Cutaneous squamous cell carcinoma: clinical guidelines

List of Abbreviations

AJCC – American Joint Committee on Cancer

CTCAE – Common Terminology Criteria for Adverse Events

ECOG – Eastern Cooperative Oncology Group

RECIST – Response Evaluation Criteria in Solid Tumors

TNM – (stands for tumor, node, and metastasis) is the international classification of malignant tumor stages.

UICC – Union for International Cancer Control

IV – intravenous

ATC – Anatomical Therapeutic Chemical Classification System – an international drug classification system

AK – actinic keratosis

cSCC – cutaneous squamous cell carcinoma

NOS – not otherwise specified

BT – brachytherapy

WHO – World Health Organization

CT – computed tomography

RT – radiotherapy

PT – physical therapy

MAL – methyl aminolevulinate (methyl aminolevulinic acid)

mAb – monoclonal antibodies (ATC code: L01XC)

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

NMSC – non-melanoma skin cancers

PET/CT – positron emission tomography combined with computed tomography

SFD – single focal dose

TFD – total focal dose

US – ultrasound examination

PDT – photodynamic therapy

ECS – extracapsular spread

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

Brachytherapy (BT) - contact irradiation of the tumor

Second stage of rehabilitation – inpatient rehabilitation in medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, and the period of residual disease symptoms.

Incisional punch biopsy – a method of obtaining a full-thickness skin tissue sample, where the lateral resection margins may contain elements of the tumor (or nevus). Performed using a special punch needle (1 to 5 mm in diameter). One of the preferred methods (along with excisional biopsy) for establishing the diagnosis of cSCC.

Intraoperative morphological control of all resection margins (peripheral and deep) – a variant of urgent intraoperative frozen-section pathological examination of surgical specimens during surgical interventions for skin tumors. It differs from the standard method in the ways of cutting, marking, and preparing specimens to evaluate the resection margins (see also Table 19). Intraoperative control of all peripheral and deep resection margins is generally performed on fresh-frozen cryostat sections, achieving a visual assessment of up to 99% of the resection margin area. This method contrasts with the standard 'bread-loafing' histological examination technique, in which less than 1% of the removed tissue surface is evaluated.

Curettage – a medical procedure in which a special instrument (curette or medical spoon) is used to clean out (scrape) the tumor from the skin surface.

Anterior segment optical coherence tomography (OCT) -a non-invasive, informative, and sensitive method that allows for in vivo 'optical biomicrometry' of cutaneous squamous cell carcinoma of the eyelid, including the palpebral commissure.

Tumor surface imprint - a methodological technique for obtaining material for cytological examination.

First stage of rehabilitation – rehabilitation during the period of specialized treatment for the primary disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the primary disease.

Planar (shave) resection of skin neoplasms – a method for removing exophytic and flat skin neoplasms in the plane of the skin using a razor blade or scalpel. In cases of suspected cutaneous melanoma, it is a suboptimal diagnostic method because it does not reliably determine the thickness of the neoplasm and thus prevents correct staging of the disease.

Prehabilitation – rehabilitation from the moment of diagnosis until the start of treatment (surgery/chemotherapy/radiation therapy).

Radiological response evaluation - evaluation of treatment response using the results of radiological examinations (computed tomography, magnetic resonance imaging, positron emission tomography, radiography, etc.) compared with the results of previous radiological examinations in accordance with one or more response evaluation systems (such as RECIST or WHO)

Resectable cutaneous squamous cell carcinoma and/or resectable metastases of cutaneous squamous cell carcinoma – cutaneous squamous cell carcinoma or its metastases (typically regional lymph node metastases) that can be subjected to radical R0 surgical resection. Resectability assessment can be influenced by factors such as the volume (number and size) of metastatic lymph node involvement, relationship with major vessels, and underlying tissues (e.g., bone). The assessment of process resectability is highly subjective and may vary from institution to institution and from surgeon to surgeon.

Third stage of rehabilitation – rehabilitation during the early and late rehabilitation periods, and the period of residual disease symptoms in departments (offices) of rehabilitation, physiotherapy, exercise therapy, reflexology, manual therapy, psychotherapy, medical psychology, and speech therapy (defectology offices) providing outpatient medical care, in day hospitals, as well as by mobile home-visiting teams (including in sanatorium-resort organizations).

Ocular ultrasound – scanning using ultrasound waves. Ultrasound is a non-invasive, contact instrumental method used in the diagnosis of cutaneous squamous cell carcinoma of the eyelid, including the palpebral commissure, and in assessing its treatment efficacy.

Photodynamic therapy (PDT) – a method of treating oncological diseases, certain skin conditions, or infectious diseases based on the use of light-sensitive substances—photosensitizers—and light of a specific wavelength. The sensitizer is administered into the body, most often intravenously, but can also be applied topically. PDT substances have the property of selectively accumulating in the tumor or other target tissues (cells). The pathologically affected tissues are then irradiated with light of a wavelength corresponding to or close to the maximum absorption of the dye.

Excisional biopsy of a skin neoplasm – a method of obtaining a skin tissue sample in which the neoplasm is removed totally (completely) with a small (1–3 mm) margin of surrounding healthy tissue. This method of obtaining morphological material is preferred when cutaneous melanoma is suspected.

Epiluminescence microscopy (dermatoscopy) – a non-invasive skin examination technique (viewing the skin under magnification) using a dermatoscope, which typically consists of a magnifier (×10), a non-polarized light source, a transparent plate, and a liquid medium between the instrument and the skin. Modern dermatoscopes may use a liquid medium or instead apply polarized light to compensate for skin surface reflections. When the obtained images or video clips are digitally recorded or processed, the device may be called a digital epiluminescence dermatoscope.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Cutaneous squamous cell carcinoma (hereinafter cSCC) is a malignant skin tumor originating from epithelial cells (keratinocytes) of the skin epidermis and/or the epidermis of hair follicles. Cutaneous squamous cell carcinoma is the second most common tumor after basal cell carcinoma among all non-melanoma skin cancers. The frequency of regional metastasis is 10-15% and depends on the location and size of the primary lesion [1].

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

There is no single etiological factor for the development of skin tumors. The most significant risk factor for sporadic (non-hereditary) forms of cutaneous squamous cell carcinoma should be considered exposure to ultraviolet B radiation (wavelength 290–320 nm) and ultraviolet A radiation (wavelength 320–400 nm) [2]. At the same time, skin sensitivity to ultraviolet radiation varies among individuals and can be classified into 6 types, where types 1 and 2 exhibit the highest sensitivity (and, accordingly, the highest probability of sunburn), while types 5 and 6 exhibit the lowest [3]. The risk of developing cutaneous squamous cell carcinoma increases with a cumulative sun exposure duration of approximately 30,000 hours, after which it reaches a plateau [4].

Other risk factors to note include congenital or acquired immunodeficiency (e.g., following organ transplantation or in other conditions requiring immunosuppressants, lymphomas, chronic lymphocytic leukemia, HIV) [2]. Analysis of post-transplant patient registries demonstrates a 5- to 113-fold higher risk of developing cutaneous squamous cell carcinoma compared to the general population [5-15].

An association between artificial ultraviolet radiation (including PUVA therapy) and an increased risk of non-melanoma skin tumors has been described [16]. Individuals with a history of exposure to arsenic and ionizing radiation also have an increased risk of cutaneous squamous cell carcinoma [2]. In many cases, non-melanoma skin tumors develop against the background of preexisting precancerous lesions (such as actinic keratosis), which can also frequently be detected in adjacent areas of skin near the malignant tumor [17].

Cutaneous squamous cell carcinoma also develops in the area of scars or non-healing wounds. Cutaneous squamous cell carcinoma is the most frequent tumor developing on the background of a preexisting scar or a chronic non-healing wound. Cutaneous squamous cell carcinoma developing on the background of a scar or wound has a poorer prognosis and recurs more frequently after treatment [18-27].

Precancerous conditions, such as actinic keratosis or cutaneous squamous cell carcinoma in situ (Bowen's disease), if left untreated, may progress into invasive forms of cancer that can metastasize [28-30].

