more than 10 polyps >1 cm in size, endoscopic polypectomy is recommended [55,87].

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

Comment: it must be remembered that regardless of the results of endoscopic polypectomy, patients require regular follow-up monitoring, as this method is purely supportive and cannot replace radical surgery [55]. Contraindications to endoscopic polypectomy include: suspicion of malignancy in any of the polyps, high-grade dysplasia in the polyp tissue based on biopsy results, and a significant increase in the number and size of polyps between two consecutive colonoscopies [55].

• In attenuated FAP with identified biallelic pathogenic variants in the MUTYH gene, as well as when a small number of polyps are found in the rectum, colectomy with ileorectal anastomosis is recommended [35,56,57].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: the clinical presentation of FAP caused by pathogenic variants in the MUTYH gene is characterized by predominant involvement of the right colon and a minimal number of polyps in the rectum, making it possible to preserve the rectum during surgical treatment [56]. When attenuated FAP is diagnosed in patients over 45 years of age with no signs of polyp malignancy and predominant right-sided colonic involvement, preservation of the rectum and formation of an ileorectal anastomosis are also feasible. Following this procedure, patients require annual endoscopic surveillance with removal of newly formed rectal polyps [57].

3.2.3 MAP

• For patients with MAP presenting with 20–99 polyps and the possibility of complete endoscopic colonic clearance (with no more than 10 polyps >1 cm in size), endoscopic removal of colorectal polyps is recommended [12, 87].

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

• When biallelic pathogenic variants in the MUTYH gene are identified, or when more than 100 polyps are found in the colon with a minimal number of polyps in the rectum, colectomy with ileorectal anastomosis is recommended [35,56,57,86].

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

• For MAP with 100 or more polyps and multiple rectal involvement, all patients are recommended to undergo proctocolectomy with ileal pouch-anal anastomosis and a diverting ileostomy [12].

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

3.3 Treatment of CRC in the setting of APS

In most cases, the diagnosis of FAP reveals single or synchronous multiple malignant colorectal tumors. Furthermore, colorectal cancer symptoms often play a leading role in the clinical presentation.

When a malignant colorectal tumor is detected in a patient with FAP, neoadjuvant/adjuvant treatment (if necessary) for colorectal cancer is advisable (see the clinical guidelines "Colon and Rectosigmoid Cancer" and "Rectal Cancer") [58,59]. When colorectal cancer develops in the setting of FAP, treatment of the oncological disease takes priority according to its localization and stage [58,59].

• During surgical treatment of a patient with colorectal cancer in the setting of FAP, the surgical intervention is recommended to be performed according to the oncological principles outlined in the clinical guidelines for the diagnosis and treatment of colon and rectal cancer [58,59], supplemented by the removal of the remaining parts of the colon.

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

• During surgical treatment of a patient with colorectal cancer and FAP who has confirmed biallelic pathogenic variants in the MUTYH gene and fewer than 100 colorectal polyps, segmental resection of the colon is recommended in accordance with the oncological principles outlined in the clinical guidelines for the diagnosis and treatment of colon and rectal cancer [58,59].

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

followed by annual endoscopic surveillance and removal of detected polyps in the remaining parts of the colon [86].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

Comment: according to the results of a systematic review with meta-analysis of surgical tactics in patients with MUTYH-associated polyposis (MAP), generalizing data on 474 patients with MAP, CRC was diagnosed in 56% of patients, the vast majority of whom (87%) underwent segmental colon resections. At the same time, metachronous cancers occurred in only 5% of cases. The authors conclude that despite the risk of CRC development, which in most observations had a non-aggressive course, the clinical course of MUTYH-associated polyposis is relatively favorable. For this category of patients, it is possible to limit treatment to the resection of the colon segment affected by cancer with annual endoscopic monitoring and removal of polyps detected in the remaining parts of the colon [86].

3.4 Treatment of desmoid tumors in patients with APS

Desmoid tumors are histologically benign, but potentially locally aggressive neoplasms that affect about 15% of patients with FAP. Unlike other desmoid tumors, FAP-associated desmoids are usually located in the abdominal cavity and involve the mesentery of the small intestine. Most of them arise after previous surgical treatment. Risk factors for the development of desmoids include a family history of such tumors, intra-abdominal surgical interventions, and the location of the APC mutation between codons 148 and 1800 in the APC gene [60]. When these factors coincide, the risk of developing an intra-abdominal desmoid tumor reaches 65% [61].

There are no proven predictors of desmoid tumor growth. Some of them may spontaneously stop growing, some regress, and others continue to grow relentlessly. In a small number of patients, this growth can be rapid and uncontrolled.

• When a desmoid tumor located in the thickness of the abdominal wall or in the abdominal cavity is detected in patients with FAP, conservative therapy with high-dose antiestrogens in combination with a non-steroidal anti-inflammatory drug from the acetic acid derivatives group and related compounds is recommended [35,88].

