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p63, a member of the p53 gene family, encodes multiple proteins that may either transactivate p53 responsive genes (TAp63) or act as a dominant-negative factor toward p53 and p73 (Delta Np63). p63 is expressed in many epithelial compartments and p63(-/-) mice fail to develop skin, prostate, and mammary glands among other defects. It has been previously shown that p63 is expressed in normal urothelium. This study reports that p63 is regulated in bladder carcinogenesis and that p63 expression is lost in most invasive cancers whereas papillary superficial tumors maintain p63 expression. Examination of bladder carcinoma cell lines reveals that certain lines derived from invasive carcinomas maintain expression of Delta Np63, as demonstrated by both immunoblotting and confirmed by isoform-specific quantitative reverse transcriptase-polymerase chain reaction. Another novel finding reported in this study is the fact that p63(-/-) mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium. These data indicate that in contrast to the skin and prostate, p63 is not required for formation of a bladder epithelium but is indispensable for the specific differentiation of a transitional urothelium.

PURPOSE: Controversy exists over the ability of morphology to predict the biologic behavior of Hürthle cell carcinoma. The aim of this study was to conduct a critical histopathologic review of Hürthle cell carcinoma and to correlate morphologic parameters with clinical outcome. PATIENTS AND METHODS: Patients with histologically confirmed Hürthle cell carcinoma treated between 1940 and 2000 form the basis of this study. Adenomas were excluded. Tumors of unknown malignant behavior ([UMB] n = 17) had solid growth pattern, incomplete capsular invasion (Ci), or both but no vascular invasion (Vi). Minimally invasive carcinomas ([MIC] n = 23) had one focus of intra- or extracapsular Vi, one focus of complete Ci, or both. Widely invasive carcinomas ([WIC] n = 33) demonstrated more than one focus of Vi, more than one focus of Ci, or both. The primary end points were relapse-free survival (RFS) and disease-specific survival (DSS). Rates of recurrence/death were estimated by Kaplan-Meier method. The univariate influence of prognostic factors on end points was analyzed by log-rank test, and multivariate analysis was performed by Cox regression. RESULTS: Median follow-up was 8 years. No patients with UMB or MIC relapsed or died of disease. Of WIC, 73% relapsed and 55% died of disease. Age, size, and extent of resection did not influence outcome. Adverse predictors of RFS and DSS among WIC were extrathyroidal extension, nodal metastasis, positive margin, and solid growth pattern (P < .05). Both Ci and Vi were associated with worse DSS (P < .05). On multivariate analysis, extrathyroidal extension and nodal metastases were independent predictors of outcome (P < .05). CONCLUSION: Patients with Hürthle cell carcinoma have a prognosis that is predicted by well-defined histomorphologic characteristics. Unlike differentiated thyroid cancer, nodal metastases predict a worse outcome in widely invasive Hürthle cell carcinoma, as does extrathyroidal extension.

BACKGROUND Rhabdomyosarcoma (RMS) in adults (age ≥ 16 years) is rare, accounting for less than 3% of adult soft tissue sarcomas. There is little information describing the disease biology or clinicopathologic factors that influence survival in adults with RMS. The objective of this study was to define the factors in patients with adult RMS that predict outcome, disease progression, and survival. METHODS Eighty-four adult patients with a pathologic diagnosis of RMS that was confirmed by immunohistochemistry were identified by a prospective inpatient data base during the period 1982–-1999 and were analyzed for disease specific survival and metastasis free survival using the Kaplan–Meier actuarial method. Statistical significance was evaluated using the log-rank test for univariate influence and a Cox regression model for multivariate influence. RESULTS The median disease specific survival was 22 months. Patient age, extent of disease, tumor size at the time of diagnosis, and margin status after resection were significant predictors of disease specific survival. Patients who underwent a complete resection had a significantly longer median survival (105 months) compared with any other subgroup of patients. The histologic subtype did not predict patient survival but did vary with patient age. Most notably, the proportion of the pleomorphic subtype increased with advancing age, accounting for 42% of RMS in patients over the age of 40 years. CONCLUSIONS The most important predictors of outcome in patients with adult RMS are patient age, tumor size, extent of disease, and margin status after resection. In contrast to patients with pediatric RMS, no association was noted between survival and histologic subtype in this group of patients with adult RMS. All histologic subtypes of RMS are aggressive malignancies with poor disease specific survival despite aggressive multimodality management. Cancer 2001;91:794–803. © 2001 American Cancer Society.