Cutaneous squamous cell carcinoma cells exhibit a very high diversity of somatic mutations, significantly higher than in other types of malignant tumors. Most of these mutations carry the UV damage signature (cytosine to thymine substitutions, C>T or CC>TT) [31].

There is also a number of hereditary syndromes associated with a potential risk of cutaneous squamous cell carcinoma: albinism, as well as xeroderma pigmentosum [28, 29, 32-36].

Currently, evidence is emerging that certain medications may increase the risk of developing cutaneous squamous cell carcinoma. Such medications include diuretics, calcium channel blockers, beta-blockers (combined relative risk 1.14–1.21), and certain antineoplastic drugs (e.g., BRAF protein kinase inhibitors) [37-39].

1.3 Epidemiology of the Disease or Condition

In the Russian Federation (as in many countries worldwide), squamous cell carcinoma is not recorded separately from other non-melanoma skin tumors; however, according to some data, cutaneous squamous cell carcinoma accounts for up to 15–20% of all cases of non-melanoma skin tumors [40]. Therefore, statistics here and hereafter are presented for all non-melanoma skin tumors.

Cutaneous squamous cell carcinoma is considered the second most common tumor among non-melanoma skin cancers in humans [41, 42]. The incidence varies greatly depending on latitude and is significantly higher in individuals with fair skin phototypes [2]. Consequently, the highest incidence of non-melanoma skin cancers in the world is observed in Australia, where every second resident develops non-melanoma skin cancer by the age of 70, while the lowest is in parts of Africa [2, 4, 40-42]. Patients with two or more non-melanoma skin cancers have a substantially higher risk of developing new ones, and multiple non-melanoma skin cancers are more common in men [43].

In 2022, there were 79,399 new cases of non-melanoma skin tumors diagnosed in the Russian Federation (29,686 in men and 49,713 in women). In 2022, the crude incidence rate (both sexes) was 54.12 per 100,000 population, and the age-standardized rate was 26.49 per 100,000 population (26.94 and 26.62 for women and men, respectively). In the overall morbidity structure, non-melanoma skin tumors accounted for 12.7% in 2018 (both sexes), 10.5% in men, and 14.6% in women. The average annual growth rate of crude incidence rates over 10 years was 0.37% in men and 0.37% in women. The mean age of patients at diagnosis was 69.7 years (both sexes), 68.4 years (men), and 70.5 years (women). The cumulative risk of developing non-melanoma skin tumors (period 2012–2022, age 0–74 years) was 3.03% [44, 45].

In 2022, 714 men and 792 women died from non-melanoma skin tumors in Russia; the crude mortality rate (both sexes) was 1.03 per 100,000 population, and the age-standardized mortality rate was 0.41 per 100,000 population (0.29 in women and 0.59 in men). The mean age at death was 73.7 years (both sexes), 71.1 years (men), and 70.1 years (women). In 2017, 25 cases of melanoma were registered in patients under 20 years of age [44, 45].

The proportion of patients with a morphologically verified diagnosis among all patients with a newly diagnosed malignant neoplasm in Russia in 2018 was 99.2%. In 2022, at the time of diagnosis, Stage I was established in 83.2%, Stage II in 13.6%, Stage III in 2.3%, Stage IV in 0.6%, and stage was unknown in 0.2%. Among newly diagnosed patients, the disease was detected proactively in 36.6% (compared to 45.5% in 2018). One-year mortality rate following diagnosis was 0.5% [44, 45].

At the end of 2022, there were 435,938 patients under active dispensary observation (298.9 per 100,000 population), of whom 160,090 patients (36.7%) had been under observation for 5 years or more. The patient accumulation index was 6.5, and mortality was 0.3% (compared to 0.9% in 2008). According to available reporting forms, in 2022, radical treatment was completed in 68,034 patients (86.0% of newly diagnosed cases), with 75.1% of non-melanoma skin cancer patients (among those eligible for radical treatment) receiving surgery alone, 21.3% receiving radiation therapy alone, 3.5% receiving combined or multimodality treatment (excluding chemoradiotherapy), and 0.2% receiving chemoradiotherapy. There are no data on completed cases of medical therapy (drug therapy) alone [44, 45].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems (hereinafter referred to as ICD-10).

Other malignant neoplasms of skin (C44) [46]:

• C44.0 Malignant neoplasm of skin of lip;

o Excludes: malignant neoplasm of lip (C00)

• C44.1 Malignant neoplasm of skin of eyelid, including canthus;

o Excludes: connective tissue of eyelid (C49.0)

• C44.2 Malignant neoplasm of skin of ear and external auditory canal;

o Excludes: connective tissue of ear (C49.0)

• C44.3 Malignant neoplasm of skin of other and unspecified parts of face;

• C44.4 Malignant neoplasm of skin of scalp and neck;

• C44.5 Malignant neoplasm of skin of trunk (including perianal skin, anus and demarcation zone, breast);

o Excludes: anal canal [anus] NOS (C21.0)

• C44.6 Malignant neoplasm of skin of upper limb, including shoulder region;

• C44.7 Malignant neoplasm of skin of lower limb, including hip region;

• C44.8 Malignant neoplasm of overlapping sites of skin;

• C44.9 Malignant neoplasm of skin, unspecified;

1.5 Classification of the disease or condition

1.5.1. International Histological Classification

The International Histological Classification of Cutaneous Squamous Cell Carcinoma and Certain Keratinocytic Skin Tumors is presented below (see Table 1) [1]:

Table 1. International Histological Classification of Epidermal and Keratinocytic Tumors

* - this code was introduced for the first time in the 4th edition of the WHO classification (2018)

1.5.2. Staging

For staging of cutaneous squamous cell carcinoma, the current version of the AJCC/UICC TNM classification should be used, currently the 8th edition (2017) [47]

Morphological confirmation is mandatory for the staging procedure of squamous cell carcinoma. Assessment of lymph node status for staging purposes is performed using clinical examination and instrumental imaging

Skin cancer classification differs depending on the anatomical region. Currently, cutaneous squamous cell carcinoma is classified separately in 1) the head and neck region, 2) the eyelid skin, including the eyelid commissure, and 3) all other anatomical regions.

1.5.2.1. Skin cancer (excluding eyelid skin, including eyelid commissure, scalp and neck skin, perianal skin, vulva and penis) (C44.5 – 7, C63.2).

This classification applies only to skin cancer (excluding Merkel cell carcinoma) of the specified localizations

Assessment of primary tumor extent (cT) is performed using clinical examination; assessment of lymph node status (N) and the presence or absence of distant metastases (M) is performed using clinical examination and instrumental imaging

The T criterion reflects the extent of the primary tumor (see Table 2)

Table 2. Primary tumor staging (T)

In the case of synchronous multiple primary skin lesions, the tumor should be classified with the maximum (worst) T category, and the number of individual tumors should be indicated in parentheses, e.g., T₂₍₅₎.

The N criterion indicates the presence or absence of regional lymph node metastases (see Table 4)

Regional lymph nodes for tumors located predominantly on one side of the body (left or right) are considered to be:

— Head and neck: ipsilateral parotid, submandibular, cervical, and supraclavicular lymph nodes;

— Chest wall: ipsilateral axillary lymph nodes;

— Upper extremity: ipsilateral epitrochlear and axillary lymph nodes;

— Abdomen, lower back, and buttocks: ipsilateral inguinal lymph nodes;

— Lower extremity: ipsilateral popliteal and inguinal lymph nodes;

— Anal margin and perianal skin: ipsilateral inguinal lymph nodes.

If a tumor is located in border zones, lymph nodes on both sides may be considered regional. Table 3 lists anatomical landmarks for defining 4-cm-wide border zones.

Table 3. Anatomical landmarks of border zones for defining regional lymph node basins

If metastases are detected in lymph nodes outside the specified regional metastatic zones, they should be classified as distant metastases.