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

Comments: due to the small number and quality (retrospective, uncontrolled) of the conducted studies, there is no convincing data on the preferred methods of treatment for desmoid tumors. However, in a prospective cohort study including 64 patients with intra-abdominal desmoid tumors arising against the background of FAP, after treatment with high-dose antiestrogens in combination with a non-steroidal anti-inflammatory drug from the acetic acid derivatives group and related compounds for at least 1 year, a tumor response (in the form of stabilization or regression) was demonstrated in 85% of cases. After achieving a positive response, the dose of drugs was reduced in 60% of patients, against which background only one tumor recurrence was noted after 10 years [62]. Thus, the role of surgical treatment of desmoid tumors should be limited to the correction of secondary changes caused by the local nature of tumor growth - obstruction of the gastrointestinal tract, urinary tract, etc.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no specific rehabilitation measures for patients with FAP. In some patients whose surgical intervention for FAP ended with the formation of an ileal pouch and an ileoanal anastomosis, deterioration of continence function is possible. Medical rehabilitation measures are aimed at the fastest possible recovery in the postoperative period and the achievement of a socially acceptable degree of adaptation of patients in society after surgical treatment. At the same time, rehabilitation for such patients is carried out in three stages: Stage 1 (early rehabilitation) is carried out immediately after surgical intervention up to the 14th day. The main tasks are: restoration of normal functioning of the gastrointestinal tract, control of homeostasis, relief of postoperative pain syndrome, activation of the patient, healing of postoperative wounds. The second stage of rehabilitation begins after the 15th day and continues as needed thereafter, aimed at the final healing of postoperative wounds with control over the activity of the gastrointestinal tract and other body systems. This stage can be carried out both on an outpatient basis and in a day or 24-hour hospital setting. The third stage of rehabilitation is carried out in the late postoperative period in patients with both a permanent ileostomy and before reconstructive surgery. The main rehabilitation actions at this stage are compensation of gastrointestinal tract function, as well as measures aimed at identifying disorders and correcting the function of the rectal sphincter apparatus.

Patients with FAP who have undergone surgery with the formation of a temporary/permanent ileostomy need to use ostomy bags and stoma care products [63]. For stoma care in the early postoperative period, a special postoperative ostomy bag is used, which is applied immediately after the operation. A hole corresponding to the size of the stoma is cut in the adhesive faceplate. The transparent bag and removable cover make it possible to monitor the state of the stoma in the early postoperative period. For further stoma care, a single- or two-piece system is selected for the patient, taking into account the functional characteristics of the stoma, the topography of the peristomal area, individual preferences, and the patient's ability to be trained.

• Before performing reconstructive surgery, patients with FAP are recommended to undergo an examination of the functions of the sphincter apparatus of the rectum (sphincterometry, profilometry, pudendal nerve terminal motor latency study) followed by an examination (consultation) by a functional diagnostics physician if functional disorders are detected [45,46].

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

Comment: in some patients whose surgical intervention for FAP ended with the formation of an ileal pouch, a decrease in continence function is possible due to the removal of the rectal ampulla and intraoperative trauma to the sphincter apparatus as a result of the formation of the ileoanal anastomosis [64,85].

• If a patient with FAP who has undergone colectomy with proctectomy and formation of an ileal pouch and ileoanal anastomosis is found to have grade 2-3 anal sphincter insufficiency before reconstructive surgery, a 10-day cycle of electrical stimulation using biofeedback (biofeedback therapy and tibial neuromodulation) in a day or 24-hour hospital setting is recommended in order to improve the expected quality of life of patients [46,65].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: according to the literature, in the rehabilitation of patients with anal sphincter insufficiency, a treatment method based on biofeedback (BFB), aimed at improving the contractility of the external sphincter and pelvic floor muscles by increasing both the strength and duration of voluntary contraction, has found widespread use [46,65]. This method involves the body's own resources in the rehabilitation process with the development of correct skills at the level of creating new conditioned reflex connections. Tibial neuromodulation is also an effective method, in which an electric current along certain nerve pathways modulates the previously existing activity in other nerve pathways or centers. Percutaneous electrical stimulation of the posterior tibial nerve is used for functional diseases of the pelvic organs, since fibers from the II and III sacral segments of the spinal cord pass as part of the posterior tibial nerve, playing a significant role in the innervation of the rectum, bladder, and their sphincters. It has been proven that the muscular structures of the disconnected sphincter apparatus can respond to biofeedback therapy and tibial neuromodulation with an increase in both tone and the strength of voluntary contractions [46,65]. Tibial nerve stimulation is carried out using a cutaneous stimulating electrode, which allows the patient, after a preliminary training course, to continue the treatment course independently at home. In this case, the course of treatment with daily stimulation sessions can be extended up to 1-3 months. Control of the effectiveness of BFB therapy is carried out before the start and at the end of each course of procedures by a comprehensive physiological study of the function of the rectal sphincter apparatus (sphincterometry + physiological study of the reservoir function of the formed pouch). With an improvement in the parameters of tone and contractility of the anal sphincters, the issue of performing reconstructive surgery aimed at restoring the natural passage through the gastrointestinal tract can be raised [46].

