**3. Pathogenesis and genetics**

Melanocytes are derived from the neural crest cells. They migrate to the cutis and mucocutaneous junctions during the embryonal life. The chief function of melanocytes is their antioxidant activity, which helps to counteract the free radicals generated by the ultraviolet rays. Additionally, they contribute to the regional immune response [9, 10]. It has been postulated that the malignant transformation of melanocytes occurs due to oxidative stress and/or immunosuppression [9]. Other theories on AM suggest that they may be derived from Schwann cells of autonomic nervous system or the cells of the amine-precursor uptake and decarboxylation (APUD) system of the gastrointestinal tract [11]. Ultraviolet rays play a central role in the development of cutaneous melanoma (CM) unlike mucosal melanoma (MM). Hence, other pathways are involved in the development of MM which are poorly understood.

MM have different mutation profile compared to cutaneous melanomas [12]. BRAF mutations are infrequent, with an increased rate of c-KIT overexpression [13]. The incidence of BRAF, NRAS and c-KIT mutations are 5–16%, 14–18% and 11–15% respectively [14–16]. The mutation profiles of mucosal melanomas indicate that they have potential sensitivity to CDK4/6 and MEK inhibitors [16]. A study by Newell et al. have identified various mutational signatures in mucosal melanomas [16]. They found that mutations for melanoma in facial sites are different from that found in lower body sites. For example, SF3B1 hotspot mutations are common in AM and vulvovaginal melanomas, unlike other sites. Another study by Donizy et al. found that high poly (ADP-ribose) polymerase 1 (PARP-1) expression alone and along with high indoleamine 2,3-dioxygenase 1 (IDO-1) expression in mucosal melanomas was associated with worse overall and disease-specific survival [17]. Some studies have speculated that some viruses such as human papilloma virus (HPV) and human herpes virus (HHV-8) could be involved in the development of primary MM [11]. However, HPV DNA and HHV-8 DNA could not be detected in cases with AM [18, 19].

## **4. Clinical features**

#### **4.1 Clinical signs and symptoms**

The clinical features of AM mimic that of benign anorectal disorders leading to delay in diagnosis. The main clinical symptoms include bleeding per rectum, perianal pain, pruritus ani, tenesmus, perianal mass, inguinal mass (**Figure 1**). It is more frequent in females than males (1.7:1). It is most frequently observed in 6th and 7th decade of life [5]. The most important aspect of clinical diagnosis is a careful perianal and per-rectal examination. AM appears as an ulcerated or nodular lesion with an irregular surface showing brown or black pigmentation (**Figure 1**). Moreover, these are vascular lesions which bleed on touching. Frequently, in about 20% cases, the pigmentation may be absent. In small lesions, a high index of suspicion is required for timely diagnosis due its appearance similar to hemorrhoids. Hence, whenever in doubt, incisional or excisional biopsy should be performed for histopathological examination to diagnose AM. Another important clinical finding in cases of AM is the presence of inguinal lymphadenopathy. Inguinal lymph nodal metastases are usually seen in cases of anal melanoma. In cases with inguinal lymphadenopathy, fine needle aspiration and cytological examination for the enlarged lymph nodes can help in making the diagnosis.

Serum markers can aid in the diagnosis of AM. However, they are elevated in advanced cases of melanoma and often used as an adjunct to the other investigations for diagnosis. Lactate dehydrogenase (LDH) is a commonly used marker

**53**

**Figure 2.**

*CT (A) and MRI (B, C).*

*Anorectal Melanoma*

poor prognosis.

**Figure 1.**

**4.2 Radiological studies**

*DOI: http://dx.doi.org/10.5772/intechopen.93759*

for the detection of distant metastases in patients with melanoma [20]. Other markers include S-100B, melanoma inhibitor activity (MIA) protein, enolase and YKL-40 [21–24]. Elevated levels of these markers have been associated with a

*Perianal examination showing the ulcerated mass in a patient with locally advanced anorectal melanoma.*