Table 4. Regional lymph node staging (N)

The M criterion indicates the presence or absence of distant metastases (see Table 5)

Table 5. Distant metastasis staging (M)

Certain poor prognostic factors are summarized in Section 7 (Additional Information [including factors influencing the outcome of the disease or condition]). In the AJCC classification, the presence of such factors may upgrade the stage from I to II [7].

Stage grouping is presented in Table 6:

Table 6. Stage grouping of non-melanoma skin cancers

1.5.2.2. Skin cancer of the head and neck (excluding eyelid skin and canthus) (C44.0, C44.2 – C44.4).

The T criterion reflects the extent of the primary tumor (see Table 2) in Section 1.5.2.1.

For head and neck skin cancer, there are specific features in the staging of regional lymph nodes (see Table 7)

Table 7. Regional lymph node staging (N)

The M criterion indicates the presence or absence of distant metastases (see Table 5) in Section 1.5.2.1.

Stage grouping is presented in Table 6 in Section 1.5.2.1.

1.5.2.3. Skin cancer of the eyelid, including canthus (C44.1).

Eyelid skin cancer has specific staging features for both the primary tumor and regional lymph nodes.

Morphological confirmation is mandatory. Assessment of the extent of the primary tumor (cT) and lymph node status (N) is performed via clinical examination; presence or absence of distant metastases (M) is evaluated via clinical examination and instrumental imaging studies

Regional lymph nodes for the eyelid, including the canthus, are considered to be the preauricular, submandibular, and cervical lymph nodes.

The T criterion reflects the extent of the primary tumor (see Table 8)

Table 8. Primary tumor staging (T)

The N criterion indicates the presence or absence of regional lymph node metastases (see Table 9)

Table 9. Regional lymph node staging (N)

The M criterion indicates the presence or absence of distant metastases (see Table 5) in Section 1.5.2.1.

Stage grouping is presented in Table 10:

Table 10. Stage grouping of non-melanoma tumors of the eyelid skin, including the canthus

1.5.3. Classification according to recurrence risk factors [48]

From a practical standpoint, squamous cell carcinoma should be classified according to recurrence risk (see Table 11). In this case, tumor location (see Table 12), clinical features, and morphological features are taken into account (see Table 11). Therefore, performing a biopsy with subsequent pathomorphological examination when planning destructive treatment methods is extremely important.

Table 11. Clinical and morphological risk factors for squamous cell carcinoma recurrence [48, 49]

Risk-based localization groups for recurrence are listed in Table 12.

Table 12. Risk of squamous cell carcinoma recurrence depending on the primary tumor site[48, 50]

Squamous cell carcinoma arising on the genitalia, mucous membranes, and auricle is also associated with a higher risk of metastasis [19, 50]

[1] Deep invasion is defined as invasion beyond the subcutaneous fat OR greater than 6 mm (measured from the granular layer of the adjacent normal epidermis to the base of the tumor); perineural invasion (for T3 staging) is defined as clinical or radiologic involvement of named nerves, BUT without invasion or extension through skull base foramina

[2] Note: contralateral lymph node metastases from primary tumors located outside the head and neck should be considered distant metastases

[3] Clinical signs of extracapsular extension include skin or soft tissue involvement, fixation or firm attachment to underlying muscle or other adjacent structures, as well as clinical signs of nerve involvement

[4] Pain, burning, decreased sensation, paresthesia, facial nerve palsy, diplopia, blurred vision, etc. are symptoms that may occur when a motor or sensory nerve is involved in the tumor process.

1.6 Clinical presentation of the disease or condition

Cutaneous squamous cell carcinoma most commonly develops on areas of skin exposed to chronic ultraviolet radiation: the head, neck, dorsal hands, and forearms. Clinical signs of photodamage include atrophy, telangiectasias, solar lentigines, and seborrheic keratosis. cSCC develops more frequently in men than in women. Patients with skin phototypes 1 and 2 are at risk for developing cSCC[51].

cSCC more frequently develops from precursor or background conditions, which include actinic keratosis, chronic infections such as osteomyelitis, chronic inflammation, burns (Marjolin's ulcer), human papillomavirus infection, and rarely cSCC develops de novo [52].

One of the frequent precursors is actinic keratosis (AK), which clinically can be presented by 3 grades. Grade 1 AK is an irregular erythematous macule with a smooth surface, often multiple. Over time, the macule becomes more demarcated, thin whitish scales appear on its surface, and the lesion becomes palpable. This clinical picture corresponds to Grade 2 AK. As the surface scales accumulate and acquire a yellowish tint, Grade 3 AK is diagnosed. An increase in the number of scales on the surface of AK leads to the formation of a cutaneous horn. In such advanced stages, it is impossible to distinguish actinic keratosis from an invasive form of cutaneous squamous cell carcinoma (cSCC) without pathomorphological data. A specific variant of AK is actinic cheilitis, involving the vermilion border of the lower lip, characterized by a well-demarcated area with surface scales and crusts[53, 54].

Non-invasive forms of cSCC include Bowen's disease and erythroplasia of Queyrat. Bowen's disease is characterized by a solitary, irregular psoriasiform plaque with clear margins and tightly adherent dry scales on the surface. It is typically unresponsive to topical anti-inflammatory therapy. Whitish-yellow scales unevenly cover the surface of the neoplasm. Without treatment, the lesion continues to slowly increase in size and over many years evolves into an invasive form of cSCC. Bowen's disease may present with pigmentation. Erythroplasia of Queyrat is a non-invasive form of cSCC localized on the integumentary tissues of the penis, clinically manifesting as a red plaque with distinct borders and a moist, shiny surface when lesions are localized on the integumentary tissues of the penis.

According to the WHO 2018 classification, keratatoacanthoma is a highly differentiated form of cSCC. Clinically, this form presents as a single dark red nodule measuring 2.0 cm or more, with a specific central crateriform depression filled with keratin masses. Keratoacanthoma may undergo spontaneous resolution. [49, 54]

Early manifestations of invasive cSCC may resemble the clinical picture of the hypertrophic form of AK (Grade 3) and may present as a red plaque with yellow-white scales. Without treatment, the lesion becomes large and elevated, forming a firm, dark-red nodule with a necrotic crust in the center. [55]

cSCC arising de novo manifests as a solitary dark-red nodule with a multi-layered crust in the center. Forceful removal of the crusts leads to the formation of an ulcer filled with foul-smelling necrotic masses. The resulting ulcer can lead to the destruction of underlying anatomical structures.[56]

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1) patient complaints and medical history;

2) physical examination (clinical inspection) data and, in some cases, dermatoscopy;

3) vital pathomorphological examination data of biopsy or surgical material, or, in some cases, cytological examination of tumor material.

Table 13 presents the diagnostic workup plan according to the clinical stage of cSCC. Recommendations for the implementation of specific medical interventions are provided in the relevant sections.

Table 13. Diagnostic workup plan according to the clinical stage of the disease

2.1 Complaints and Anamnesis

Comments: The patient should be actively questioned and the presence of the following risk factors for disease onset and recurrence should be documented in the medical records: 1) presence or absence of immunosuppression; 2) prior radiation therapy; 3) previous treatment for skin neoplasms; 4) presence of hereditary diseases or syndromes; 5) number of sunburns; 6) history of thermal/chemical/radiation burns; 7) contact with occupational hazards, such as arsenic; 8) treatment for inflammatory skin diseases, e.g., psoriasis; 9) presence or absence of long-term non-healing wounds or ulcers.

2.2 Physical Examination

Comment: there is significant variation and uncertainty regarding the diagnostic accuracy of visual inspection; the error rate of visual inspection is quite high. Therefore, other diagnostic methods must also be used to ensure accurate diagnosis of malignant skin neoplasms. It should also be noted that multiple primary synchronous tumors (melanomas and non-melanoma skin cancers) can be detected in 5-10% of patients [66-68].

