7. Differential Diagnosis
Cutaneous clear cell sarcoma (
CCS): The main differential diagnosis of CMTCT is primary or metastatic cutaneous clear cell sarcoma (CCS). Similar to CMTCT, primary superficial CCS typically presents as a single dermal/subcutaneous nodule or multilobulated tumor organized in nests or fascicles of spindle and epithelioid cells with pale to eosinophilic cytoplasm, surrounded by delicate collagen fibers
[25]. It involves the dermis and possibly the subcutis in an infiltrative manner, and can also rarely display epidermotropism, with isolated tumoral nests at the dermo-epidermal junction
[26]. In the majority of cases, wreath-like giant cells, which are different from the multinucleated giant cells of CMTCT in terms of the distribution of the nuclei, are present. Immunohistochemically, CCS displays positivity for S100-protein, HMB-45, MelanA and SOX10. The pathogenic driver event of CCS is rearrangement of the
EWSR1 gene with
ATF1 (90% of the cases),
CREB1 or
CREM as fusion partners
[27][28]. Compared to CCS, CMTCT displays mostly a pushing border rather than an infiltrating one and does not involve the epidermis. Furthermore, CMTCT appears to behave in a less aggressive fashion than CCS; hence distinction between these two entities, possibly with the input of molecular techniques, is imperative. Based on their case of recurrent and metastasizing CMTCT, Bontoux et al.
[2] argued that this entity represents a cutaneous CCS with a fusion other than the most common
EWSR1::ATF1. Currently, there is no evidence that the two neoplasms share similar pathways of pathogenesis, and a definitive classification of CMTCT would be premature. More studies with emphasis on the activity of the
CRTC1::TRIM11 fusion product are needed to further classify CMTCT.
Other melanocytic neoplasms: Primary or metastatic melanoma confined to the dermis/subcutis lies within the differential and has been the initial diagnosis in 5 cases of CMTCT.
[1] Primary dermal melanoma (PDM) also presents as a single nodule or multilobulated tumor composed of spindle, or epithelioid cells arranged in sheets or nests
[29][30]. Since a subset of PDMs behave in a low grade fashion compared to similar thickness conventional melanomas, it is plausible that some of them may represent CMTCT.
[1] The detection of
CRTC1::TRIM11 fusion and/or the lack of characteristic mutations and cytogenetic abnormalities of PDM could aid in the distinction between the two entities
[4][31][32][33]. To exclude a metastatic or regressing melanoma, an extensive histopathologic and clinical work-up are necessary. TRIM11 immunohistochemistry may also have some value as a screening tool for CMTCT; however, TRIM11 has not been examined in melanoma and other dermal proliferations with melanocytic differentiation. More studies are necessary to determine the marker’s diagnostic utility.
[1] Albeit rare,
NTRK-fused metastatic Spitz melanomas with corresponding anti-Trk immunoreaction have been reported in the literature
[34]. Therefore, Trk immunohistochemistry may not be useful in the differential diagnosis.
Spitz tumors also display spindled and/or epithelioid cytological features; however, the majority of them have a different pathway of pathogenesis with fusions in oncogenic kinase drivers, such as
ROS1, ALK, NTRK1, NTRK3, MAP3K8, MET, BRAF, and RET [35][36]. As mentioned above CMTCT expresses TrkA by IHC, however,
NTRK1 rearrangements have not been described. Spitz tumors with
NTRK fusions display distinct histologic features that may aid in the differential diagnosis. They are usually compound, with epidermal hyperplasia and thin rete ridges
[37]. Approximately half of them display a wedge-shaped architecture, and the majority of them is composed of small spindle and/or epithelioid cells that can form rosette-like structures
[35][38].
Clear cell tumor with melanocytic differentiation and MITF rearrangements: Recently, de la Fouchardiere et al.
[39] reported seven cases of an intradermal tumor with clear cell features and expression of melanocytic markers, harboring the
ACTIN (
ACTG1 or
ACTB)
::MITF fusion. Similar to CMTCT, as well as to CSS, the neoplasm presented as a dermal nodule, occasionally involving the subcutis, in patients of all ages. The lesional cells mostly displayed a clear-appearing cytoplasm, and were arranged in small nests or cords; however, they were typically more confluent. The degree of atypia and mitotic activity was also similar to those of CMTCT. MelanA, HMB-45, MITF, S100-protein, and SOX10 immunoreaction confirmed the melanocytic differentiation of this tumor. Although
MITF hyperactivity could explain the morphologic and immunohistochemical phenotype of this neoplasm, the exact mechanism of action of the
ACTIN::MITF chimera is still unknown. De la Fouchardiere et al.
[40] also reported a case of clear cell tumor with melanocytic differentiation (diffuse SOX10, MITF and S100-protein positivity), harboring
MITF::CREM fusion, and resembling clear cell sarcoma. Compared to CMTCT, the neoplasm displayed a higher degree of atypia, an infiltrating pattern of growth, and perineural invasion.
Other soft tissue neoplasms: Myoepithelial tumors display epithelioid or spindle cytology with S100-protein and SOX10 immunoreactivity. However, in contrast to CMTCT they also display immunoreaction for (myo)epithelial markers such as EMA, low-molecular weight cytokeratins, calponin, and p63 and a subset of them harbors
EWSR1 rearrangements
[41]. Epithelioid schwannoma and epithelioid malignant peripheral nerve sheath tumor (MPNST) lie in the differential as well, but they are consistently negative for melanocytic markers including MITF, and a subset of them shows loss of INI1 expression.
[42][43]
Paraganglioma-like dermal melanocytic tumor (PDMT): Paraganglioma-like dermal melanocytic tumor is an entity that was first reported by Deyrup et al. in 2004
[44]. Similar to CMTCT, PDMT is described as a relatively well-circumscribed nodule or multinodular tumor confined to the dermis and/or subcutis with epithelioid to spindle cells arranged in nests, packets, or cords, and surrounded by fibrous septa. A subset of cases exhibits an infiltrating growth pattern. By immunohistochemistry, PDMT is positive for S-100 protein, MITF and HMB-45, variably positive for MelanA and negative for cytokeratins, EMA, SMA, CD34, and synaptophysin. Given the fact that data on the molecular profile of PDMT are not available and both entities display a similar biologic behavior, it is conceivable that a subset of them may harbor the
CRTC1::TRIM11 fusion.