Diane L. Carlson

Follicular Variant of Papillary Thyroid Carcinoma A Clinicopathologic Study of a Problematic Entity

There is continuous debate regarding the optimal classification, prognosis, and treatment of the follicular variant of papillary thyroid carcinoma (FVPTC). The objective of this study was to assess the behavior of FVPTC, especially its encapsulated form, and shed more light on its true position in the classification scheme of well differentiated thyroid carcinoma.

Clinical Utility of 18F-FDG PET/CT in Assessing the Neck After Concurrent Chemoradiotherapy for Locoregional Advanced Head and Neck Cancer

For patients with locoregional advanced head and neck squamous cell carcinoma (HNSCC), concurrent chemoradiotherapy is a widely accepted treatment, but the need for subsequent neck dissection remains controversial. We investigated the clinical utility of 18F-FDG PET/CT in this setting. Methods: In this Institutional Review Board (IRB)–approved and Health Insurance Portability and Accountability Act (HIPPA)–compliant retrospective study, we reviewed the records of patients with HNSCC who were treated by concurrent chemoradiation therapy between March 2002 and December 2004. Patients with lymph node metastases who underwent 18F-FDG PET/CT ≥ 8 wk after the end of therapy were included. 18F-FDG PET/CT findings were validated by biopsy, histopathology of neck dissection specimens (n = 18), or clinical and imaging follow-up (median, 37 mo). Results: Sixty-five patients with a total of 84 heminecks could be evaluated. 18F-FDG PET/CT (visual analysis) detected residual nodal disease with a sensitivity of 71%, a specificity of 89%, a positive predictive value (PPV) of 38%, a negative predictive value (NPV) of 97%, and an accuracy of 88%. Twenty-nine heminecks contained residual enlarged lymph nodes (diameter, ≥1.0 cm), but viable tumor was found in only 5 of them. 18F-FDG PET/CT was true-positive in 4 and false-positive in 6 heminecks, but the NPV was high at 94%. Fifty-five heminecks contained no residual enlarged nodes, and PET/CT was true-negative in 50 of these, yielding a specificity of 96% and an NPV of 98%. Lack of residual lymphadenopathy on CT had an NPV of 96%. Finally, normal 18F-FDG PET/CT excluded residual disease at the primary site with a specificity of 95%, an NPV of 97%, and an accuracy of 92%. Conclusion: In patients with HNSCC, normal 18F-FDG PET/CT after chemoradiotherapy has a high NPV and specificity for excluding residual locoregional disease. In patients without residual lymphadenopathy, neck dissection may be withheld safely. In patients with residual lymphadenopathy, a lack of abnormal 18F-FDG uptake in these nodes also excludes viable tumor with high certainty, but confirmation of these data in a prospective study may be necessary before negative 18F-FDG PET/CT may become the only, or at least most-decisive, criterion in the management of the neck after chemoradiotherapy.

Re: Human Papillomavirus DNA and p53 Polymorphisms in Squamous Cell Carcinomas From Fanconi Anemia Patients

Fanconi anemia is an autosomal recessive disorder characterized by congenital malformations, bone marrow failure, and the development of squamous cell carcinomas (SCCs) and other cancers. Recent clinicopathologic evidence has raised the possibility that an environmental factor such as human papillomavirus (HPV) may be involved in the pathogenesis of SCCs in Fanconi anemia patients. Given the high prevalence of p53 mutations in SCCs among the general population and the lack of p53 mutations in HPV-related carcinogenesis, we evaluated the role of HPV and p53 mutations and polymorphisms in SCC from Fanconi anemia patients. We used polymerase chain reaction (PCR) screening and real-time PCR to detect and quantify HPV DNA in DNA extracted from microdissected SCCs obtained from 24 Fanconi anemia patients (n = 25 SCCs; case subjects) and 50 age-, sex-, and tumor site-matched SCC patients without Fanconi anemia (n = 50 SCCs; control subjects). We PCR-amplified and sequenced exons 4-9 of the p53 gene from SCC DNA. We detected HPV DNA in 84% of the SCC specimens from the case subjects and in 36% of the SCC specimens from the control subjects (P<.001). The prevalence of p53 mutations in SCCs from the case subjects (0%, 0/25) was statistically significantly lower than that of SCCs from the control subjects (36%, 12/33; P<.001). A greater proportion of patients with Fanconi anemia and SCC were homozygous for Arg72, a p53 polymorphism that may be associated with increased risk for HPV-associated human malignancies, than an ethnically-matched cohort of Fanconi anemia patients without SCC (75% versus 51%; P =.05). These data suggest that Fanconi anemia is associated with increased susceptibility to HPV-induced carcinogenesis.

Lymph node density is a significant predictor of outcome in patients with oral cancer

The impact of lymph node metastases on prognosis in patients with oral cavity squamous cell carcinoma (OSCC) has been well recognized. However, accurate stratification of risk for recurrence among patients with lymph node metastases is difficult based on the existing staging systems. In the current study, the utility of lymph node density (LND) was evaluated as an alternative method for predicting survival.

Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.