Comment: dermoscopic features specific to Bowen's disease include dotted or glomerular vessels, often arranged linearly, and yellow structureless areas; the pigmented form of Bowen's disease is characterized by brown structureless areas, brown dots and globules arranged linearly; features characteristic of the invasive form of cutaneous squamous cell carcinoma (cSCC), including keratoacanthoma, are: hairpin-like vessels at the periphery of the lesion, centrally located yellow structureless areas, polymorphic vessels, targetoid structures (or keratin follicular plugs), white lines, and in pigmented forms of cSCC – grey-brown dots and globules [70, 72–75].

Comments: it should be noted that physical examination of lymph nodes does not rule out the need for ultrasound examination of lymph nodes in patients with a confirmed diagnosis, as physical examination alone lacks sufficient accuracy.

Comment: full-thickness skin biopsy and subsequent histopathological examination of the biopsy material should always be preferred, as cytological examination of scrapings or imprint smears can yield both false-negative and false-positive results [76].

2.3 Laboratory Diagnostics

• Prior to morphological confirmation of the diagnosis, laboratory diagnostics is not recommended unless intercurrent pathology or the patient's general condition necessitates it for the safe performance of a biopsy [48].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.4 Instrumental Diagnostics

In the absence of symptoms, taking into account the frequency of regional and distant metastasis of cSCC, it is recommended to perform diagnostic examinations of varying scope depending on the stage of the disease (established by clinical examination and histological report) to detect occult metastases. When planning local treatment, it is important to perform the most complete preoperative staging possible if perineural invasion, involvement of underlying soft tissues or other structures, or bone involvement is suspected.

Comment: in the presence of clinical signs of involvement of structures such as bone, it is recommended to perform contrast-enhanced computed tomography (in the absence of contraindications) of the anatomical region involved in the tumor process. When perineural invasion or soft tissue involvement is suspected, contrast-enhanced magnetic resonance imaging should be preferred (in the absence of contraindications) [48, 93–101].

Comment: the treatment and examination plan should not be formulated prior to obtaining histological (or, in some cases, cytological) examination results.

2.5 Other Procedures

Comments: Incisional punch biopsy can be safely performed in an outpatient setting using a specialized instrument—a punch biopsy needle—with the exception of certain anatomical areas (e.g., eyelid skin).

o Histological subtype of cSCC (in accordance with the 2018 WHO classification of skin tumors [103])

o Presence or absence of any features that increase the risk of local recurrence, including, but not limited to, such characteristics as

• degree of differentiation;

• tumor invasion beyond the subcutaneous adipose tissue;

• presence of perineural invasion (if a nerve in the hypodermis is involved or any nerve > 0.1 mm in diameter);

• depth (thickness in mm or anatomical level) of invasion;

• presence of vascular invasion;

• presence of lymphatic invasion

GDR CLE 5Grade of recommendation C (level of evidence – 5)

o Histological subtype of squamous cell carcinoma (in accordance with the 2018 WHO international classification of skin tumors) [103]),

o Depth of invasion, in mm

o Anatomical level of invasion

o Tumor extension beyond the subcutaneous adipose tissue;

o tumor invasion beyond the subcutaneous adipose tissue;

o presence of perineural invasion (if a nerve in the hypodermis is involved or any nerve > 0.1 mm in diameter)

o Depth (thickness in mm or anatomical level) of invasion

o Presence of vascular invasion;

o Presence of lymphatic invasion

o Status of peripheral and deep resection margins

o When obtaining specimens from surgical treatment with intraoperative control of all resection margins, the depth of invasion (in mm) cannot be reliably determined; in this case, it is permissible to indicate the anatomical level of invasion.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

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

The choice of treatment tactics for patients with squamous cell carcinoma should be made individually, taking into account the extent of the tumor process, its location, prognostic factors (including biopsy data), the patient's general condition (severity of comorbid conditions), and life expectancy. The main goal of treatment for patients with cutaneous squamous cell carcinoma (CSCC) should be the complete removal of the tumor, while striving to maximally preserve the function of the involved organ and achieve the best cosmetic results. Surgical approaches are often the most effective and efficient ways to achieve a cure, but considerations of function preservation, cosmetic outcomes, patient preferences, and general health may lead to the choice of radiation therapy as the primary treatment to achieve an optimal overall outcome. Some patients at high risk of developing multiple primary tumors (e.g., in immunosuppression or albinism) may require careful monitoring and preventive measures.

Recommendations on the use of these methods, including dosing regimens for the specified drugs, are presented below.

3.1 Treatment of localized disease stages (I-II)

3.1.1 Treatment of low-risk squamous cell carcinoma

Comment: when performing standard surgical excision, it is recommended to mark orientation landmarks (12 o'clock) on the removed tumor and on the patient's body, which may be necessary when planning re-excision in case the tumor is found at the resection margin during routine histological examination

Table 14. Surgical tactics for cutaneous squamous cell carcinoma depending on the risk of recurrence and primary tumor size [105-122].

o curettage and electrocoagulation

o radiation therapy,

o cryodestruction,

o photodynamic therapy

o or topical agents with antitumor activity [123-146].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comment: Curettage and electrocoagulation can be used by an oncologists for small (<2 cm), well-demarcated CSCC lesions with non-aggressive histology in low-risk areas. Curettage and electrocoagulation are not indicated for recurrent or high-risk CSCC. Curettage should be performed with a sharp curette until healthy tissue is reached, the obtained material should be sent for lifelong pathomorphological examination, and only after that should electrocoagulation of the tumor bed be performed

Comment: the choice of the type of radiation therapy (contact X-ray therapy, gamma and electron beam therapy, brachytherapy) and the dose fractionation regimen is carried out depending on the size and location of the tumor, the patient's condition, preferences, and the capabilities of the medical institution. Brachytherapy is not considered a standard approach in the treatment of cutaneous squamous cell carcinoma and can be considered only in a strictly selected group of patients (e.g., skin cancer of the eyelids, including the canthus). Possible doses and regimens of external beam radiation therapy and brachytherapy are given in Table 15.

Table 15. Regimens and doses of standalone external beam radiation therapy in low-risk cutaneous squamous cell carcinoma.

Comment: hypofractionated radiation therapy regimens are presented in Table 16.

Table 16. Hypofractionated radiation therapy

Comment: when administering external beam radiation therapy using an electron or photon beam, it is advisable to use boluses of various thicknesses to ensure an adequate skin dose.

Comment: disadvantages include scarring, difficulty in assessing recurrence, and the lack of histological examination of the surgical specimen and proof of complete removal. A biopsy is required prior to the procedure to verify the diagnosis. Cryosurgery is not suitable for local recurrence of the disease or high-risk tumors. When performing cryosurgery, cryoprobes of an appropriate size that best match the shape of the tumor should be used. The skin should be firmly anchored to the underlying bone or cartilage. Freezing intensity can be monitored using an impedance meter (500–1000 kΩ, which corresponds to a freezing time of 30–60 seconds depending on the tumor size). Typically, 1–2 freeze-thaw cycles are performed.

Comment: for invasive forms of cSCC, surgical treatment should be preferred. PDT is not recommended for high-risk cSCC.

For photodynamic therapy of cutaneous cSCC in situ (Bowen's disease, Queyrat's erythroplakia) as well as actinic keratosis, finished pharmaceutical formulations of ALA- and methyl aminolevulinate-based creams or gels for topical use are applied (extemporaneous preparation is not permitted). A course of PDT consists of drug administration and a PDT session. Prior to topical application of the drug, curettage of the skin neoplasm with a curette or scalpel blade is performed without anesthesia, if necessary. Following complete hemostasis, the drug is applied to the tumor surface extending 0.5–1.0 cm onto the surrounding healthy skin, followed by an occlusive water- and light-impermeable dressing. Exposure time is 3–4 hours. After exposure, the occlusive dressing is removed, and drug residues are wiped off with a dry gauze pad. A laser light source with a wavelength of 630±2 nm is used for photodynamic therapy. The laser irradiation dose is 75–200 J/cm2. Based on indications, prior to the PDT session, fluorescence diagnostics with a 400–405 nm light source may be performed to determine the required light spot diameter. Treatment consists of 2–4 PDT courses at intervals of 1–3 weeks [132, 167-173]. The response is evaluated 1.5–2 months after the second course. There are no restrictions regarding light exposure. In case of partial regression confirmed morphologically, PDT with chlorin e6 solutions/concentrates may be performed.