5. Prevention and Dispensary Observation

Given that FAP is an hereditary disease, specific prevention does not exist [1,2]. Despite this, there are data studying the use of non-steroidal anti-inflammatory and antirheumatic drugs as chemopreventive agents in patients with FAP. At the same time, it has been demonstrated that the administration of non-steroidal anti-inflammatory drugs from the acetic acid derivative group and related compounds, as well as from the coxib group, reduces the number and size of polyps in the short term [66-69], however, long-term cancer prevention as an endpoint was not achieved in large randomized trials [70-72].

Considering FAP as an obligate precancerous condition, it is important to clarify that the only way to prevent CRC is timely surgical treatment, as described in section 3. Preventive measures also include a thorough family history taking in a patient with FAP, carrying out necessary genetic testing, and a comprehensive examination of close blood relatives for the timely detection of FAP patients before the onset of clinical symptoms.

FAP is frequently accompanied by the development of multiple polyps also in the upper gastrointestinal tract (stomach, duodenum). At the same time, fundic gland polyps are detected in 80% of patients with FAP [73] and are completely benign formations without malignant potential, without increasing the risk of gastric cancer [74]. At the same time, the presence of adenomatous polyps in the duodenum in FAP is associated with a cancer risk in 5% of cases [75].

• Patients with FAP are recommended to undergo esophagogastroduodenoscopy starting from the age of 25 years; in those patients diagnosed with FAP at a later age, from the moment of FAP diagnosis [35,41].

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

Comment: considering the incidence of duodenal cancer reaching 5%, prophylactic organ removal is not used. At the same time, for those patients in whom duodenal cancer was diagnosed during dynamic monitoring, a survival advantage was demonstrated compared to those who sought medical attention already with clinical symptoms [76]. Currently, to stage duodenal involvement and determine monitoring intervals, it is customary to use the Spigelman A.D. classification (Table 1).

Table 1. Classification of duodenal involvement in FAP and corresponding management tactics (according to Spigelman A.D. [37,38]).

• All patients with FAP who have undergone proctocolectomy with ileorectal/ileal pouch-anal anastomosis are recommended to undergo an annual endoscopic examination of the remaining part of the rectum and the small intestinal pouch [12,35,36,81].

LoE AGoE 3Level of evidence – A ( grade of recommendation – 3)

Comment: in the remaining part of the rectum after surgical treatment, new polyps may appear, which, in the absence of necessary control, tend to malignant transformation. In addition, 12–18 months after ileostomy closure, morphological changes in the epithelial lining develop in the pouch, characterized by flattening and a reduction in the number of villi leading to their atrophy ("colonic metaplasia"), which potentially leads to the risk of malignant transformation of the pouch mucosa [79,80]. Thus, as a result of a systematic review of 54 studies summarizing data on 5,010 patients operated on for FAP, it was noted that the cumulative risk of developing adenomas in the small intestinal pouch and the remaining part of the rectum during pouch-rectal anastomosis formation was 85% by 20 years after surgery. The risk of detecting adenomas after surgery with ileorectal anastomosis formation was 85% by 5 years after surgery and 100% by 10 years. The cumulative risk of developing cancer by 30 years after surgical treatment of FAP was 24% [81].

• All patients who have undergone surgical treatment for FAP are recommended to undergo an annual comprehensive ultrasound/CT of the abdominal cavity and pelvic organs for the timely detection of possible desmoid tumors [89,90].

GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)

Comment: FAP-associated desmoids are usually located in the abdominal cavity, involve the small bowel mesentery, and occur after surgery. Risk factors for desmoid development are considered to be a family history of such tumors, abdominal surgery, and the location of the APC mutation between codon 148 and 1800 in the APC gene [60]. When these factors coincide, the risk of developing an intra-abdominal desmoid tumor reaches 65% [61,82].

6. Organization of Medical Care

Primary specialized health care for patients with FAP is provided by a coloproctologist, an oncologist, and other medical specialists in medical organizations licensed for the relevant types of medical activities.

In case of suspected or detected FAP in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), medical specialists, and mid-level medical personnel shall refer the patient in the established manner for a consultation to a medical organization that includes a coloproctologist's office and/or an outpatient coloproctology center (department) to receive primary specialized health care. The consultation in the specified structural units of the medical organization must be carried out no later than 15 working days from the date of issuing the referral for consultation.

