**3. Classification**

The eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) staging system is based upon an evaluation of the primary tumor, the regional lymph nodes and lymphatic drainage, and the presence or absence of distant metastases. The information from TNM staging is then combined to classify patients into AJCC prognostic stage groups. There are four major growth patterns of melanoma: lentigo maligna, nodular, superficial spreading, and acral lentiginous. In an observational study of close to 120,000 patients with melanoma, nodular melanoma was an independent risk factor for death, after controlling for thickness, ulceration, and stage [11]. Nevertheless, the eighth edition of the American Joint Committee on Cancer tumor, node, and metastasis staging system,

which relies upon the primary tumor thickness and other features, involvement of regional lymph nodes, and presence or absence of distant metastases, should be used to stage melanomas of any growth pattern. Most melanomas arise as superficial tumors that are confined to the epidermis, where they may remain for several to many years. During this stage, known as the horizontal or "radial" growth phase, the melanoma is almost always curable by surgical excision alone. Melanomas that infiltrate into the dermis are considered to be in a "vertical" growth phase and have metastatic or "tumorigenic" potential. Nodular melanomas have no identifiable radial growth or in situ phase and appear to enter the vertical growth phase from their inception, resulting in thicker tumors at diagnosis.

In order to determine the stage of melanoma and, consequently, the physician's tactics and therapy regimen, it is common to use the levels of Clarke's invasion (1969), as well as the international TNM system. The level of invasion by Clark allows you to determine the number of layers of the epidermis affected by melanoma at the time of its detection. The system for determining the level of invasion according to Clark is historically the first system for determining the stage of invasion of melanoma into the epidermis, according to which tumors are divided into five stages (**Table 1**).

The depth of invasion is determined by the stages of Breslow (1970) [12]:


After establishing the categories T, N, and M, they are grouped to determine the stage of the disease, which is expressed in Roman numerals from I to IV.

Stage 0: melanoma in situ (Clark level I), 99.9% survival rate Stage I/II: invasive melanoma, survival rate of 89–95% T1a: primary tumor thickness less than 1.0 mm, without ulceration <1/mm<sup>2</sup> T1b: primary tumor thickness less than 1.0 mm, with ulceration ≥1/mm2 T2a: thickness of the primary tumor 1.01–2.0 mm, without ulceration. Stage II: high-risk melanoma, 45–79% survival T2b: primary tumor thickness 1.01–2.0 mm, with ulceration T3a: primary tumor thickness 2.01–4.0 mm, without ulceration T3b: primary tumor thickness 2.01–4.0 mm, with ulceration T4a: thickness of the primary tumor is more than 4.0 mm, without ulcerationT4b: thickness of the primary tumor is more than 4.0 mm, with ulceration. Stage III: regional metastases, survival 24–70% N1: single lymph node affected N2: from two to three affected lymph nodes or regional metastases of the skin N3: four affected lymph nodes or one lymph node with regional skin metastases. Stage IV: distant metastases, survival rate of 7–19% M1a: distant skin metastases, normal LDH. M1b: lung metastases, normal LDH. M1c: other distant metastases or any distant metastases with elevated LDH [6, 8].

The American Joint Committee on Cancer recently published its eighth edition of staging criteria, which went into effect as of 1 January, 2018. The impact of Breslow depth and mitoses has been adjusted in the new AJCC staging. The most significant change is that all tumors with a Breslow depth of 0.8–1.0 mm are now staged as T1b. Non-ulcerated tumors with a Breslow depth of <0.7 mm are still

**59**

*Melanoma and Pregnancy: Risks, Current, and Forecast DOI: http://dx.doi.org/10.5772/intechopen.86928*

classified as T1a. In addition, Breslow depth is now reported to the nearest 10th decimal place. Therefore, with rounding, T1b tumors encompass 0.75–1.04 mm or any ulcerated tumor of <0.7 mm [8]. Mitoses are no longer part of the criteria to upstage from T1a to T1b. There were no changes to T2–T4 staging. The clinical stage

**Clark stage Characteristics Patient** 

All tumor cells are in the epidermis and do not reach the basal membrane

The tumor reaches the border between the papillary and reticular dermis. The tumor enters the phase of vertical growth

Tumor cells infiltrate the papillary layer of the dermis 72–96%

Tumor cells are detected in the reticular layer of the dermis 31–67%

The tumor invades in the fatty tissue 12–48%

**survival**

98–100%

46–90%

One of the theories supporting the possible effect of pregnancy on tumor transformation is that pregnancy is considered a state of immunodeficiency, necessary to prevent the development of an immune response to fetal antigens. Although the exact mechanism by which tolerance to the fetus development is unclear, several immunological changes may allow the fetus to develop and grow. During pregnancy, the level of granulocytes increases, the number of monocytes remains unchanged, and a significant decrease in lymphocytes is also observed. T-lymphocyte activity is suppressed, and a disruption in the production of interleukins and interferon-G is demonstrated. However, the function of B-lymphocytes remains unchanged, and therefore the immune system during pregnancy is described as a bias toward the humoral immunity, which is more responsible for the formation of antibodies. This change in the balance of Th1 and Th2 cells is similar to the immunological state of patients with oncology [6]. Another possible mechanism of fetal tolerance involves the secretion of protein B7-H1 (CD274) by trophoblast cells; the B7-H1 protein induces apoptosis of activated T cells. This is important because it is also reported that melanoma can elude immune surveillance and secrete B7-H1. The combined secretion of B7-H1 can lead to the fact that melanoma during pregnancy grows and metastasizes more quickly. In addition, it was found that human leukocyte antigen HLA-G is expressed by placental trophoblast cells. Recent studies have shown the role of mutations BRAF V600E in 50% of all skin melanoma development [9]. The fact is that under the influence of excessive UV irradiation, there is a V600 mutation consisting of replacing valine with leucine (V600L), lysine (V600K), or glutamic acid (V600E) in the 600th position, which serves as a signal for the onset of neoplastic transformation. An important role in determining the prognosis is also the age and gender of the patient (women have a better prognosis), tumor localization, lymph node involvement, and the presence of tumor suppressor genes

groups were not altered; T1a is still stage 1A, and T1b is still stage 1B [8].

**4. Etiopathogenesis**

*Microscopic melanomas by Clark (1969) [7].*

The level of invasion I

The level of invasion II

The level of invasion III

The level of invasion IV

The level of invasion V

**Table 1.**


#### **Table 1.**

*Cutaneous Melanoma*

five stages (**Table 1**).

which relies upon the primary tumor thickness and other features, involvement of regional lymph nodes, and presence or absence of distant metastases, should be used to stage melanomas of any growth pattern. Most melanomas arise as superficial tumors that are confined to the epidermis, where they may remain for several to many years. During this stage, known as the horizontal or "radial" growth phase, the melanoma is almost always curable by surgical excision alone. Melanomas that infiltrate into the dermis are considered to be in a "vertical" growth phase and have metastatic or "tumorigenic" potential. Nodular melanomas have no identifiable radial growth or in situ phase and appear to enter the vertical growth phase from

In order to determine the stage of melanoma and, consequently, the physician's tactics and therapy regimen, it is common to use the levels of Clarke's invasion (1969), as well as the international TNM system. The level of invasion by Clark allows you to determine the number of layers of the epidermis affected by melanoma at the time of its detection. The system for determining the level of invasion according to Clark is historically the first system for determining the stage of invasion of melanoma into the epidermis, according to which tumors are divided into

The depth of invasion is determined by the stages of Breslow (1970) [12]:

After establishing the categories T, N, and M, they are grouped to determine the

T1a: primary tumor thickness less than 1.0 mm, without ulceration <1/mm<sup>2</sup> T1b: primary tumor thickness less than 1.0 mm, with ulceration ≥1/mm2 T2a: thickness of the primary tumor 1.01–2.0 mm, without ulceration.

T4a: thickness of the primary tumor is more than 4.0 mm, without ulcerationT4b: thickness of the primary tumor is more than 4.0 mm, with ulceration.

N2: from two to three affected lymph nodes or regional metastases of the skin N3: four affected lymph nodes or one lymph node with regional skin metastases.

M1c: other distant metastases or any distant metastases with elevated LDH [6, 8].

The American Joint Committee on Cancer recently published its eighth edition of staging criteria, which went into effect as of 1 January, 2018. The impact of Breslow depth and mitoses has been adjusted in the new AJCC staging. The most significant change is that all tumors with a Breslow depth of 0.8–1.0 mm are now staged as T1b. Non-ulcerated tumors with a Breslow depth of <0.7 mm are still

their inception, resulting in thicker tumors at diagnosis.

• Thin: the depth of invasion is less than 0.75 mm.

Stage II: high-risk melanoma, 45–79% survival

Stage III: regional metastases, survival 24–70%

Stage IV: distant metastases, survival rate of 7–19%

M1a: distant skin metastases, normal LDH. M1b: lung metastases, normal LDH.

N1: single lymph node affected

• Intermediate: the depth of invasion is 0.76–3.99 mm.

• Thick (deep): the depth of invasion is more than 4 mm.

stage of the disease, which is expressed in Roman numerals from I to IV.

Stage 0: melanoma in situ (Clark level I), 99.9% survival rate Stage I/II: invasive melanoma, survival rate of 89–95%

T2b: primary tumor thickness 1.01–2.0 mm, with ulceration T3a: primary tumor thickness 2.01–4.0 mm, without ulceration T3b: primary tumor thickness 2.01–4.0 mm, with ulceration

**58**

*Microscopic melanomas by Clark (1969) [7].*

classified as T1a. In addition, Breslow depth is now reported to the nearest 10th decimal place. Therefore, with rounding, T1b tumors encompass 0.75–1.04 mm or any ulcerated tumor of <0.7 mm [8]. Mitoses are no longer part of the criteria to upstage from T1a to T1b. There were no changes to T2–T4 staging. The clinical stage groups were not altered; T1a is still stage 1A, and T1b is still stage 1B [8].

## **4. Etiopathogenesis**

One of the theories supporting the possible effect of pregnancy on tumor transformation is that pregnancy is considered a state of immunodeficiency, necessary to prevent the development of an immune response to fetal antigens. Although the exact mechanism by which tolerance to the fetus development is unclear, several immunological changes may allow the fetus to develop and grow. During pregnancy, the level of granulocytes increases, the number of monocytes remains unchanged, and a significant decrease in lymphocytes is also observed. T-lymphocyte activity is suppressed, and a disruption in the production of interleukins and interferon-G is demonstrated. However, the function of B-lymphocytes remains unchanged, and therefore the immune system during pregnancy is described as a bias toward the humoral immunity, which is more responsible for the formation of antibodies. This change in the balance of Th1 and Th2 cells is similar to the immunological state of patients with oncology [6]. Another possible mechanism of fetal tolerance involves the secretion of protein B7-H1 (CD274) by trophoblast cells; the B7-H1 protein induces apoptosis of activated T cells. This is important because it is also reported that melanoma can elude immune surveillance and secrete B7-H1. The combined secretion of B7-H1 can lead to the fact that melanoma during pregnancy grows and metastasizes more quickly. In addition, it was found that human leukocyte antigen HLA-G is expressed by placental trophoblast cells. Recent studies have shown the role of mutations BRAF V600E in 50% of all skin melanoma development [9]. The fact is that under the influence of excessive UV irradiation, there is a V600 mutation consisting of replacing valine with leucine (V600L), lysine (V600K), or glutamic acid (V600E) in the 600th position, which serves as a signal for the onset of neoplastic transformation. An important role in determining the prognosis is also the age and gender of the patient (women have a better prognosis), tumor localization, lymph node involvement, and the presence of tumor suppressor genes

(CDKN2A, CDK4) and proliferative markers (PCNA, Ki-67) and the presence of thromboses and thromboembolism. Thrombotic complications are the most common complications of paraneoplastic syndrome, manifested by arterial and venous thrombotic occlusions, migrating thrombophlebitis, pulmonary embolism, palpable non-bacterial thromboendocarditis, paradoxical bleeding, and thrombotic microangiopathy. Clinically, venous thromboembolism and malignant neoplasm have two main manifestations: firstly, thrombosis can be the only clinical manifestation of the tumor process, and secondly, in patients with cancer at all stages of the disease, thrombosis may develop [7, 10, 11]. Approximately 10% of melanomas are familial. Among subjects from melanoma families, defined as kindreds in which melanoma occurred in two or more blood relatives, the likelihood of developing melanoma is even greater among those family members who have dysplastic nevi. In a subset of these kindreds, the apparent familial pattern of inheritance may be attributable to clustering of sporadic cases in families who share common heavy sun exposure and susceptible skin type, making genetic analysis and risk stratification more challenging. This concept is substantiated by studies in which *CDKN2A* mutation status, sun exposure, and prevalence of dysplastic/benign nevi influence melanoma risk in families unselected for family history as well as melanoma-prone families.
