Susan Muller

KIT Gene Mutations and Copy Number in Melanoma Subtypes

Purpose: We recently identified a KIT exon 11 mutation in an anorectal melanoma of a patient who had an excellent response to treatment with imatinib. To determine the frequency of KIT mutations across melanoma subtypes, we surveyed a large series of tumors. Experimental Design: One hundred eighty-nine melanomas were screened for mutations in KIT exons 11, 13, and 17. KIT copy number was assessed by quantitative PCR. A subset of cases was evaluated for BRAF and NRAS mutations. Immunohistochemistry was done to assess KIT (CD117) expression. Results:KIT mutations were detected in 23% (3 of 13) of acral melanomas, 15.6% (7 of 45) of mucosal melanomas, 7.7% (1 of 13) of conjunctival melanomas, 1.7% (1 of 58) of cutaneous melanomas, and 0% (0 of 60) of choroidal melanomas. Almost all the KIT mutations were of the type predicted to be imatinib sensitive. There was no overlap with NRAS mutations (11.1% of acral and 24.3% of mucosal tumors) or with BRAF mutations (absent in mucosal tumors). Increased KIT copy number was detected in 27.3% (3 of 11) of acral and 26.3% (10 of 38) of mucosal melanomas, but was less common among cutaneous (6.7%; 3 of 45), conjunctival (7.1%; 1 of 14), and choroidal melanomas (0 of 28). CD117 expression, present in 39% of 105 tumors representing all melanoma types, did not correlate with either KIT mutation status or KIT copy number. Conclusions: Our findings confirm that KIT mutations are most common in acral and mucosal melanomas but do not necessarily correlate with KIT copy number or CD117 expression. Screening for KIT mutations may open up new treatment options for melanoma patients.

Phosphoglycerate Mutase 1 Coordinates Glycolysis and Biosynthesis to Promote Tumor Growth

It is unclear how cancer cells coordinate glycolysis and biosynthesis to support rapidly growing tumors. We found that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), commonly upregulated in human cancers due to loss of TP53, contributes to biosynthesis regulation in part by controlling intracellular levels of its substrate, 3-phosphoglycerate (3-PG), and product, 2-phosphoglycerate (2-PG). 3-PG binds to and inhibits 6-phosphogluconate dehydrogenase in the oxidative pentose phosphate pathway (PPP), while 2-PG activates 3-phosphoglycerate dehydrogenase to provide feedback control of 3-PG levels. Inhibition of PGAM1 by shRNA or a small molecule inhibitor PGMI-004A results in increased 3-PG and decreased 2-PG levels in cancer cells, leading to significantly decreased glycolysis, PPP flux and biosynthesis, as well as attenuated cell proliferation and tumor growth.

p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells

Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer and frequently metastasizes to LNs. Identifying metastasis-promoting factors is of immense clinical interest, as the prognosis for patients with even a single unilateral LN metastasis is extremely poor. Here, we report that p90 ribosomal S6 kinase 2 (RSK2) promotes human HNSCC cell invasion and metastasis. We determined that RSK2 was overexpressed and activated in highly invasive HNSCC cell lines compared with poorly invasive cell lines. Expression of RSK2 also correlated with metastatic progression in patients with HNSCC. Ectopic expression of RSK2 substantially enhanced the invasive capacity of HNSCC cells, while inhibition of RSK2 activity led to marked attenuation of invasion in vitro. Additionally, shRNA knockdown of RSK2 substantially reduced the invasive and metastatic potential of HNSCC cells in vitro and in vivo in a xenograft mouse model, respectively. Mechanistically, we determined that cAMP-responsive element-binding protein (CREB) and Hsp27 are phosphorylated and activated by RSK2 and are important for the RSK2-mediated invasive ability of HNSCC cells. Our findings suggest that RSK2 is involved in the prometastatic programming of HNSCC cells, through phosphorylation of proteins in a putative signaling network. Moreover, targeting RSK2 markedly attenuates in vitro invasion and in vivo metastasis of HNSCC cells, suggesting that RSK2 may represent a therapeutic target in the treatment of metastatic HNSCC.

Primary mucosal melanoma of the head and neck. Comparison of clinical presentation and histopathologic features of oral and sinonasal melanoma