For PDT in cutaneous cSCC in situ with areas of microinvasion or an exophytic component, chlorin e6 solutions/concentrates are used (See also Table 17). The drug is administered intravenously at a dose of 1 mg/kg of the patient's body weight, dissolved in 150–200 ml of isotonic sodium chloride solution. Intravenous infusion is performed in a darkened room, and the vial with the prepared solution is shielded with a light-proof material. Three hours after administration, fluorescence diagnostics with a 400–405 nm light source is performed to delineate tumor margins on the skin surface; fluorescence is evaluated visually using filter glasses. A laser light source with a wavelength of 662±2 nm is used for photodynamic therapy. The laser irradiation dose is 300–350 J/cm2. Treatment consists of 1 course of photodynamic therapy with response assessment after 1–2 months. The light restriction period is 4 days following chlorin e6 administration. In case of partial tumor regression, a repeat course of photodynamic therapy with chlorin e6 solution/concentrate may be performed [174-178].

Table 17. Regimens of photosensitizer administration for photodynamic therapy of basal cell skin cancer

Table 18. Application regimens of #imiquimod for cutaneous squamous cell carcinoma in situ (Bowen's disease)

3.1.2 Treatment of high-risk squamous cell carcinoma

Comment: this type of surgery requires a trained team of oncologic surgeons, plastic surgeons, and pathologists and can be performed in specialized centers. Intraoperative histological examination should be performed according to the following sectioning, marking, and specimen preparation methods: Mohs micrographic surgery and slow Mohs (3D Histology Evaluation of Dermatologic Surgery, margin strip method, "Tübingen torte", "Munich" method) (see Table 19). In all cases where intraoperative histological evaluation using Mohs or slow Mohs methods is not feasible, the recommended safe margin of at least 4 mm from visible borders should be applied.

Table 19. Methods of surgical treatment with intraoperative morphological control of all resection margins (peripheral and deep)

The standard loafing histological examination method should not be used to assess resection margins and completeness of tumor removal, as this method evaluates less than 1% of the removed tissue surface.

Comment: when performing standard surgical excision, it is recommended to mark orientation landmarks (12 o'clock) on the excised specimen and on the patient's body, which may be necessary when planning re-excision if the tumor is found at the resection margin during routine histological examination

Comment: sentinel lymph node biopsy is performed in specialized institutions equipped with the necessary equipment and trained personnel.

Table 20. Regimens and doses of definitive external beam radiation therapy for high-risk cutaneous squamous cell carcinoma

Table 21. Regimens and doses of external beam postoperative radiation therapy to the primary tumor area

3.1.3 Treatment of high-risk squamous cell carcinoma localized to the skin of the eyelids (including the eyelid commissure)

The principles of treatment for high-risk cSCC localized to the eyelids described in section 3.1.2 are supplemented by the provisions of this section.

• In case of non-radical surgical removal of the neoplasm, it is recommended to administer external beam or contact radiation therapy (brachytherapy) (see Table 20, as well as tables 14, 18, 19) [182, 184-190].

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

Comment: Contact radiation therapy (brachytherapy) using ophthalmic applicators as an independent treatment method can be used when the tumor thickness is no more than 3 mm (see Table 22). Brachytherapy for larger tumor sizes is possible using multi-field irradiation. Planning of brachytherapy with ophthalmic applicators is based on the tumor base, and the surface dose of 90-120 Gy is determined as a derivative from the depth dose distribution curve of radiation in soft biological tissue.

Table 22. Regimens and doses of brachytherapy for squamous cell carcinoma of the eyelid skin

Comments: the choice of radiation therapy type (close-focus X-ray therapy, gamma and electron therapy, brachytherapy) and dose fractionation regimen is made depending on the size and localization of the tumor, the patient's condition, preferences, and the capabilities of the medical institution. It is recommended to exclude critical eye structures from the irradiation field. When administering external beam radiation therapy, the same approaches and regimens are used as for cSCC of other localizations (see Tables 15, 18, 19).

3.2 Treatment of cutaneous squamous cell carcinoma with regional lymph node metastases (Stage III)

• Patients after radical surgical treatment for squamous cell carcinoma metastases in regional lymph nodes are recommended to undergo adjuvant radiation therapy (see Table 23) [199, 201, 212-221].

GRB CLEL 4Grade of Recommendation - C (Level of Evidence - 4)

Comment: in patients with the primary tumor localized in the head and neck, the rate of lymph node involvement in the parotid salivary gland area is up to 82%. This fact should be taken into account when planning the scope of examination and treatment for patients with squamous cell carcinoma of the skin of the head and neck

Table 23. Regimens and doses of external beam radiation therapy for cutaneous squamous cell carcinoma with regional lymph node involvement or high risk of regional lymph node involvement

3.3 Treatment of patients with metastatic and unresectable cutaneous squamous cell carcinoma (stage III unresectable and stage IV)

• For patients with metastatic and unresectable cSCC, it is recommended to administer monoclonal antibodies blocking the interaction between programmed cell death receptor (PD-1) and its ligands, in the absence of contraindications. Regimes are listed below (Table 24) [223-229].

GCR BLEL 3Grade of Recommendations — B (Level of Evidence — 3)

Comment: currently, a drug from the class of PD-1 monoclonal antibody blockers has been investigated in a well-designed study and demonstrated efficacy in patients with cutaneous squamous cell carcinoma [227, 230-237]. For registered drugs (pembrolizumab**, nivolumab**), efficacy data for this pathology are derived from small non-randomized studies or individual clinical cases.

Table 24. Regimes of antineoplastic drug administration in metastatic or unresectable cutaneous squamous cell carcinoma.

• For patients who have not responded to monotherapy with PD-1 monoclonal antibody blockers, or for patients with contraindications to PD-1 monoclonal antibody blockers, in the absence of contraindications, it is recommended to administer chemotherapy or EGFR monoclonal antibody therapy in combination with radiation therapy or as a monotherapy regimen [243-253] (see Table 25 and Table 26).

GCR CLEL 4Grade of Recommendations — C (Level of Evidence — 4)

Table 25. Chemotherapy regimens used concurrently with radiation therapy in unresectable locally advanced cutaneous squamous cell carcinoma.

Table 26. Chemotherapy regimens used as monotherapy

• When performing antitumor drug therapy, when calculating drug doses based on body surface area or body weight, it is recommended to round actual doses within 5% of the calculated doses [260, 261].

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

• For patients with locally advanced or metastatic cSCC in case of progression or stabilization during therapy with monoclonal antibodies (mAbs) targeting PD-1 inhibitors, it is recommended to administer drug therapy according to the following regimen:

Pembrolizumab 200 mg IV infusion once every 21 days + #cetuximab 400 mg/m2 (loading dose) followed by 250 mg/m2 IV infusion weekly [262]

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

• For patients with locally advanced or metastatic cSCC in the second and subsequent lines after chemotherapy, it is recommended to administer anti-PD-1 immunotherapy according to the following regimen: pembrolizumab 200 mg IV infusion once every 21 days continuously until disease progression, unacceptable toxicity, or up to 2 years of therapy (35 infusions) [240].

