Mismatch repair protein expression and microsatellite instability: a comparison of clear cell sarcoma of soft parts and metastatic melanoma

Abstract

Clear cell sarcoma of soft parts is a rare soft tissue malignancy that shows phenotypic overlap with cutaneous melanoma but can be distinguished by the presence of a t(12;22) translocation. Microsatellite instability (MSI), a variation in the lengths of short repeat DNA segments in the genome, has been implicated in melanoma tumorigenesis, but is rare or absent in clear cell sarcoma. Defects in the mismatch repair (MMR) enzyme complex correlate with MSI in some tumor types, allowing the use of immunohistochemistry for the MMR proteins hMLH1 and hMSH2 to predict the presence of MSI. To determine if the association between MMR defects and MSI extends to clear cell sarcoma, we compared a group of nine clear cell sarcomas to 11 metastatic melanomas on the basis of MSI and the expression of MMR proteins. MSI was studied using fluorescence-based multiplexed PCR of five loci. Immunohistochemistry was evaluated on formalin-fixed paraffin-embedded tissue for hMLH1, hMHS2 and hMSH6. MSI was present in only 1/9 (11%) clear cell sarcoma case and in 8/11 (73%) melanoma cases. Immunostaining for hMLH1 and hMSH2 was preserved in all the clear cell sarcomas but loss of immunostaining for one or both proteins was seen in 6/11 melanomas (55%). hMSH6 was detected in 7/9 (78%) clear cell sarcomas and 10/11 (91%) of melanomas. Clear cell sarcoma and metastatic melanoma differed significantly with respect to the presence of MSI (P ¼ 0.010) and staining for hMLH1 and/or hMSH2 (P ¼ 0.014) but not hMSH6 (P ¼ 0.57). Mismatch repair, and consequently genomic instability may contribute to tumorigenesis in melanoma but not clear cell sarcoma. Immunostaining for hMLH1 and hMSH2 and MSI analysis may be helpful in the differential diagnosis of large soft tissue or visceral malignancies with melanocytic differentiation. Modern Pathology (2006) 19, 950-957.

Clear cell sarcoma: A case mimicking primary cutaneous malignant melanoma

“…However, microsatellite instability (a variation in the lengths of short repeat DNA segments in the genome) and genetic alterations involving chromosomes 1, 5, and 6 have been implicated in MM pathogenesis, but are rare or absent in CCS. [15] Therefore, cytogenetic data could be a clue for establishing the correct diagnosis. [5–711]…”

Microsatellite Instability in Sarcoma: Fact or Fiction?

“…Five studies observed a high frequency of MSI [37–41], ranging from 25–50%, where the 8 remaining studies report a low frequency of MSI [42–49], ranging from 0–14%. Two independent studies came to similar conclusions that the absence of MSI in clear cell sarcoma can be used as a useful adjunct (in addition to detection of the t(12 : 22) translocation) when differentiating clear cell sarcoma from malignant melanoma of soft parts [44, 48]. Three studies that detected MSI also assessed clinical outcomes; 2 of which concluded MSI-positive tumors were predictive of an inferior clinical outcome [38, 40], while the remaining study found no clinical correlate [49].…”

“…Using fluorescent labels of similar molecular size, coelectrophoresis and a migration standard, migration errors are minimized, and smaller microsatellite alterations can be accurately detected [50, 55]. Six of the studies listed in Table 1 used a version of this newer technique, with 4 of these studies detecting MSI (range: 11%–40% of tumors) [41, 48, 49, 56]. Microsatellite amplifications can also be assessed via subcloning and direct sequencing techniques, yet although this technique has the advantage of being highly sensitive and accurate for detecting small microsatellite polymorphisms, it is a time consuming process and not conducive to high-volume analyses.…”

“…A simple strategy to avoid this confounding issue would be to assess the Bethesda panel of microsatellite loci for MSI separately to any loci assessed for LOH and allelic imbalance. Only three studies listed in Table 1 assessed MSI in strict accordance with the Bethesda guidelines [46, 48, 49], and MSI was infrequently observed these series. Furthermore, none of the three series detected the MSI-H phenotype.…”

Loss of Heterozygosity and Microsatellite Instability Are Rare in Sporadic Dedifferentiated Liposarcoma: A Study of 43 Well-Characterized Cases

“…Taken together, these findings suggest that defective DNA repair mechanisms may contribute to sarcoma pathogenesis. The role of mismatch repair defects in sporadic sarcomas is poorly understood, although studies 5,7,8 so far suggest that such defects seem to be rare. Liposarcoma, specifically the well-differentiated and dedifferentiated subgroup, represents the most commonly occurring sporadic (ie, not Lynch syndrome associated) soft tissue sarcoma.…”