Oral tongue cancer gene expression profiling: Identification of novel potential prognosticators by oligonucleotide microarray analysis

BackgroundThe present study is aimed at identifying potential candidate genes as prognostic markers in human oral tongue squamous cell carcinoma (SCC) by large scale gene expression profiling.MethodsThe gene expression profile of patients (n=37) with oral tongue SCC were analyzed using Affymetrix HG_U95Av2 high-density oligonucleotide arrays. Patients (n=20) from which there were available tumor and matched normal mucosa were grouped into stage (early vs. late) and nodal disease (node positive vs. node negative) subgroups and genes differentially expressed in tumor vs. normal and between the subgroups were identified. Three genes, GLUT3, HSAL2, and PACE4, were selected for their potential biological significance in a larger cohort of 49 patients via quantitative real-time RT-PCR.ResultsHierarchical clustering analyses failed to show significant segregation of patients. In patients (n=20) with available tumor and matched normal mucosa, 77 genes were found to be differentially expressed (P< 0.05) in the tongue tumor samples compared to their matched normal controls. Among the 45 over-expressed genes, MMP-1 encoding interstitial collagenase showed the highest level of increase (average: 34.18 folds). Using the criterion of two-fold or greater as overexpression, 30.6%, 24.5% and 26.5% of patients showed high levels of GLUT3, HSAL2 and PACE4, respectively. Univariate analyses demonstrated that GLUT3 over-expression correlated with depth of invasion (P<0.0001), tumor size (P=0.024), pathological stage (P=0.009) and recurrence (P=0.038). HSAL2 was positively associated with depth of invasion (P=0.015) and advanced T stage (P=0.047). In survival studies, only GLUT3 showed a prognostic value with disease-free (P=0.049), relapse-free (P=0.002) and overall survival (P=0.003). PACE4mRNA expression failed to show correlation with any of the relevant parameters.ConclusionThe characterization of genes identified to be significant predictors of prognosis by oligonucleotide microarray and further validation by real-time RT-PCR offers a powerful strategy for identification of novel targets for prognostication and treatment of oral tongue carcinoma.

Paracrine Regulation of Pancreatic Cancer Cell Invasion by Peripheral Nerves

BACKGROUND The ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown. METHODS We used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function. RESULTS Nerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean = 187.1 microm, 95% confidence interval [CI] = 148 to 226 microm vs 14.4 microm, 95% CI = 9.58 to 19.22 microm, difference = 143 microm; P < .001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras-mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/-, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P < .001; n = 60-66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFalpha1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice. CONCLUSION These data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer.

Long-term regional control and survival in patients with "low-risk," early stage oral tongue cancer managed by partial glossectomy and neck dissection without postoperative radiation: the importance of tumor thickness.

The objectives of this study were to determine the incidence of locoregional failure in patients with low‐risk, early stage oral tongue squamous cell cancer (OTSCC) who undergo partial glossectomy and ipsilateral elective neck dissection without receiving postoperative radiation.

Prognostic factors of recurrence in salivary carcinoma ex pleomorphic adenoma, with emphasis on the carcinoma histologic subtype: a clinicopathologic study of 43 cases

Carcinoma ex pleomorphic adenoma is a rare salivary gland neoplasm, especially when the malignant component is only intracapsular/minimally invasive. Moreover, only few studies have assessed the behavior of carcinoma ex pleomorphic adenoma according to the histologic subtype. Forty-three cases of carcinoma ex pleomorphic adenoma were identified over a 27-year period and subjected to a detailed histopathologic analysis. There were 13 intracapsular/minimally invasive and 30 widely invasive carcinomas. There were 15 myoepithelial carcinomas, 25 salivary duct carcinomas, 2 adenocarcinomas not otherwise specified, and 1 carcinosarcoma. There was a trend toward a higher frequency of myoepithelial carcinomas in widely invasive tumors (13/30, 43%) than in intracapsular/minimally invasive (2/13, 15%) carcinoma ex pleomorphic adenoma (P = .095). Adequate follow-up was available for 38 patients. Vascular invasion and distant metastases correlated with decreased disease-free survival and disease-specific survival (P < .05), whereas the extent of invasion and the presence of a high mitotic rate or atypical mitoses correlated with decreased disease-free survival only (P < .05). There was a trend toward worse disease-free survival and disease-specific survival in patients with myoepithelial carcinoma (P = .08). Within the intracapsular/minimally invasive carcinoma ex pleomorphic adenoma group, both myoepithelial carcinoma (2/2, 100%) had metastatic disease, whereas only 1 of 11 nonmyoepithelial carcinoma relapsed (P = .038). Vascular invasion, high mitotic rate, and histologic subtype were found to correlate with recurrence in carcinoma ex pleomorphic adenoma. Patients with intracapsular/minimally invasive tumor have a more favorable outcome than patients with widely invasive neoplasm, but intracapsular/minimally invasive carcinoma ex pleomorphic adenoma can recur and cause death. The presence of myoepithelial carcinoma subtype increases the risk of recurrence in carcinoma ex pleomorphic adenoma, especially within the group of intracapsular/minimally invasive tumors.

A phase 2 study of bevacizumab with cisplatin plus intensity‐modulated radiation therapy for stage III/IVB head and neck squamous cell cancer

For patients with stage III through IVB head and neck squamous cell carcinoma (HNSCC), concurrent high‐dose cisplatin plus radiation therapy is a widely accepted standard of care. HNSCC tumors that express high levels of vascular endothelial growth factor have been associated with a worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation.