**5.1 History and risk factors**

Key questions that should be asked to patients presenting with a lesion that is of concern or for a general examination of their nevi include:


The patient's phenotypic features associated with an increased risk of melanoma should also be assessed. They include:

**61**

fetus [1, 2].

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

• presence of a large number (>50) of melanocytic nevi (common nevi)

• presence of atypical melanocytic nevi (benign nevi that clinically share some of the clinical features of melanoma, such as large diameter, irregular borders, and

Clinicians assess the probability that a pigmented lesion is a melanoma using a complex cognitive process that includes a combination of the following steps: visual analysis and pattern recognition, comparative analysis of nevus patterns in an

• Visual analysis and pattern recognition typically assess whether a given pigmented lesion has one or more features that may suggest melanoma, including asymmetry, irregular borders, variegated color, and diameter > 6 mm. These features have been included in the widely adopted ABCDE checklist: **A**symmetry (if a lesion is bisected, one half is not identical to the other half), **B**order irregularities, **C**olor variegation (the presence of multiple shades of red, blue, black, gray, or white), **D**iameter ≥ 6 mm, and **E**volution (a lesion that is changing in size, shape, or color or a new lesion, a clinical prediction rule that was devised to help clinicians and laypeople identify suspicious lesions).

• The intrapatient comparative analysis uses the so-called "ugly duckling" sign, which refers to the presence of a single lesion that does not match the patient's

• A history of change in size, color, or shape of a preexisting melanocytic lesion (the "E" for "evolution" in the ABCDE checklist) is the most important clinical criterion for the diagnosis of melanoma. A change can be noted by the patient or documented by comparison of serial clinical or dermoscopic images.

The evaluation and management of the pregnant woman are similar to that of the nonpregnant woman and are based upon the stage of disease. However, there are potential concerns that arise even in the initial biopsy of suspected melanoma. As the stage of disease becomes more advanced, evaluation and management decisions become more complex in order to ensure safety of the mother and the

A changing pigmented lesion during pregnancy that is clinically and dermatoscopically of concern as a possible melanoma should be biopsied immediately, as it would be in a nonpregnant patient. Excisional biopsy is the optimal way to evaluate a primary cutaneous melanoma. If the pregnant patient is considered a candidate for sentinel lymph node biopsy, there is controversy about the technique and timing of the procedure. In the case of a woman with advanced melanoma, imaging studies may be considered. According to a Committee Opinion Summary published by the American College of Obstetrics and Gynecologists' Committee on Obstetric

nevus phenotype (the so-called signature nevus).

**6. Management of melanoma during pregnancy**

• fair-complexioned phototype

individual patient, and dynamic analysis:

• red or blond hair

multiple colors)

• light eye color

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


*Cutaneous Melanoma*

history as well as melanoma-prone families.

**5. Factors of the risk and clinical picture**

concern or for a general examination of their nevi include:

the clinical diagnosis [14].

**5.1 History and risk factors**

cancers?

(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

The clinical recognition of melanoma, and in particular of early melanoma, may be challenging, even for the most experienced dermatologist. It has been estimated that the sensitivity of the clinical diagnosis of experienced dermatologists is approximately 70% [13]. However, the use of diagnostic aids such as dermoscopy, which requires some training, may greatly improve the sensitivity and specificity of

Key questions that should be asked to patients presenting with a lesion that is of

• Does the patient have a personal or family history of melanoma or other skin

• Does the patient have a history of excessive sun exposure and/or tanning bed use?

• Does the patient have a cancer-prone syndrome (e.g., familial atypical multiple

• Did the patient receive prolonged psoralen plus ultraviolet A (PUVA) therapy?

The patient's phenotypic features associated with an increased risk of melanoma

• Did the patient suffer severe sunburns during childhood or teenage years?

mole-melanoma syndrome or xeroderma pigmentosum)?

• Is the patient immunosuppressed?

should also be assessed. They include:

• When was the lesion (or a change in a preexisting lesion) first noticed?

**60**


Clinicians assess the probability that a pigmented lesion is a melanoma using a complex cognitive process that includes a combination of the following steps: visual analysis and pattern recognition, comparative analysis of nevus patterns in an individual patient, and dynamic analysis:


## **6. Management of melanoma during pregnancy**

The evaluation and management of the pregnant woman are similar to that of the nonpregnant woman and are based upon the stage of disease. However, there are potential concerns that arise even in the initial biopsy of suspected melanoma. As the stage of disease becomes more advanced, evaluation and management decisions become more complex in order to ensure safety of the mother and the fetus [1, 2].

