Malignant melanoma is the most serious type of skin cancer arising from the abnormal proliferation of epidermal melanocytes, and it continues to be a substantial clinical challenge. Although most histopathological diagnoses can be rendered based exclusively upon morphologic criteria, a small proportion of cutaneous melanocytic lesions including dysplastic nevi and Spitz nevi pose diagnostic difficulties. Current prognostic methods for melanoma are limited in their ability to accurately predict individual risk of disease progression and outcome. The sole effective cure for melanoma is surgical resection of the primary tumor before it grows to a Breslow thickness greater than 1 mm. Despite many years of intensive basic and clinical research, no systemic treatment that improves overall survival in most patients with unresectable metastatic melanoma has been developed. It is imperative to identify molecules that have diagnostic and prognostic values in melanoma and are critical to melanomagenesis so that more effective therapeutic targeting agents can be developed.
IMP3, also known as L523S and overexpression of K homology domain-containing protein overexpressed in cancer, is an IGF-II messenger RNA-binding protein (IMP) Citation[1] that functions to promote tumor cell proliferation by enhancing IGF-II protein expression Citation[2]. IMP3 is a 580-amino acid oncofetal protein with two RNA recognition motifs and four K homology domains that is encoded by a 4350-bp mRNA transcript produced by the IGF2BP3 gene on chromosome 7p11.5 Citation[3]. IMP3 expression has been identified to a variable degree in a number of normal tissues, including placenta, gonads, germinal centers of lymphoid follicles, intestinal mucosa and hair follicles Citation[1,4,5], as well as a wide variety of malignancies including germ cell neoplasms, extrapulmonary small cell carcinoma, cholangiocarcinoma, and Merkel cell carcinoma, and carcinomas of the pancreas, kidney, ovary, bladder, lung and uterus Citation[4–19]. Interestingly, we found that pulmonary and extrapulmonary high-grade neuroendocrine carcinomas express IMP3, but carcinoid tumors do not Citation[4,7,19]. Furthermore, IMP3 is involved in the progression of urothelial tumors from low grade to high grade in both papillary and flat lesions Citation[12]. IMP3 has also been reported to have a significant prognostic value in urinary bladder carcinoma Citation[13] and renal cell carcinoma Citation[9,10]. The hypothesis that IMP3 is expressed in malignant melanoma but not in nevi and is a progressive biomarker of malignant melanoma was tested in a study by Pryor et al. in the recent issue of Modern PathologyCitation[20].
Diagnostic value of IMP3 in malignant melanoma
In the study by Pryor et al., melanocytic lesions including benign nevi, dysplastic nevi, Spitz nevi and malignant melanomas were analyzed for expression of IMP3 Citation[20]. IMP3 was not detected in either benign or dysplastic nevi. Spitz nevi occasionally expressed IMP3 but the immunostaining intensity was very weak. By contrast, the majority of malignant melanomas expressed IMP3, and the immunostaining intensity was moderate to strong. These findings indicate that IMP3 has a diagnostic value in segregating nevi from malignant melanoma.
Prognostic value of IMP3 in malignant melanoma
The most widely utilized prognostic factors for malignant melanoma are Breslow depth–tumor thickness and sentinel lymph node status Citation[21]. When there is distant metastasis, malignant melanoma is generally considered incurable. The 5-year survival rate is less than 10% Citation[22]. No biomarkers have been absolutely correlated with these clinical observations. In the study by Pryor et al., the groups were divided based on the thickness of melanoma or metastatic status Citation[20]. The extent and intensity of immunohistochemical stain for IMP3 were evaluated in these groups. The studies revealed that the malignant melanomas with Breslow depth greater than 1 mm expressed IMP3 more than those with Breslow depth less than 1 mm and IMP3 is more expressed in metastatic melanoma. These studies indicate that IMP3 is a novel progression biomarker in malignant melanoma.
In summary, the study by Pryor et al. (n = 56) indicates that IMP3 has both diagnostic and prognostic values in malignant melanoma Citation[20]. Large samples are required together with survival data to further validate the findings. Moreover, further mechanistic studies are warranted to determine whether IMP3 plays an important role in melanomagenesis, and whether it is a therapeutic target for new modalities in the treatment of malignant melanoma.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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