Paul W. Biddinger

Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas.

Papillary carcinoma is the most common type of thyroid malignancy. It has been recently shown that these tumors commonly have one of three genetic alterations: BRAF point mutations, RET/PTC rearrangements, or RAS point mutations. In this study, we analyze the relationship between these alterations and the microscopic features of papillary carcinomas, their clinical features, and prognostic characteristics. Ninety-seven papillary carcinomas were studied; in all cases, frozen tissue was available for nucleic acid extraction. Of 96 unselected cases, 42% were positive for BRAF, 18% for RET/PTC, and 15% for RAS mutations. Morphologic features were evaluated in detail in 61 cases and 6 characteristic nuclear features and 3 additional microscopic features were assessed quantitatively. At least 4 nuclear features were found in each tumor, with nuclear pseudoinclusions being the least frequent finding in all mutation groups. BRAF mutations were associated with older patient age, typical papillary appearance or the tall cell variant, a higher rate of extrathyroidal extension, and more advanced tumor stage at presentation. RET/PTC rearrangements presented at younger age and had predominantly typical papillary histology, frequent psammoma bodies, and a high rate of lymph node metastases. Tumors with RAS mutations were exclusively the follicular variant of papillary carcinoma and correlated with significantly less prominent nuclear features and low rate of lymph node metastases. These findings demonstrate that BRAF, RET/PTC, and RAS mutations are associated with distinct microscopic, clinical, and biologic features of thyroid papillary carcinomas.

PAX8-PPARγ Rearrangement in Thyroid Tumors: RT-PCR and Immunohistochemical Analyses

A PAX8-PPAR&ggr; rearrangement has been recently identified in follicular thyroid carcinomas, but not in follicular adenomas or other thyroid tumors. We report here the analyses of PAX8-PPAR&ggr; in a series of 118 thyroid tumors using a newly developed RT-PCR assay to detect this rearrangement in frozen and paraffin-embedded tissues and using immunostaining with a PPAR&ggr; antibody. PAX8-PPAR&ggr; was detected by RT-PCR in eight of 15 (53%) follicular carcinomas and two of 25 (8%) follicular adenomas but not in 35 papillary carcinomas (including 12 follicular variants), 12 Hurthle cell carcinomas, 12 Hurthle cell adenomas, two anaplastic carcinomas, one poorly differentiated carcinoma, or 16 hyperplastic nodules. The prevalence was higher in follicular carcinomas from patients with a history of radiation exposure (three of three). Strong, diffuse nuclear immunostaining with the PPAR&ggr; antibody correlated with the presence of PAX8-PPAR&ggr; detected by RT-PCR. Most sporadic follicular carcinomas positive for PAX8-PPAR&ggr; were overtly invasive, whereas tumors lacking the rearrangement were predominantly minimally invasive. The two follicular adenomas positive for PAX8-PPAR&ggr; had trabecular growth pattern and thick capsule, but no invasion, and thus may represent “pre-invasive” follicular carcinomas. The absence of PAX8-PPAR&ggr; rearrangements in Hurthle cell tumors and papillary thyroid carcinomas highlights the differences in the molecular pathogenesis of these thyroid tumors.

Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression

We have previously reported that loss of p53 tumor suppressor protein results in centrosome hyperamplification, which leads to aberrant mitosis and chromosome instability. Since p53 is either deleted or mutated in human cancers at a high frequency, we investigated whether human cancers showed centrosome hyperamplification. Screening of advanced stage breast ductal carcinomas and squamous cell carcinomas of the head and neck (SCCHN) revealed that centrosome hyperamplification is frequent in both tumor types. Moreover, through the analyses of p53 in SCCHN samples by direct sequencing and by loss-of-heterozygosity test, we found that p53 mutations correlated with occurrence of centrosome hyperamplification. However, in some cases, we observed centrosome hyperamplification in tumors that retained wild-type p53. These tumors contained high levels of Mdm2. Since Mdm2 can inactivate p53 through physical association, we investigated whether Mdm2 overexpression induced centrosome hyperamplification. We found that Mdm2 overexpression, like loss of p53, induced centrosome hyperamplification and chromosome instability in cultured cells.

