# Melanoma Metastases Arising at Unexpected Sites: Gallbladder and Uterus
## 4 Discussion  
Gastrointestinal metastases from malignant melanoma are most commonly located in the small bowel (35-65%), colon and rectum (5-9%), and stomach (5-7%) [9; 10]. Isolated gallbladder metastasis from malignant melanoma is exceptionally rare. Gallbladder metastasis may be clinically asymptomatic or present as acute cholecystitis, and is often diagnosed after cholecystectomy or abdominal ultrasound performed for other reasons, accordingly [9; 10]. Apparently, due to their asymptomatic course, we are not aware of the  
Figure 2: (**A**) Low magnification showing a uniformly hypercellular and heavily pigmented tumor (H&E; original magnification 50\(\times\)); (**B**) most of the lesion is composed of pigmented epithelioid cells with large eosinophil cytoplasm and hyperchromatic nuclei (H&E; original magnification 200\(\times\)); (**C**,**D**) tumor cells exhibit heterogeneous, strong and diffuse immunoreactivity for Melan-A (**C**) and SOX10 (**D**), respectively (immunoperoxidase; original magnifications 200\(\times\)). real prevalence of gallbladder metastases: autopsy reports show that the prevalence of gallbladder metastases ranges between 15 and 20%, with melanoma alone as the most common metastatic malignancy of the gallbladder (50-67%) [4; 11]. Instead, primary malignant melanoma of the gallbladder is extremely rare, with only a few case reports published in the literature [12], being a diagnosis of exclusion when no prior diagnosis of melanoma has been identified. In 1999, some clinicians reported 19 cases of melanoma of the gallbladder registered since 1970, with only 3 of them being isolated metastasis of gallbladder [13]. Since then, quite a few cases have been reported in the literature [4; 9; 11; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22]. Most of them report the same macroscopic and clinical evidence that we encountered in our patient: a polypoid lesion of the mucosa in a patient with acute cholecystitis-like symptoms. The clinical and histopathological differential diagnosis between primary gallbladder and metastatic melanoma can be challenging. Some colleagues [23; 24] reported that mucosal and metastatic melanomas have remarkable similarities in terms of pathological findings, size, number and location of lesions, and the presence of extrabilary lesions. Certainly, the history of primary melanoma located on the skin or at other most commonly affected anatomic sites allows us to suspect the metastatic nature of the lesion. Although, according to some authors, the absence of junctional activity (i.e., the intraepithelial extension to the mucosa overlying the tumor) better fits the diagnosis of metastatic rather than primary disease [25], other clinicians have also described junctional activity in cases of metastatic involvement of the gallbladder, not considering this criterion sufficient to distinguish between primary and metastatic melanoma [26]. The following clinico-pathological criteria have been reported as useful for distinguishing primary gallbladder melanoma from metastatic involvement: (i) the exclusion of previous primary melanoma, (ii) the absence of synchronous involvement of multiple sites, (iii) the presence of a solitary lesion, (iv) its polypoid or papillary shape, and (v) the presence of a junctional melanocytic component. Among these criteria, the first one seems to have more impact on the differential diagnosis since it has been widely demonstrated that metastatic melanoma to gallbladder can have a polypoid/papillary shape (as in our case), that it can represent the only site affected, and can exhibit a junctional component [27]. Moreover, as the clinical/histological evidence of regression in cutaneous melanoma has been associated with long-term metastases, even after a decade from the diagnosis, the possibility of metastasis from a primary melanoma in complete regression must be included in the differential diagnosis of all gallbladder masses with morphology and immunohistochemical profile consistent with those of melanoma [26; 28].