ABSTRACT
Desmoplastic melanoma (DM) and malignant peripheral nerve sheath tumor (MPNST) can appear morphologically and immunophenotypically similar. We attempted to determine whether microarray comparative genomic hybridization could detect copy number differences between them to aid in the diagnosis. S-100 immunohistochemistry was performed on 5 cases of DM and 9 cases of MPNST using formalin-fixed paraffin-embedded specimens. Genomic DNA was extracted from microdissected cells. Whole genome amplification was performed on 5 of 5 DMs and 6 of 9 MPNST cases. A multiplex polymerase chain reaction assay was used to determine the quality of the DNA samples, which were run on the Spectral Chip 2600 bacterial artificial chromosome array platform. DM showed gains involving chromosomes 1p, 2p, 9q, 13q, 14q, and 20q and losses involving chromosomes 5p, 11p, 12q, 15q, and 18q. Several cancer-associated genes were involved, including gain of BCL2L1, ARTN, AMPK, NRAS, and CCNA1 and loss of IGF2, CDKN1C, PAX6, WT1, TRAF6, MAPK8IP1, and IMP3. MPNST had gains involving chromosomes 1p, 2q, and 19p and loss of chromosome 21q. Gains of MUM1, APC2, MAP2K2, JMJD2B, SP110, PTMA, GPI, and CDKN2D were detected. DM and MPNST have chromosomal alterations detected by array comparative genomic hybridization that might be useful in distinguishing these 2 tumors, although further studies with a larger sample size will be needed to test this.
Subject(s)
Biomarkers, Tumor/genetics , Chromosomes, Human , Comparative Genomic Hybridization/methods , Gene Dosage , Melanoma/genetics , Nerve Sheath Neoplasms/genetics , Oligonucleotide Array Sequence Analysis , Skin Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Diagnosis, Differential , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Melanoma/chemistry , Melanoma/pathology , Middle Aged , Nerve Sheath Neoplasms/chemistry , Nerve Sheath Neoplasms/pathology , Predictive Value of Tests , Skin Neoplasms/chemistry , Skin Neoplasms/pathologyABSTRACT
Depending on the Breslow depth of the primary melanoma, sentinel lymph node biopsy is considered as standard of care for the staging of cutaneous melanoma, and is one of the most important prognostic factors. The histologic analysis of these specimens becomes difficult to interpret when benign intranodal nevic cells mimic metastases. Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP3), also known as K homology domain-containing protein overexpressed in cancer or L523S, is a member of the insulin-like growth factor-II mRNA-binding protein family and has been shown to have diagnostic utility in distinguishing cutaneous melanoma from benign nevi. In this study, 43 sentinel lymph node biopsy specimens, including 13 with benign intranodal nevi and 30 with metastatic melanoma (two cases containing both benign nevi and metastatic melanoma), from 41 patients were immunohistochemically analyzed with a monoclonal antibody against IMP3. None of the benign intranodal nevi expressed IMP3, whereas 21 out of 30 (70%) of the lymph nodes containing metastatic melanoma did. It seems that IMP3 is helpful in distinguishing benign intranodal nevi from metastatic melanoma in sentinel lymph node biopsy specimens, and could be a valuable diagnostic adjunct in sentinel lymph node biopsy assessment in which questions arise as to the malignancy of the melanocytes present.
Subject(s)
Biomarkers, Tumor/analysis , Lymph Nodes/chemistry , Melanoma/diagnosis , Neoplasm Proteins/analysis , Nevus/diagnosis , RNA-Binding Proteins/analysis , Sentinel Lymph Node Biopsy , Skin Neoplasms/diagnosis , Diagnosis, Differential , Humans , Immunohistochemistry , Lymph Nodes/pathology , Lymphatic Metastasis , Melanoma/chemistry , Melanoma/secondary , Nevus/chemistry , Predictive Value of Tests , Skin Neoplasms/chemistry , Skin Neoplasms/secondaryABSTRACT
Merkel cell carcinoma is an uncommon and aggressive primary cutaneous neuroendocrine carcinoma with a high rate of recurrence and metastasis. Optimal management is controversial; consequently, it is imperative to identify the signaling pathways involved in the pathogenesis of Merkel cell carcinoma so that effective therapeutic targeting agents can be developed. We previously reported that K homology domain-containing protein overexpressed in cancer is expressed in high-grade neuroendocrine carcinomas of the lung and extrapulmonary small cell carcinomas. The K homology domain-containing protein overexpressed in cancer (KOC), also known as L523S and IMP-3, is an insulin-like growth factor II messenger RNA-binding protein that promotes tumor cell proliferation by enhancing insulin-like growth factor II protein expression. Expression of KOC in Merkel cell carcinoma has not been investigated. We studied 20 Merkel cell carcinomas by immunohistochemistry using a monoclonal antibody against L523S/KOC. Of 20 Merkel cell carcinomas, 18 (90%) overexpressed KOC, with 11 (55%) overexpressing KOC in greater than 90% of tumor cells, 3 (15%) overexpressing KOC in 50% to 90% of tumor cells, 3 (15%) overexpressing KOC in 10% to 50% of tumor cells, and 1 (5%) overexpressing KOC in less than 10% of tumor cells. The immunostaining intensity was variable, with moderate to strong staining in 14 cases and weak staining in the remaining 4. Extent of expression of K homology domain-containing protein overexpressed in cancer predicted metastasis (P = .04) and was weakly correlated with increased tumor size (P = .08). In conclusion, Merkel cell carcinoma expresses K homology domain-containing protein overexpressed in cancer with an expression pattern similar to high-grade neuroendocrine carcinomas of the lung and extrapulmonary small cell carcinomas. We propose K homology domain-containing protein overexpressed in cancer as a potential target molecule for the treatment of high-grade neuroendocrine carcinomas, irrespective of anatomical location, and a potential marker to predict metastatic disease.
Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Merkel Cell/metabolism , Neoplasm Proteins/biosynthesis , RNA-Binding Proteins/biosynthesis , Skin Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Merkel Cell/pathology , Carcinoma, Neuroendocrine/metabolism , Female , Humans , Immunohistochemistry , Male , Middle Aged , Skin Neoplasms/pathologySubject(s)
Esophageal Neoplasms/diagnosis , Heart Atria/pathology , Heart Neoplasms/diagnosis , Lymphoma, Large B-Cell, Diffuse/diagnosis , Aged , Echocardiography , Endoscopy, Gastrointestinal , Esophageal Neoplasms/diagnostic imaging , Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Fatal Outcome , Heart Atria/diagnostic imaging , Heart Neoplasms/diagnostic imaging , Heart Neoplasms/pathology , Humans , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/pathology , Magnetic Resonance Imaging , MaleABSTRACT
Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP-3), also known as K homology domain-containing protein overexpressed in cancer (KOC) and L523S, is a member of the insulin-like growth factor-II mRNA-binding protein family and is expressed during embryogenesis and in some malignancies. IMP-3 expression in melanocytic neoplasms has not been investigated. Fifty-six melanocytic neoplasms from 48 subjects were immunohistochemically studied using a monoclonal antibody against L523S/IMP-3. IMP-3 expression in melanoma was significantly higher than in Spitz nevi (P<0.05), and the staining intensity in the Spitz nevi was weak. IMP-3 expression in metastatic melanoma was significantly higher than in primary cutaneous melanoma with a Breslow depth =1 mm (P<0.01). None of the benign nevi and dysplastic nevi expressed IMP-3. Our study demonstrates that IMP-3 is expressed in malignant melanoma but not in benign nevi, even when dysplastic features are present; IMP-3 is expressed in a significantly higher proportion of melanomas than Spitz nevi; and IMP-3 is expressed in metastatic melanomas significantly more than in thin melanomas. In conclusion, IMP-3 appears to be involved in the progression of malignant melanoma and may play an important role in the regulation of the biologic behavior of this tumor. Additionally, IMP-3 may have diagnostic utility in distinguishing melanoma from benign nevic cells, dysplastic nevi, and Spitz nevi.
Subject(s)
Biomarkers, Tumor/analysis , Melanoma/metabolism , Melanoma/pathology , Neoplasm Proteins/metabolism , RNA-Binding Proteins/metabolism , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Adolescent , Adult , Aged , Diagnosis, Differential , Disease Progression , Female , Humans , Immunohistochemistry , Male , Middle Aged , Nevus/metabolism , Nevus/pathology , Precancerous Conditions/metabolism , Precancerous Conditions/pathologyABSTRACT
BACKGROUND: Nephrogenic systemic fibrosis is a rare fibrosing condition that occurs in patients with renal insufficiency. While its histologic characteristics have been well described, the etiology and pathogenesis have not been fully characterized. Several recent studies support the theory that gadolinium-based contrast agents play a causative role in the development of the disease. Erythropoietin therapy and endothelial damage from surgical procedures have also been suggested as potential contributing factors. OBJECTIVE: This study attempts to help contribute to the understanding of this novel disorder. METHODS: We performed a retrospective chart review of 6 patients diagnosed with nephrogenic systemic fibrosis at our institution. Emphasis was placed on identification of potential putative etiologic agents including gadolinium, erythropoietin therapy, and previous surgical procedures. RESULTS: All patients had documented exposure to gadolinium-based contrast agents. Three of the 6 patients were treated with erythropoietin, and all patients underwent a previous surgical procedure. LIMITATIONS: This study is limited by its small size; therefore, the findings and results may not be applicable to all patients with this disorder. CONCLUSION: Our data suggest that gadolinium plays a primary role in nephrogenic systemic fibrosis and that prior surgery may be a contributory factor.