Prevalence of RET/PTC Rearrangements in Hashimoto's Thyroiditis and Papillary Thyroid Carcinomas

The relationship between Hashimotos thyroiditis (HT) and follicular cell-derived thy roid cancer remains unclear. Recently, 2 studies reported a 95% prevalence of RET/PTC rearrangements in histologically benign tissue affected by HT, suggesting that multiple occult tumors exist in HT patients with high frequency. We tested the prevalence of RET/PTC rearrangements in 26 HT, in 6 papillary carcinomas arising in the background of HT, and in 27 papillary carcinomas not associated with HT. We detected no RET/PTC rearrangements in HT or papillary carcinomas arising in the background of HT, in contrast to a 33% prevalence among papillary carcinomas not associated with HT. However, the expression of wild-type RET was found in more than half of papillary carcinomas. These results suggest that, if the association be tween HT and thyroid cancer exists, its molecular basis is different from RETIPTC rearrangement. Int J Surg Pathol 10(1):15-22, 2002

Esthesioneuroblastoma and Sinonasal Undifferentiated Carcinoma: Impact of Histological Grading and Clinical Staging on Survival and Prognosis

Objectives Hyams proposed a histological grading system for esthesioneuroblastoma in which grade I tumors have an excellent prognosis and grade IV tumors are uniformly fatal. The Hyams grading system predated advanced craniofacial techniques, extensive use of immunohistochemistry, and the recognition of sinonasal undifferentiated carcinoma (SNUC) as a distinct entity. Therefore we aimed to determine whether Hyams classification is useful in predicting outcome for esthesioneuroblastoma and SNUC.

Tumor angiogenesis as a prognostic indicator in T2-T4 oral cavity squamous cell carcinoma : A clinical-pathologic correlation

Tumor angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis in breast and other cancers. Studies in head and neck cancer have suggested a similar correlation, but results have been inconclusive. This study was performed to determine the correlation between angiogenesis and oral tumor behavior.

Tumor angiogenesis in T1 oral cavity squamous cell carcinoma: Role in predicting tumor aggressiveness

Angiogenesis is necessary for tumor growth and metastasis. In breast and other cancers angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis. Some studies of head and neck cancer have shown a similar correlation, although results are inconclusive. This study was performed to determine whether tumor angiogenesis can be used as a prognostic indicator for early oral cancers.

Lethal intrauterine fetal trauma.

Eight cases of lethal intrauterine fetal trauma secondary to motor vehicle accidents are retrospectively studied. In each instance the mother survived, usually sustaining only minor injuries. Some degree of placental abruption or infarction occurred in each case, but fetal abnormalities were more varied. Significant fetal injuries were limited to the head and included two instances of skull fracture associated with cortical lacerations and contusions. Six of the eight fetuses were stillborn, and the other two died during the first postnatal day. At least five of the mothers were unrestrained at the time of the accident, three of whom experienced abdominal impact against the steering wheel but no external abdominal injuries. Although two mothers were wearing seat belts, in only one instance could the seat belt be implicated in contributing to the fetal injury. This study shows that lethal placental or direct fetal injury can occur even though maternal injuries are minor or insignificant. The findings also support current recommendations for use of three-point restraints.

Prognostic Indicators for Squamous Cell Carcinoma of the Oral Cavity: A Clinicopathologic Correlation†

Fifty‐three patients with T1 squamous cell cancer of the floor of mouth and ventral surface of the tongue with a known clinical outcome were retrospectively analyzed and arbitrarily divided into “aggressive” and “nonaggressive” groups based on their clinical behavior. Various host and tumor factors were then evaluated in an attempt to determine whether the tumor behavior could have been predicted. The paraffin‐embedded tumor specimens were evaluated for tumor differentiation, tumor thickness and tumor invasion, microvessel density, and p53 expression. In addition, a composite morphologic grading score was obtained by combining cell differentiation, nuclear polymorphism, mitosis activity, depth of infiltration, type of infiltration, and lymphatic infiltration. No single technique appeared capable of identifying “aggressive” behavior, although possibly an evaluation of composite factors might show promise in the future.

The Loss of Heterozygosity in Retinoblastoma and p53 Suppressor Genes As a Prognostic Indicator for Head and Neck Cancer

Inactivation of tumor suppressor genes, including p53 and retinoblastoma(Rb), are commonly found in all cancers, including head and neck squamous cell carcinoma. Alterations at either p53 or Rb, however, are only weakly associated with tumor aggressiveness. In many cancers loss of heterozygosity (LOH) at multiple loci is associated with decreased survival. The polymerase chain reaction and highly informative microsatellite markers were used to compare DNA from matched sets of 63 head and neck squamous cell cancers and normal tissue for LOH at the p53 and Rb loci. At p53, 50 were informative, with LOH occurring in 19 (38%). Of the 57 that were informative at Rb, LOH occurred in 21 (37%). Of the 46 that were informative at both p53 and Rb, LOH occurred in 10 (22%) at both loci. When LOH for p53 and Rb individually was compared to stage, differentiation, and survival, there was no correlation. However, the patients with LOH at both loci had a significantly poorer survival (P = .009). This strongly supports the contention that simultaneous alterations of these two tumor suppressor genes favor tumor aggressiveness and can be used as a prognostic indicator.