We reviewed all cases of head and neck mucosal melanomas (HNMM) treated at Emory University and affiliated hospitals during a 20 year period and evaluate overall survival, recurrences and efficacy of treatment. Comparisons were made between sinonasal melanoma (SNM) and oral cavity melanoma (OCM) including clinical features, histopathologic features, treatment, and clinical outcomes. We analyzed pathologic features and clinical outcomes of 22 cases of primary SNM and eight cases of OCM treated at Emory University Hospital between 1986 and 2006. Sixteen patients were stage I (53%), nine patients were stage II (30%) and five patients were stage III (17%). Mean age was 67.5 years with a range from 32 to 85 years. Sixty percent were men and 92% were white. The average follow-up time was 22.1 months and the median was 15.5 months. The average delay between onset of symptoms and diagnosis was 5.6 months. Patients with SNM had a lower incidence of nodal metastasis at initial presentation when compared with OCM (22% vs. 50%) (p<.08). Surgical resection was the primary treatment and was performed in 27/30 patients (90%). Two patients with SNM and 1 patient with OCM, because of advanced stage at diagnosis had no treatment. Radiation was used in 50% (15) of the patients and radiation as postoperative therapy was administered to 44.8% (13) of the patients. The combination of surgery, radiation and adjuvant therapy was administered to 39.2% (11/2 8) of the patients. The recurrence rate at the time of closing this study was 43.3% (13 patients) with a mean time for development of recurrences of 13.1 months. Twenty-five patients (83%) died during the course of this study. Nineteen deaths (82%) corresponded to patients with SNM and six deaths (75%) to patients with OCM. The overall survival mean time was 21 months (median 12.5) with a range between 1 and 143 months. The 1, 2, 3, and 5 year survival rate for this study was 53.3%, 40%, 15% and 10%, respectively. The oral cavity was the location for the two patients still alive after 5 years. Although survival time correlated with Stage, particularly Stage 1, this was not statistically significant. Survival time did not correlate with surgery or adjuvant therapy. Statistically significant differences were noted between the pathologic features of OCM and SNM. These significant pathologic differences did not correlate with disease specific survival: OCM and SNM (median survival, 17 months vs. 12 months). Mucosal melanoma of the head and neck is a rare entity. Unfortunately, most patients present with advanced local disease. Local, regional recurrences and distant metastasis still occur despite the implementation of aggressive treatment, including surgery, radiation and adjuvant therapy. Despite significant pathologic differences between SNM and OCM, no survival advantage was seen.

Ameloblastic fibrosarcoma of the jaws. A clinicopathologic and DNA analysis of five cases and review of the literature with discussion of its relationship to ameloblastic fibroma.

Ameloblastic fibrosarcoma, the malignant counterpart of the ameloblastic fibroma, is a rare odontogenic tumor characterized by benign epithelium and a malignant fibrous stroma. We have compared nuclear DNA content of five ameloblastic fibrosarcomas and three ameloblastic fibromas by image analysis. The three ameloblastic fibromas were diploid, whereas 1 of 5 ameloblastic fibrosarcomas was aneuploid. There was no correlation with histologic grade and aneuploidy. These five new cases were also added to a review of the literature, bringing the total cases of reported ameloblastic fibrosarcomas to 51. The ameloblastic fibrosarcoma occurs at a later age (mean, 27.5 years) compared with reported ameloblastic fibromas (mean, 14.6 to 22 years), which supports a step-wise malignant transformation. There was histologic documentation that 44% of ameloblastic fibrosarcomas developed in ameloblastic fibromas. In view of this data and of the reported cumulative recurrence rate of 18.3% for ameloblastic fibroma, it is recommended that ameloblastic fibromas be treated with complete surgical excision and long-term follow up rather than simple curettage or enucleation.

Intraosseous schwannoma of the mandible: A case report and review of the literature

Schwannomas are benign neoplasms originating from the neural sheath and occurring most often in the soft tissues of the head and neck. Intraosseous schwannomas, however, are rare. The most common site of occurrence for these unusual lesions is the mandible. This article documents a case of an intramandibular schwannoma and provides a review of the literature on intraosseous schwannomas, with special attention to cases arising in the mandible and the maxilla.

Basal cell adenocarcinoma of the salivary glands: Report of seven cases and review of the literature

Basal cell adenocarcinoma (BCAC) is a rare, recently described salivary gland tumor. The authors report the clinicopathologic features of 7 new cases and compare the results with 65 additional cases in the English literature to comprehend its natural history.

Distinctive E-cadherin and epidermal growth factor receptor expression in metastatic and nonmetastatic head and neck squamous cell carcinoma: predictive and prognostic correlation.

The authors investigated whether coexpression and localization of E‐cadherin (E‐cad) and epidermal growth factor receptor (EGFR) had predictive and/or prognostic correlations with lymph node metastasis and/or survival in patients with squamous cell carcinoma of the head and neck (SCCHN).

Clear cell odontogenic carcinomas show EWSR1 rearrangements: a novel finding and a biological link to salivary clear cell carcinomas.

Clear cell odontogenic carcinomas (CCOCs) are a rare tumor of the jaws, which have considerable morphologic and immunophenotypic overlap with (hyalinizing) clear cell carcinomas (CCCs) of salivary origin. Fluorescence in situ hybridization for EWSR1 was performed on 12 CCOCs, 14 CCCs, and a control set of other miscellaneous clear cell tumors of the head and neck region. EWSR1 was rearranged in 12/13 (92.3%) CCCs and 5/8 (62.5%) CCOCs. EWSR1 testing failed in 1 CCC and 4 CCOCs. Two cases initially diagnosed as CCOCs that were negative for the EWSR1 translocation, were reclassified as clear cell calcifying epithelial odontogenic tumors. ATF1 involvement was confirmed by fluorescence in situ hybridization analysis in 1 CCOC. In this study, we demonstrate for the first time the EWSR1-ATF1 translocation in a CCOC and demonstrate a concrete link between CCCs and at least a subset of CCOCs.

Primary intraosseous squamous carcinoma. Report of two cases

Two cases of primary intraosseous squamous carcinoma (PIOSC) are reported. One PIOSC is in the mandible of a 24-year-old man and appears to be a keratinizing PIOSC arising de novo. The other PIOSC presented in the edentulous maxilla of a 56-year-old man and was diagnosed as a PIOSC arising from an odontogenic cyst. The 2nd tumor subsequently metastasized to a cervical lymph node. Previous reports have noted a favorable prognosis for PIOC arising in odontogenic cysts, and only 3 other instances of metastases of a PIOSC in an odontogenic cyst have been documented.