A changing pigmented lesion during pregnancy that is clinically and dermatoscopically of concern as a possible melanoma should be biopsied immediately, as it would be in a nonpregnant patient. Excisional biopsy is the optimal way to evaluate a primary cutaneous melanoma. If the pregnant patient is considered a candidate for sentinel lymph node biopsy, there is controversy about the technique and timing of the procedure. In the case of a woman with advanced melanoma, imaging studies may be considered. According to a Committee Opinion Summary published by the American College of Obstetrics and Gynecologists' Committee on Obstetric

Practice, chest radiograph with appropriate shielding, ultrasonography, and magnetic resonance imaging (MRI; preferably without gadolinium) are the techniques of choice for imaging of the pregnant female [15]. In addition, studies such as other radiography, computed tomography (CT) scan (without contrast), and nuclear medicine imaging studies can be utilized since they are typically administered at doses that do not lead to fetal harm.

Some studies have suggested that melanomas diagnosed during pregnancy are more often of greater Breslow depth [16], but a larger proportion of studies have not observed a significant difference. Likewise, a retrospective review analyzed both clinical and pathologic characteristics of 34 melanomas diagnosed during pregnancy and up to 1 year after delivery and compared these with melanomas from age- and disease-matched controls. There was no significant difference in Breslow depth, ulceration, mitotic rate, stage of disease, anatomic location of the primary tumor, histologic subtype, Clark level, regression, necrosis, or vascular invasion [2].

While melanoma is the most common cancer to metastasize to the fetus, metastasis across the placenta to the fetus is rare and is only observed in women with widely metastatic disease [17–19] (**Figure 1**). Even if placental involvement with melanoma is identified, it has been estimated that the fetus is affected in only 25% of these cases. In cases of maternal advanced disease, it is important to alert the pathologist to perform meticulous sectioning of the placenta since many sections may be needed to detect small foci of melanoma.

The general approach to the treatment of pregnancy-associated melanoma is based upon the same prognostic factors as for nonpregnant woman. Melanoma diagnosed during pregnancy is a rare clinical case presentation which must be mastered. In the absence of guidelines for this clinical challenge, we performed a review of the literature and provide a practical guideline on how to manage such rare clinical cases based on our clinical experience. Expecting mothers require adequate counseling and explanation of all therapeutic options as they take responsibility for more than their own lives. However, they should be guided through the process of diagnostic and therapeutic measures in a potentially life-threatening situation. Pregnancy itself is no reason to withhold any type of necessary melanoma surgery. Perioperative management, however, requires certain adjustments in order to comply with this special situation. If indicated, even adjuvant and palliative systemic therapies need to be given to the patient, but they also have to be adapted to the specific circumstances as data is still sparse, especially for the new first- and second-line therapies with antibodies and targeted molecules.

Management becomes more complex once the need for SLNB is established or if the patient has more advanced disease and should be individualized. In advanced melanoma, the newest agents, such as BRAF inhibitors (vemurafenib and dabrafenib) and checkpoint inhibitors [nivolumab and ipilimumab (anti-programed cell death-1 and anti-CTLA, respectively)], may be teratogenic [17–21]. The FDA-approved patient labeling recommends avoidance of pregnancy and lactation during BRAF inhibitor therapy and up to 2 weeks after the last dose, during ipilimumab therapy and up to 3 months after the last dose, and during nivolumab therapy and up to 5 months after the last dose.

The patient with a thin melanoma with excellent prognosis need not delay future pregnancies or avoid the use of oral contraceptives or hormone replacement therapy, if the latter are indicated.

The combination of pregnancy and the high stage of melanoma are a dangerous condition requiring careful risk assessment by the obstetrician-gynecologist and oncologist. Earlier, women with melanoma III and IV stages were artificially interrupted by pregnancy according to medical indications. However, at present, in relation to risk stratification and pregnancy management in women with melanoma

**63**

**Figure 1.**

*lymph node with the germination of the capsule (c).*

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

associated with pregnancy, there is a view that therapeutic approaches are almost the same as those of nonpregnant ones and are determined by the stage of the disease. For patients with a history of melanoma and multiple dysplastic nevi, a more frequent dermatological examination during pregnancy is suggested. With regard to recommendations for the implementation of the reproductive function, it is shown that a future pregnancy should not be delayed in a woman with a thin localized melanoma with a favorable prognosis. For patients with progressive

*Histological examination of biopsy (intraoperative) material (hematoxylin-eosin staining). The material is represented by a lymph node located among adipose tissue with tumor metastasis (a), which has the structure of epithelioid cell melanoma with a high content of pigment (b). The tumor totally replaces the tissue of the* 

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

*Cutaneous Melanoma*

doses that do not lead to fetal harm.

may be needed to detect small foci of melanoma.

second-line therapies with antibodies and targeted molecules.

and up to 5 months after the last dose.

therapy, if the latter are indicated.