The coloproctologist organizes a timely qualified examination of the patient, including determining the severity of clinical symptoms, endoscopic examination, taking biopsy material, and a geneticist consultation. The geneticist takes a family history, draws up a pedigree, and prescribes DNA diagnostics in a genetics laboratory.

If treatment and in-depth inpatient examination are necessary, the patient is referred by the attending physician to a coloproctology department or another medical organization providing inpatient medical care to patients in the profile "coloproctology".

The coloproctologist of a medical organization that includes a coloproctologist's office, outpatient coloproctology center (department), refers the patient to medical organizations that include a coloproctology department and a genetics laboratory for inpatient medical care (if it is impossible to establish a diagnosis during primary specialized health care) to provide specialized, including high-tech, medical care. The timeframe for initiating specialized, excluding high-tech, medical care is determined by the decision of the patient selection committee for hospitalization depending on the severity of clinical symptoms, and this timeframe must not exceed 30 calendar days from the date of issuing the hospitalization referral.

Specialized, including high-tech, medical care for FAP is provided by coloproctologists in medical organizations that include a coloproctology department, possess a license, the necessary material and technical base, and certified specialists, in inpatient and day hospital settings, and includes diagnosis, treatment of FAP requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care for FAP are determined by the coloproctologist with a multidisciplinary concilium if necessary.

Indications for emergency or urgent hospitalization of a patient to a medical organization are:

1) Presence of FAP complications requiring emergency and urgent specialized medical care.

2) Presence of FAP treatment complications requiring emergency and urgent specialized medical care.

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

1) Need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in a 24-hour or day hospital setting.

2) Presence of indications for specialized treatment of adenomatous polyposis syndrome (surgical intervention) requiring monitoring in an inpatient or day-inpatient setting.

Indications for discharging a patient from a medical organization are:

1) Completion of a course of treatment or a stage of specialized, including high-tech, medical care in an inpatient or day-inpatient setting, provided there are no complications of treatment requiring drug correction and/or inpatient medical interventions.

2) Refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-inpatient setting prescribed by the medical board of the organization providing treatment for adenomatous polyposis syndrome, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or inpatient medical interventions.

3) The need to transfer the patient to another medical organization specializing in the relevant medical care profile. The conclusion on the feasibility of transferring the patient to a specialized medical organization is made after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the planned receiving medical organization.

7. Additional Information

No.

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of primary health care in adults with adenomatous polyposis syndrome (ICD-10 codes: D12)

Criteria for assessing the quality of specialized medical care in adults with adenomatous polyposis syndrome (ICD-10 codes: D12)

References

Appendix A1. Working Group Composition

Most members of the working group are members of the Association of Coloproctologists of Russia. There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Coloproctologists

2. Gastroenterologists

3. Endoscopists

4. Surgeons

5. Oncologists

6. General practitioners (family physicians)

7. Internists

8. Geneticists

9. Laboratory Geneticists

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

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Rating scale for levels of evidence (LE) for preventive, therapeutic, and rehabilitation methods (interventions)

Table 3. Rating scale for grades of recommendation (GR) for preventive, diagnostic, therapeutic, and rehabilitation methods (interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding 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

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 24, 2024) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

2. Decree of the Government of the Russian Federation No. 1968 dated November 17, 2021 "On Approval of the Rules for the Phased Transition of Medical Organizations to the Provision of Medical Care Based on Clinical Guidelines Developed and Approved in Accordance with Parts 3, 4, 6–9, and 11 of Article 37 of the Federal Law 'On the Fundamentals of Protecting the Health of Citizens in the Russian Federation'."

3. Order of the Ministry of Health of the Russian Federation No. 206n dated April 2, 2010 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to the Population with Diseases of the Colon, Anal Canal, and Perineum of the Coloproctological Profile".

4. Order of the Ministry of Health of the Russian Federation No. 168n dated March 15, 2022 "On Approval of the Procedure for Conducting Dispensary Observation for Adults".

5. Order of the Ministry of Health of the Russian Federation No. 1363n dated December 23, 2020, "On approval of the Procedure for referring insured persons to medical organizations, the functions and powers of whose founders are exercised by the Government of the Russian Federation or federal executive bodies, for the provision of medical care in accordance with the uniform requirements of the basic compulsory medical insurance program".

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

If the patient has close relatives who were previously diagnosed with APS, early-onset colorectal cancer, or a history of multiple colorectal polyps, it is necessary to consult a physician to undergo required examinations and potential early diagnosis of APS.

Patients diagnosed with APS must remember the mandatory lifelong regular dynamic follow-up and scheduled examinations even after surgical treatment, since target organs in APS include not only elements of the gastrointestinal tract, but also other systems and organs.

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

Information is not available.