Table 27. Hypofractionated radiotherapy

3.4 Supportive care in patients with cutaneous squamous cell carcinoma

The principles of treatment and prevention of nausea and vomiting in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "PREVENTION AND TREATMENT OF NAUSEA AND VOMITING" [263]

The principles of treatment and prevention of bone complications in patients with basal cell carcinoma of the skin correspond to the principles outlined initudes "USE OF OSTEOMODIFYING AGENTS FOR THE PREVENTION AND TREATMENT OF BONE PATHOLOGY IN MALIGNANT NEOPLASMS" [264]

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "TREATMENT OF INFECTIOUS COMPLICATIONS OF FEBRILE NEUTROPENIA AND ADMINISTRATION OF COLONY-STIMULATING FACTORS" [265]

The principles of prevention and treatment in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "CORRECTION OF HEPATOTOXICITY" [266]

The principles of prevention and treatment of cardiovascular complications in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE CORRECTION OF CARDIOVASCULAR TOXICITY OF ANTITUMOR DRUG THERAPY" [267]

The principles of prevention and treatment of skin complications in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE DRUG TREATMENT OF DERMATOLOGICAL REACTIONS IN PATIENTS RECEIVING ANTITUMOR DRUG THERAPY" [268]

The principles of nutritional support in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR NUTRITIONAL SUPPORT IN CANCER PATIENTS" [269]

The principles of prevention and treatment of nephrotoxicity in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE CORRECTION OF NEPHROTOXICITY OF ANTITUMOR DRUGS" [270]

The principles of prevention and treatment of thromboembolic complications in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE PREVENTION AND TREATMENT OF THROMBOEMBOLIC COMPLICATIONS IN CANCER PATIENTS" [271]

The principles of prevention and treatment of the consequences of drug extravasation in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "RECOMMENDATIONS FOR THE MANAGEMENT OF THE CONSEQUENCES OF ANTITUMOR DRUG EXTRAVASATION" [272]

The principles of prevention and treatment of immune-mediated adverse events in patients with basal cell carcinoma of the skin correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE MANAGEMENT OF IMMUNE-MEDIATED ADVERSE EVENTS" [273]

3.5 Diet therapy.

Diet therapy is not used in the treatment of patients with cutaneous squamous cell carcinoma.

[1] Hereinafter in tables 22–24, in the column "Planned duration of treatment", "continuously" means the continuation of therapy until confirmed disease progression or the development of unacceptable toxicity.

[2] Hereinafter in tables 22–24, in the column "Planned duration of treatment", "continuously" means the continuation of therapy until confirmed disease progression or the development of unacceptable toxicity

4. Medical Rehabilitation and Sanatorium-Resort Treatment

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

4.1. Pre-rehabilitation

Comment: it is advisable to advise the patient to increase physical activity 2 weeks before surgery in order to reduce hospital stay and the risk of postoperative complications, as well as to improve quality of life in the postoperative period [275].

4.2. Surgical treatment

4.2.1. First stage of rehabilitation

Comment: Risk factors are classified as local, systemic, genetic, and lifestyle-related. Local risk factors: hypertrophic and keloid scars are more common in anatomical areas subject to regular stretching during daily body movements, including major joints, the anterior chest wall, the scapular region, and the lower abdomen. Systemic factors include high levels of the female hormone estrogen, hypertension, and Castleman disease. Genetic factors include several single nucleotide polymorphisms, Rubinstein-Taybi syndrome, and hereditary exostoses. Lifestyle-related factors include intense sports and physical labor [280–296].

4.2.2. Second stage of rehabilitation

4.2.3. Third stage of rehabilitation

4.3. Chemotherapy

• This recommendation is based on the results of systematic reviews by Nicole L. Stout et al., 2017 and R. Segal et al., 2017 on the effect of exercise in patients with other malignancies—it is recommended to incorporate aerobic exercise during chemotherapy, which increases hemoglobin and erythrocyte levels, reduces the duration of leukopenia and thrombocytopenia, and increases the likelihood of completing the planned chemotherapy course [308, 309].

GOR CLOE 5Grade of Recommendation — C (Level of Evidence — 5)

4.4. Radiation therapy

4.5. Principles of psychological rehabilitation in patients with malignant skin neoplasms

Comment: most frequently in psycho-oncology research, 3 coping styles are observed among patients with melanoma and NMSC:

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

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

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

Overall, studies show that patients who use active (problem-focused) coping strategies demonstrate better adjustment to the disease than those who use passive or avoidant coping styles [327-330]

Patients who used active behavioral coping methods reported higher levels of self-esteem and energy, fewer physical symptoms, and reduced irritability and asthenia [331, 332].

In contrast, in patients with early-stage melanoma and NMSC, a positive correlation was demonstrated between avoidance coping methods and anxiety, depression, confusion, and unstable mood [327, 331-333]

Boesen et al. demonstrated that structured interventions offering psychoeducational support help reduce distress and mood disorders and lead to more active use of coping strategies among patients with melanoma and NMSC [334, 335].

Comment: The results of psychological correction measures demonstrate low levels of depression, confusion, asthenia, apathy, and general depressed mood among patients with melanoma and NMSC [327]. Furthermore, numerous studies demonstrate a positive effect of the intervention on immune system functions, including an increase in certain types of natural killer (NK) cells and enhanced tumor-fighting potential of NK cells [332]. Over 5 years of follow-up, these researchers were able to show that psychological and biological changes were, in turn, associated with recurrence and survival rates [331].

5. Prevention and Dispensary Observation

To date, there is no consensus regarding the frequency and intensity of follow-up for CSCC patients. The goals of patient monitoring should be the early detection of disease recurrence, early detection of second tumors (specifically a new CSCC, as well as CSCC and cutaneous melanoma), and psychosocial support for patients.

• In order to reduce the risk of developing cutaneous melanoma, NMSC (including CSCC), and to prevent the occurrence of new melanomas or other malignant skin neoplasms, it is recommended to avoid sunburn or exposure to artificial ultraviolet radiation [337-344].

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

• All patients with a previously established diagnosis of squamous cell carcinoma of the skin are recommended to perform regular self-examinations of the skin and peripheral lymph nodes and to consult a physician promptly if any abnormalities are detected [345, 346].

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

Table 28 shows the recommended follow-up schedule for patient monitoring with a previously established diagnosis, compiled on the basis of recommendations given in the "Diagnostics" section and the risks of disease progression.

Table 28 Schedule and content of follow-up visits for patients with CSCC [342, 343, 347-350]

• For patients with stage 0-I disease and low risk of recurrence after completion of treatment, it is recommended to perform a physical examination with a thorough assessment of the skin and peripheral lymph nodes every 6 months for the first 3 years, then annually for 10 years of follow-up. Instrumental examinations are recommended only when clinically indicated, in accordance with the recommendations given in the subsection "Instrumental diagnostic examinations" [342, 343, 347-350] (see also Table 28).

Level of recommendation – C (Evidence level – 5)Level of evidence – 5Level of recommendation – C (level of evidence – 5)

• For patients with stage I-II disease and high risk of recurrence after completion of treatment, it is recommended to perform a physical examination with a thorough assessment of the skin and peripheral lymph nodes every 3 months for the first 3 years, then every 6 months up to 5 years of follow-up, then annually for 10 years of follow-up. Instrumental examinations are recommended only when clinically indicated, in accordance with the recommendations given in the subsection "Instrumental diagnostic examinations" [342, 343, 347-350] (see also Table 28).

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

• For patients with stage III-IV disease after completion of treatment, it is recommended to perform physical examinations with a thorough assessment of the skin and peripheral lymph nodes every 3 months for the first 3 years, then annually for 10 years of follow-up. Instrumental examinations are recommended during the first 3 years at intervals of once every 6 months (or more frequently if indicated, in accordance with the recommendations given in the subsection "Instrumental diagnostic examinations" [342, 343, 347-350] (see also Table 28).

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

[1] see section 1.5.3

[2] see section 1.5.3

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 (as amended on May 25, 2019) "On the Fundamentals of Protecting Public Health 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 the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by an oncologist and other medical specialists at an outpatient oncological care center or in a primary oncological office, primary oncological department, or outpatient department of an oncological dispensary.

If CSCC is suspected or detected in a patient, general practitioners, district general practitioners, family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient oncology center, a primary oncology office, or a primary oncology department of a medical organization to receive primary specialized health care.

Consultation at an outpatient oncological care center or a primary oncological office/department of a medical organization must be carried out no later than 5 working days from the date of issuing the referral for consultation. The oncologist of the outpatient oncological care center (or the oncologist of the primary oncological office/department, if no such center exists) shall organize the collection of biopsy (surgical) material, as well as the execution of other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to collect biopsy (surgical) material or perform other diagnostic tests at the medical organization that houses the outpatient oncological care center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases.