Practice, chest radiograph with appropriate shielding, ultrasonography, and magnetic resonance imaging (MRI; preferably without gadolinium) are the techniques of choice for imaging of the pregnant female [15]. In addition, studies such as other radiography, computed tomography (CT) scan (without contrast), and nuclear medicine imaging studies can be utilized since they are typically administered at

Some studies have suggested that melanomas diagnosed during pregnancy are more often of greater Breslow depth [16], but a larger proportion of studies have not observed a significant difference. Likewise, a retrospective review analyzed both clinical and pathologic characteristics of 34 melanomas diagnosed during pregnancy and up to 1 year after delivery and compared these with melanomas from age- and disease-matched controls. There was no significant difference in Breslow depth, ulceration, mitotic rate, stage of disease, anatomic location of the primary tumor, histologic subtype, Clark level, regression, necrosis, or vascular invasion [2]. While melanoma is the most common cancer to metastasize to the fetus, metastasis across the placenta to the fetus is rare and is only observed in women with widely metastatic disease [17–19] (**Figure 1**). Even if placental involvement with melanoma is identified, it has been estimated that the fetus is affected in only 25% of these cases. In cases of maternal advanced disease, it is important to alert the pathologist to perform meticulous sectioning of the placenta since many sections

The general approach to the treatment of pregnancy-associated melanoma is based upon the same prognostic factors as for nonpregnant woman. Melanoma diagnosed during pregnancy is a rare clinical case presentation which must be mastered. In the absence of guidelines for this clinical challenge, we performed a review of the literature and provide a practical guideline on how to manage such rare clinical cases based on our clinical experience. Expecting mothers require adequate counseling and explanation of all therapeutic options as they take responsibility for more than their own lives. However, they should be guided through the process of diagnostic and therapeutic measures in a potentially life-threatening situation. Pregnancy itself is no reason to withhold any type of necessary melanoma surgery. Perioperative management, however, requires certain adjustments in order to comply with this special situation. If indicated, even adjuvant and palliative systemic therapies need to be given to the patient, but they also have to be adapted to the specific circumstances as data is still sparse, especially for the new first- and

Management becomes more complex once the need for SLNB is established or if the patient has more advanced disease and should be individualized. In advanced melanoma, the newest agents, such as BRAF inhibitors (vemurafenib and dabrafenib) and checkpoint inhibitors [nivolumab and ipilimumab (anti-programed cell death-1 and anti-CTLA, respectively)], may be teratogenic [17–21]. The FDA-approved patient labeling recommends avoidance of pregnancy and lactation during BRAF inhibitor therapy and up to 2 weeks after the last dose, during ipilimumab therapy and up to 3 months after the last dose, and during nivolumab therapy

The patient with a thin melanoma with excellent prognosis need not delay future pregnancies or avoid the use of oral contraceptives or hormone replacement

The combination of pregnancy and the high stage of melanoma are a dangerous condition requiring careful risk assessment by the obstetrician-gynecologist and oncologist. Earlier, women with melanoma III and IV stages were artificially interrupted by pregnancy according to medical indications. However, at present, in relation to risk stratification and pregnancy management in women with melanoma

**62**

associated with pregnancy, there is a view that therapeutic approaches are almost the same as those of nonpregnant ones and are determined by the stage of the disease. For patients with a history of melanoma and multiple dysplastic nevi, a more frequent dermatological examination during pregnancy is suggested. With regard to recommendations for the implementation of the reproductive function, it is shown that a future pregnancy should not be delayed in a woman with a thin localized melanoma with a favorable prognosis. For patients with progressive

#### **Figure 1.**

*Histological examination of biopsy (intraoperative) material (hematoxylin-eosin staining). The material is represented by a lymph node located among adipose tissue with tumor metastasis (a), which has the structure of epithelioid cell melanoma with a high content of pigment (b). The tumor totally replaces the tissue of the lymph node with the germination of the capsule (c).*

#### *Cutaneous Melanoma*

disease, it is recommended to wait at least 2–3 years before pregnancy, since during this time interval relapses are most likely [13, 15, 22]. However, this issue should be considered individually in each specific observation, since a woman of late reproductive age may be concerned about the implementation of reproduction in the event of a pregnancy failure. The problem becomes even more controversial in a woman with a common form of the disease, because her life expectancy remains unclear. Decision-making becomes much more complex in the woman with a more uncertain prognosis where a delay in future pregnancy may be considered, but this should be evaluated on a case-by-case basis.