The main role of radiological investigations is to determine the extent of the disease. Chest radiograph can detect obvious pulmonary metastases while abdominal ultrasound can detect liver metastasis [25]. Computed tomography (CT) is helpful in accurate staging of the disease (**Figure 2**). On CT, the liver lesions show late arterial enhancement and hypoattenuation of liver parenchyma in the portal venous phase [26]. The pulmonary metastases on CT chest appear as multiple end-arterial nodules with tree-in-bud appearance [25]. Magnetic resonance imaging (MRI) is a good imaging modality for accurate assessment of the local invasion of the tumor

*Anorectal melanoma appeared as a heterogeneously enhancing polypoidal mass (arrow) on contrast enhanced* 

*Melanoma*

**3. Pathogenesis and genetics**

**4. Clinical features**

**4.1 Clinical signs and symptoms**

Melanocytes are derived from the neural crest cells. They migrate to the cutis and mucocutaneous junctions during the embryonal life. The chief function of melanocytes is their antioxidant activity, which helps to counteract the free radicals generated by the ultraviolet rays. Additionally, they contribute to the regional immune response [9, 10]. It has been postulated that the malignant transformation of melanocytes occurs due to oxidative stress and/or immunosuppression [9]. Other theories on AM suggest that they may be derived from Schwann cells of autonomic nervous system or the cells of the amine-precursor uptake and decarboxylation (APUD) system of the gastrointestinal tract [11]. Ultraviolet rays play a central role in the development of cutaneous melanoma (CM) unlike mucosal melanoma (MM). Hence, other pathways are involved in the development of MM which are poorly understood. MM have different mutation profile compared to cutaneous melanomas [12]. BRAF mutations are infrequent, with an increased rate of c-KIT overexpression [13]. The incidence of BRAF, NRAS and c-KIT mutations are 5–16%, 14–18% and 11–15% respectively [14–16]. The mutation profiles of mucosal melanomas indicate that they have potential sensitivity to CDK4/6 and MEK inhibitors [16]. A study by Newell et al. have identified various mutational signatures in mucosal melanomas [16]. They found that mutations for melanoma in facial sites are different from that found in lower body sites. For example, SF3B1 hotspot mutations are common in AM and vulvovaginal melanomas, unlike other sites. Another study by Donizy et al. found that high poly (ADP-ribose) polymerase 1 (PARP-1) expression alone and along with high indoleamine 2,3-dioxygenase 1 (IDO-1) expression in mucosal melanomas was associated with worse overall and disease-specific survival [17]. Some studies have speculated that some viruses such as human papilloma virus (HPV) and human herpes virus (HHV-8) could be involved in the development of primary MM [11]. However, HPV

DNA and HHV-8 DNA could not be detected in cases with AM [18, 19].

enlarged lymph nodes can help in making the diagnosis.

The clinical features of AM mimic that of benign anorectal disorders leading to delay in diagnosis. The main clinical symptoms include bleeding per rectum, perianal pain, pruritus ani, tenesmus, perianal mass, inguinal mass (**Figure 1**). It is more frequent in females than males (1.7:1). It is most frequently observed in 6th and 7th decade of life [5]. The most important aspect of clinical diagnosis is a careful perianal and per-rectal examination. AM appears as an ulcerated or nodular lesion with an irregular surface showing brown or black pigmentation (**Figure 1**). Moreover, these are vascular lesions which bleed on touching. Frequently, in about 20% cases, the pigmentation may be absent. In small lesions, a high index of suspicion is required for timely diagnosis due its appearance similar to hemorrhoids. Hence, whenever in doubt, incisional or excisional biopsy should be performed for histopathological examination to diagnose AM. Another important clinical finding in cases of AM is the presence of inguinal lymphadenopathy. Inguinal lymph nodal metastases are usually seen in cases of anal melanoma. In cases with inguinal lymphadenopathy, fine needle aspiration and cytological examination for the

Serum markers can aid in the diagnosis of AM. However, they are elevated in advanced cases of melanoma and often used as an adjunct to the other investigations for diagnosis. Lactate dehydrogenase (LDH) is a commonly used marker

**52**

#### **Figure 1.** *Perianal examination showing the ulcerated mass in a patient with locally advanced anorectal melanoma.*

for the detection of distant metastases in patients with melanoma [20]. Other markers include S-100B, melanoma inhibitor activity (MIA) protein, enolase and YKL-40 [21–24]. Elevated levels of these markers have been associated with a poor prognosis.