The timeframe for performing pathological anatomical examinations necessary for the histological verification of a malignant neoplasm shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material at the department of pathological anatomy (pathology bureau).

If CSCC is suspected or detected during the provision of emergency medical care, patients are transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional specialized antineoplastic treatment methods.

When CSCC of the eyelid skin, including the palpebral commissure, is detected or suspected, considering the specifics of treatment, it is necessary to arrange a consultation (in-person or via telemedicine technologies) at the oncological department of ophthalmological clinics.

The oncologist of the outpatient oncological care center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases to clarify the diagnosis (if the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department is unable to establish the diagnosis, including the extent of the oncological process and the stage of the disease) and to receive specialized, including high-tech, medical care.

The timeframe for initiating specialized, excluding high-tech, medical care for patients with oncological diseases in a medical organization providing medical care to patients with oncological diseases shall not exceed 14 calendar days from the date of histological verification of the malignant neoplasm or 14 calendar days from the date of establishing a preliminary diagnosis of a malignant neoplasm (in the absence of medical indications for outpatient pathological anatomical examinations).

Specialized, including high-tech, medical care is provided by oncologists and radiation therapists in an oncological dispensary or in medical organizations providing medical care to patients with oncological diseases that hold a license, have the necessary material and technical base and certified specialists, in inpatient and day-hospital settings, and includes the prevention, diagnosis, and treatment of oncological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing care to cancer patients, the tactics of medical examination and treatment shall be determined by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary. The decision of the medical concilium shall be drawn up in a protocol, signed by the participating physicians, and entered into the patient's medical documentation.

Indications for hospitalization in a 24-hour inpatient unit or day hospital of a medical organization providing specialized, including high-tech, medical care in the profile of «oncology» are determined by a medical council of oncologists and radiation therapists, with the involvement of other medical specialists if necessary.

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

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

2) the presence of complications of treatment (surgery, radiation therapy, drug therapy, etc.) for CSCC.

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

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent observation in a 24-hour inpatient unit or day hospital;

2) the presence of indications for specialized anti-tumor treatment (surgical intervention, radiation therapy—including contact, external beam, and other types of radiation therapy—drug therapy, etc.) requiring observation in a 24-hour inpatient unit or day hospital.

Indications for discharging a patient from a medical organization are:

1) completion of the course of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour inpatient unit or day hospital, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal by the patient or their legal representative of specialized, including high-tech, medical care in a 24-hour inpatient unit or day hospital prescribed by the medical council of the oncological care organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) the need to transfer the patient to another medical organization 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 preliminary examination data by specialists of the medical organization to which the transfer is planned.

Medical procedures that can be provided as part of primary specialized medical care (i.e., on an outpatient basis) under the supervision of an oncologist:

1) incisional and excisional biopsy of a neoplasm suspicious for CSCC;

2) obtaining tumor touch preps;

3) fine-needle aspiration biopsy of superficially located organs (lymph nodes, soft tissue neoplasms);

4) core needle biopsy of superficially located organs (lymph nodes, soft tissue neoplasms);

Indications for referring a patient to another medical organization:

— clinical guidelines are intended to maximize the quality of medical care provided to patients in various clinical situations. If a medical organization lacks the capability to perform the recommended scope of medical care (for example, lacks the capability to perform surgical tumor removal with intraoperative morphological control of all resection margins), it is recommended to use the referral system to other medical organizations, including outside the constituent entity of the Russian Federation, including federal centers with appropriate equipment and personnel;

— clinical guidelines do not cover the entire diversity of real clinical practice and include only the most frequent and typical clinical situations. If a practicing physician or medical organization encounters a clinical situation not reflected in these clinical guidelines (atypical disease course, the need to initiate antitumor therapy in the presence of contraindications, progression during recommended treatments, etc.), it is recommended to use the system of telemedicine consultations or referral to national medical research centers to clarify treatment tactics;

— the detection or exacerbation of a comorbid condition unrelated to the profile of the cancer institution that prevents the implementation of this treatment stage (e.g., acute myocardial infarction, acute stroke, etc.) requires referral to specialized medical organizations.

7. Additional Information

Known prognostic factors for non-melanoma skin cancers that are recommended to be recorded are presented in Table 29 and Table 30.

Table 29. Prognostic factors in non-melanoma skin cancers (according to the 8th edition TNM classification [47])

Table 30 Prognostic factors for non-melanoma skin cancers of the eyelid, including the palpebral commissure (according to the 8th edition TNM classification [47])

The G criterion characterizes the grade of tumor differentiation:

• G_X – differentiation grade cannot be assessed;

• G₁ – well-differentiated tumor;

• G₂ – moderately differentiated tumor;

• G₃ – poorly differentiated tumor;

• G₄ – undifferentiated tumor.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of medical care are given in Table 31

Table 31. Criteria for evaluating the quality of medical care

References

Appendix A1. Working Group Composition

1. Aliev M.D., Advisor to the General Director for Scientific and Clinical Work at the National Medical Research Radiological Center of the Russian Ministry of Health, Academician of the RAS, President of the Eastern European Sarcoma Group

2. Alieva S.B., MD, Leading Researcher at the Department of Radiation Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Member of the Association of Melanoma Specialists

3. Alymov Yu. V., Cand. Sc. (Med.), Oncologist, Surgical Department No. 11 for Head and Neck Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Executive Director of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists"

4. Bokhyan B.Yu., Cand. Sc. (Med.), Senior Researcher, Department of General Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Eastern European Sarcoma Group

5. Gafton G.I., D. Sc. (Med.), Head of the Scientific Department of General Oncology and Urology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Board Member of the Association of Melanoma Specialists

6. Demidov L.V., D. Sc. (Med.), Professor, Head of the Department of Surgical Treatment Methods No. 12 (Oncodermatology), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Chairman of the Board of the Association of Melanoma Specialists

7. Dobrokhotova V.Z., Cand. Sc. (Med.), Assistant Professor at the Department of Oncology, Faculty of General Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University)

8. Kushkin D.N., Cand. Sc. (Med.), Chief Medical Officer of the Skin Clinic Medical Center, Member of MBA, AAD, IDS, ESMS, EADV, EADO,

9. Mudunov A.M., D. Sc. (Med.), Professor, Head of Surgical Department No. 11 for Head and Neck Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, President of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists"

10. Orlova K.V., Cand. Sc. (Med.), Senior Researcher, Department of Surgical Treatment Methods No. 12 (Oncodermatology), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Board Member of the Association of Melanoma Specialists

11. Protsenko S.A., D. Sc. (Med.), Head of the Department of Chemotherapy and Innovative Technologies, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Board Member of the Association of Melanoma Specialists

12. Pustynsky I.N., D. Sc. (Med.), Associate Professor at the Department of Oncology and Radiation Therapy, Faculty of General Medicine, Pirogov Russian National Research Medical University, Corresponding Member of the International Cryosurgery Society, Board Member of the Russian Society of Head and Neck Oncology Specialists

13. Samoilenko I.V., Cand. Sc. (Med.), Senior Researcher, Department of Surgical Treatment Methods No. 12 (Oncodermatology), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Board Member of the Association of Melanoma Specialists

14. Trofimova O.P., D. Sc. (Med.), Leading Researcher, Radiological Department, Department of Radiation Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Member of the Association of Melanoma Specialists

15. Filonenko E.V., D. Sc. (Med.), Professor, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Oncologist;

16. Kharatishvili T.K., D. Sc. (Med.), Professor, Leading Researcher, Department of General Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Member of the Association of Melanoma Specialists

17. Kharkevich G.Yu., Cand. Sc. (Med.), Leading Researcher, Department of Surgical Treatment Methods No. 12 (Oncodermatology), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Member of the Association of Melanoma Specialists

18. Petenko N.N., Cand. Sc. (Med.), Oncologist, Department of Surgical Treatment Methods No. 12 (Oncodermatology), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Early Diagnostics Section

1. Shlivko I.L., D. Sc. (Med.), Head of the Department of Skin and Venereal Diseases, Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation

2. Garanina O.E., Cand. Sc. (Med.), Assistant Professor at the Department of Skin and Venereal Diseases, Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation

Medical Rehabilitation Section:

1. Obukhova O.A., Cand. Sc. (Med.), Head of the Department of Medical Rehabilitation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

2. Semiglazova T.Yu., D. Sc. (Med.), Leading Researcher, Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor at the Department of Oncology, I.I. Mechnikov North-Western State Medical University of the Russian Ministry of Health;

Healthcare Organization Section:

1. Nevolskikh A.A., D. Sc. (Med.), Professor, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health;

2. Khaylova Zh.V., PhD, Chief Physician of the Clinic, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

3. Gevorkyan T.G., Cand. Sc. (Med.), Deputy Director for the Implementation of Federal Projects, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Section on the Treatment of Squamous Cell Carcinoma of the Eyelid Skin:

1. Amiryan A.G., D. Sc. (Med.), Chief Researcher, Helmholtz National Medical Research Center of Eye Diseases of the Ministry of Health of the Russian Federation

2. Borodin Yu.I., Cand. Sc. (Med.), Head of the Radiology Department, Helmholtz National Medical Research Center of Eye Diseases of the Ministry of Health of the Russian Federation, Association of Ophthalmologists;

3. Brovkina A.F., Academician of the RAS, Professor at the Department of Ophthalmology with a Course in Pediatric Ophthalmology and a Course in Ophthalmic Oncology and Orbital Pathology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Honored Scientist of the RF, Association of Ophthalmologists;

4. Bulgakova E.S., Cand. Sc. (Med.), S.N. Fyodorov Eye Microsurgery Federal State Institution of the Ministry of Health of the Russian Federation, Society of Ophthalmologists of Russia

5. Golubeva O.V., Cand. Sc. (Med.), S.N. Fyodorov Eye Microsurgery Federal State Institution of the Ministry of Health of the Russian Federation, Society of Ophthalmologists of Russia

6. Grishina E.E., D. Sc. (Med.), Prof., Moscow Regional Research Clinical Institute (MONIKI) named after M.F. Vladimirsky, Association of Ophthalmologists;

7. Zhiltsova M.G., Cand. Sc. (Biol.), Cytologist, Helmholtz National Medical Research Center of Eye Diseases of the Ministry of Health of the Russian Federation, Association of Clinical Cytologists of Russia;

8. Kleyankina S.S., Cand. Sc. (Med.), S.N. Fyodorov Eye Microsurgery Federal State Institution of the Ministry of Health of the Russian Federation, Society of Ophthalmologists of Russia

9. Panova I.E., Professor, D. Sc. (Med.), Deputy Director for Scientific Work, St. Petersburg Branch of the S.N. Fyodorov National Medical Research Center of Eye Microsurgery of the Ministry of Health of the Russian Federation, Association of Ophthalmologists;

10. Neroev V.V., Professor, Academician of the RAS, D. Sc. (Med.), Director of the Helmholtz National Medical Research Center of Eye Diseases of the Ministry of Health of the Russian Federation, President of the Association of Ophthalmologists;

11. Saakyan S.V., Professor, D. Sc. (Med.), Head of the Department of Ophthalmic Oncology and Radiology, Helmholtz National Medical Research Center of Eye Diseases of the Ministry of Health of the Russian Federation, Association of Ophthalmologists;

12. Yarovoy A.A., D. Sc. (Med.), Head of the Department of Ophthalmic Oncology and Radiology, S.N. Fyodorov Eye Microsurgery Federal State Institution of the Ministry of Health of the Russian Federation, Society of Ophthalmologists of Russia

Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• surgeons;

• radiologists;

• medical geneticists;

• dermatovenerologists;

• pathologists;

• ophthalmologists;

• medical students, residents, and graduate students.

Table 32. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 33. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table 34. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

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

2. The current nomenclature of medical services is available at: https://med-b-pb-zhdanovka-r897.gosweb.gosuslugi.ru/netcat_files/8/9/Prikaz_Minzdrava_Rossii_ot_13_10_2017_N_804n_red_ot_24_09.pdf

Table A3-1. Terms describing procedures in the clinical guideline and possible (closest) terms from the current nomenclature of medical services.

Appendix B. Physician Action Algorithms

Figure 1. Diagram of diagnosis and treatment for patients with cutaneous squamous cell carcinoma

Appendix C. Patient Information

Recommendations for self-skin examination and primary prevention of melanoma and non-melanoma skin tumors

The main risk factor for CSCC, melanoma, and other skin tumors is ultraviolet damage, which occurs due to natural causes (sunburns) or artificial causes (specific working conditions or visiting tanning salons).

Different skin types react differently to the same dose of ultraviolet radiation; while some people (with fair skin, the so-called phototype I) always develop sunburns even from minimal doses of UV light (initial stage: skin erythema), others experience minimal harm from solar UV (individuals with tanned or dark skin). The majority of the Russian population has phototypes I–III (i.e., "fair") and is therefore highly sensitive to sunburn.

Prevention of skin sunburn is a key factor in primary prevention. Sunburns during childhood and adolescence make a particularly serious contribution to increasing the risk of melanoma. General recommendations come down to the following simple rules.

1. Use data from mobile applications and weather forecasts regarding the UV index level (the UV index is an indicator characterizing the level of ultraviolet radiation). If the UV index is greater than 2, sun protection is required (see Table 353533).

Table 35. Protection measures depending on the UV index

2. Use of a broad-spectrum sunscreen (preventing both UVA and UVB radiation) with an efficacy (SPF [Sun Protecting Factor] for UVB, PPD [Persistent Pigment Darkening] for UVA) appropriate for your skin phototype (i.e., individuals with lighter skin require a higher SPF or PPD). In general, individuals with skin phototype I or II are recommended to use sunscreens with SPF 30–50+ and a maximum PPD of 42.

3. Sunscreens should be combined with other sun protection methods: wearing clothing and UV-blocking glasses, wide-brimmed hats (it is estimated that for a hat's shadow to cover the face and neck, its brim must be at least 10 cm wide), and staying in the shade.

4. Children are additionally recommended to wear special UV-protective clothing.

5. Do not use artificial tanning equipment and lamps.

Rules for applying sunscreens:

• sunscreens should be applied 30 minutes before going outside to all areas of skin exposed to solar radiation;

• reapplication should be carried out every 2 hours, as well as immediately after swimming and excessive sweating;

• photoprotection corresponding to that indicated on the sunscreen label is achieved when it is applied to the skin in an amount of 2 mg/cm²; application in a smaller volume sharply reduces the degree of skin protection from ultraviolet radiation. To understand the amount of sunscreen required for the labeled skin protection, i.e., 2 mg/cm², the "teaspoon rule" [352] has been developed:

– arm: 1/2 teaspoon of product;

– head and neck: 1/2 teaspoon;

– leg: 1 teaspoon;

– chest: 1 teaspoon;

– back: 1 teaspoon;

• if it is impossible to apply the required volume of sunscreen all at once, early reapplication (in 15 to 30 minutes) of the cream is necessary;

• sunscreens must be stored at temperatures below +30 °C and must not be used after the expiration date.

Skin examination:

During the examination, special attention should be paid to pigmented spots measuring 4–5 mm or more with asymmetry of shape or color, irregular (scalloped) borders, and uneven coloration (various shades of brown). If you notice pigmented spots that exhibit at least 2 of these characteristics, consult a dermatologist or oncologist. It is not necessary that this mole will turn out to be malignant, but further evaluation of its condition should be entrusted to a doctor. Special attention should be paid to skin lesions where any characteristics change over time (e.g., the area of the pigmented spot increases, or the "mole" becomes thicker, or, conversely, part of the "mole" begins to fade and disappear) – such lesions will also require examination by a physician specializing in the early diagnosis of skin tumors.

Fig. 2. Skin examination algorithm

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

Appendix G1. WHO/ECOG performance status scale [353].

Russian title: WHO Patient Performance Status Scale/ECOG

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

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

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655

Type: rating scale

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

Contents:

Key (interpretation): provided within the scale itself