# Melanoma Metastases Arising at Unexpected Sites: Gallbladder and Uterus
## 4 Discussion
As it is a potentially metastasing tumor, when dealing with cutaneous MM, pathologists must include in the pathologic report some prognostic and predictive information of survival and metastatic risk [1], including Breslow thickness, Clark levels, dermal mitoses, the presence/absence of microscopic tumor satellitosis, the presence/absence of ulceration and the presence/absence of regression: (i) Breslow thickness represents the most important prognostic factor of cutaneous MM, and is measured from the granular layer of the epidermis to the deepest dermal neoplastic cells. If ulceration is present, the measurement must be made starting from the base of the ulcer; TNM pathological staging of cutaneous MM is based on Breslow thickness and the presence/absence of ulceration. Thicker MMs are predictive of lower survival rates and high metastatic risk. (ii) Clark levels are a description of which skin layers are involved by MM: epidermis (Clark level I), papillary dermis (Clark level II), papillary/reticular dermis interface (Clark level III), reticular dermis (Clark level IV) and subcutaneous fatty tissue (Clark level V). (iii) Dermal mitoses represent the number of mitoses per mm\({}^{2}\) found in the dermal tumor component. While the 8 th Edition of TNM staging removed them as a pathological stage T1 category criterion, they remain a well-established and reproducible criterion of malignancy, especially in diagnostically challenging lesions. (iv) The definition of microscopic satellitosis is \"at least one discontinuous nest of tumor cells > 0.05 mm in greatest dimension, that is distant from the main invasive MM portion at least 0.3 mm with the interposition of unaffected dermis. (v) Regression is defined as the partial or complete replacement of the tumor with fibrovascular tissue, often admixed with melanin-laden histiocytes, and lymphocytic and plasma cell inflammation [41; 42]. Due to the epithelioid morphology and the absence of pigmentation of the neoplastic cells, in case no. 1, the pathological differential diagnosis also included undifferentiated metastatic carcinoma and diffuse large B-cell lymphoma/anplastic large cell lymphoma, which were excluded by the lack of immunostaining for pancytokeratins and LCA, respectively. Conversely, the histologic diagnosis of case no. 2 was more straightforward, as the presence of diffuse pigmentation strongly favored the hypothesis of metastatic MM that was promptly confirmed by immunohistochemistry. In this regard, we would like to emphasize that pathologists must be aware of the possibility of metastatic MM, even at unusual locations, especially when dealing with apparently poorly differentiated neoplasms with epitheloid/spindled morphology and prominent nucleoli, and that MM markers such as S100, Melan-A, HMB45, and SOX10 must be always included in the immunohistochemical panel in this diagnostic context. In the past decade, metastatic melanoma treatment could rely on targeted therapy with BRAF and MEK inhibitors [43]. _BRAF V600E_ mutation is found in almost half of advanced (unresectable or metastatic) melanomas. As discordances in BRAF mutational status between primary and metastatic lesions are known to be relatively rare [43,44], the common practice is to rely on the BRAF status of the primary tumor, while it is advisable to also test the metastatic lesion only in those patients with no mutation found in the primary neoplasm [44]. Immunohistochemistry (IHC) may be performed as the first mutation screening method, but it is increasingly less used, as molecular analyses are mandatory both to confirm the immunohistochemical results and to detect the _V600K_- and _V600R_-mutant cases, not identifiable by IHC, that are candidates for vemurafenib therapy [44]. The first-line systemic treatment for patients with unresectable or metastatic disease includes monotherapy protocols with pembrolizumab or nivolumab (anti-PD1) or a combination protocol with nivolumab associated with ipilimumab (anti-CTLA4).