Background Desmoid tumors are are, nonmalignant neoplasms that show locally aggressive growth but lack the potential to metastasize. Common anatomic sites include the extremity, abdominal wall, and mesentery. Little is reported about clinical features and outcome of desmoid tumors of the head and neck. Methods Twenty-one patients with desmoid tumors of the head and neck treated at MSKCC between July 1982 and June 1999 were identified from our inpatient tumor database. All patients underwent surgical resection and were prospectively followed. Clinicopathologic features and treatment modalities were evaluated. Results Patient age at diagnosis was 22 to 76 years, with a female–male ratio of 16:5. Most tumors were located in the supraclavicular fossa or the muscles of the neck (n = 19). Patients most commonly had a painless mass (n = 13) or neurologic symptoms including pain or neurologic deficit (n = 8). Extent of resection was limited to the tumor in nine patients. In the other 12, structures including the accessory or phrenic nerve, parts of the brachial plexus, or bony structures were resected. Persistent neurologic or functional deficits after surgery were noted in 12 patients. Five of 21 patients had recurrences (24%). Eleven patients received radiation therapy. In this small population, no obvious benefit for patients receiving radiation vs patients who were not irradiated, regardless of their surgical margin status, was seen. Treatment for recurrence was re-resection or re-resection plus radiation. Eighteen patients remained free of disease after treatment, two patient have stable disease and one died of other causes. No patients died of their disease. Conclusions Desmoid tumors of the head and neck are rare, fibrous neoplasms with a good prognosis but significant morbidity. Function-preserving surgery should be a primary goal to minimize morbidity. In this small group of patients, the benefits of radiation therapy in patients with positive margins could not be clearly demonstrated and should be balanced against radiation-related morbidity. © 2000 John Wiley & Sons, Inc. Head Neck 22: 814–821, 2000.

The aim of this study was to define the clinical behavior and prognostic indicators of outcome in Hurthle cell cancer (HCC). Diagnosis was confirmed for 56 patients with HCC treated between 1940 and 2000, who form the basis of this study. Primary end points were relapse-free survival (RFS) and disease-specific survival (DSS). Data were analyzed with the Kaplan-Meier method and by log-rank test. The extent of thyroid resection did not predict outcome. Recurrence was a significant predictor of tumor-related mortality. Significant adverse predictors of RFS and DSS were degree of invasion, size >4 cm, extrathyroidal extension, and initial nodal or distant metastases. The most significant predictor of outcome was extent of invasion. Eight-year RFS values for low- and high-risk groups were 100% and 24%. Corresponding rates of 8-year DSS were 100% and 58%. Widely invasive HCC is an aggressive malignancy that identifies patients who are at high risk for recurrence and tumor-related death. Patients with HCC have a prognosis that is reliably predicted by degree of invasion, tumor size, extrathyroidal disease extension, and initial nodal or distant metastasis. Recurrence portends a poor outcome. High-risk patients and those with recurrence should be considered for adjuvant therapy.

The p63 gene, located on chromosome 3q27-28, is a member of the p53 gene family. The product encoded by the p63 gene has been reported to be essential for normal development.In this study, we examined the expression pattern of p63 in human normal and tumor tissues by immunohistochemistry using a monoclonal antibody (clone 4A4) that recognizes all p63 splice variants, and by reverse transcription-PCR using isoform-specific primers.We found that p63 expression was restricted to the nucleus, with a nucleoplasmic pattern. We also observed that the expression was restricted to epithelial cells of stratified epithelia, such as skin, esophagus, exocervix, tonsil, and bladder, and to certain subpopulations of basal cells in glandular structures of prostate and breast, as well as in bronchi. Consistent with the phenotype observed in normal tissues, we found that p63 is expressed predominantly in basal cell and squamous cell carcinomas, as well as transitional cell carcinomas, but not in adenocarcinomas, including those of breast and prostate. Interestingly, thymomas expressed high levels of p63. Moreover, a subset of non-Hodgkin's lymphoma was also found to express p63. Using isoform-specific reverse transcription-PCR, we found that thymomas express all isoforms of p63, whereas the non-Hodgkin's lymphoma tended to express the transactivation-competent isoforms. We did not detect p63 expression in a variety of endocrine tumors, germ cell neoplasms, or melanomas. Additionally, soft tissue sarcomas were also found to have undetectable p63 levels.Our data support a role for p63 in squamous and transitional cell carcinomas, as well as certain lymphomas and thymomas.

Tissue microarrays allow high-throughput molecular profiling of cancer specimens by immunohistochemistry. Phenotype information of sections from arrayed biopsies on a multitissue block needs to be representative of full sections, as protein expression varies throughout the entire tumor specimen. To validate the use of tissue microarrays for immunophenotyping, we studied a group of 59 fibroblastic tumors with variable protein expression patterns by immunohistochemistry for Ki-67, p53, and the retinoblastoma protein (pRB). Data on full tissue sections were compared to the results of one, two, and three 0.6-mm core biopsies per tumor on a tissue array. Ki-67 and p53 staining was read as two categories (positive or negative). Concordance for this staining between tissue arrays with triplicate cores per tumor and full sections were 96 and 98%, respectively. For pRB staining was read as three categories (high, moderate, or negative), where concordance was 91%. The use of three cores per tumor resulted in lower numbers of lost cases and lower nonconcordance with standard full sections as compared to one or two cores per tumor. Correlations between phenotypes and clinical outcome were not significantly different between full section and array-based analysis. Triplicate 0.6-mm core biopsies sampled on tissue arrays provide a reliable system for high-throughput expression profiling by immunohistochemistry when compared to standard full sections. Triplicate cores offer a higher rate of assessable cases and a lower rate of nonconcordant readings than one or two cores. Concordance of triplicate cores is high (96 to 98%) for two category distinction and decreases with the complexity of the phenotypes being analyzed (91%).