Theresa L. Nicol

A Molecular Classification of Papillary Renal Cell Carcinoma

Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIalpha in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.

Detection of Human Papillomavirus-16 in Fine-Needle Aspirates to Determine Tumor Origin in Patients with Metastatic Squamous Cell Carcinoma of the Head and Neck

Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) often clinically present with metastases to regional lymph nodes. Fine-needle aspiration of neck masses is routinely used to establish the presence of metastatic carcinoma and in turn to initiate a subsequent workup to determine the site of tumor origin. Human papillomavirus (HPV) 16 is an important etiologic agent for HNSCCs that arise from the oropharynx but less so for tumors from non-oropharyngeal sites. HPV16 detection thus provides a strategy for localizing an important subset of HNSCCs, but this approach has not been applied to fine-needle aspiration specimens. Experimental Design: We did in situ hybridization for HPV16 on 77 consecutive aspirated neck masses diagnosed as metastatic squamous cell carcinoma. P16 immunohistochemistry was also done because p16 overexpression may serve as a surrogate marker of HPV-associated HNSCC. Results: HPV16 was detected in 13 of the 77 (17%) aspirates. By site of origin, HPV16 was detected in 10 of 19 metastases from the oropharynx but in none of 46 metastases from other sites (53% versus 0%; P < 0.0001). HPV16 was not detected in 2 branchial cleft cysts misdiagnosed as metastatic squamous cell carcinoma, but it was detected in 3 of 10 metastases from occult primary tumors. P16 expression was associated with the presence of HPV16: 12 of 13 HPV16-positive metastases exhibited p16 expression, whereas only 4 of 62 HPV16-negative metastases were p16 positive (92% versus 6%; P < 0.0001). P16 expression also correlated with site of tumor origin: 13 of 19 oropharyngeal metastases were p16 positive, whereas only 1 of 46 non-oropharyngeal metastases was p16 positive (68% versus 2%; P < 0.0001). Conclusions: HPV16 status can be determined in tumor cells aspirated from the necks of patients with metastatic HNSCC. Its presence is a reliable indicator of origin from the oropharynx.

Clinically Significant, Isolated Metastatic Disease to the Thyroid Gland

n= 5), esophageal adenocarcinoma (n= 1), pulmonary squamous cell carcinoma (n= 1), gastric leiomyosarcoma (n= 1), lingual squamous cell carcinoma (n= 1), and parotid gland carcinoma (n= 1). Three patients underwent preoperative fine-needle aspiration (FNA), all of which were suggestive of metastatic disease. The mean time from resection of the primary tumor to thyroid metastases was 3.5 ± 6.0 years (range 0–19.5 years). Total thyroidectomy (n= 5) or lobectomy (n= 5) was performed without morbidity or mortality. After a median follow-up of 5.2 years six patients are alive and two are free of disease. Moreover, no patients have had recurrent disease in the neck. Thus carcinomas metastatic to the thyroid represent a rare cause of clinically significant thyroid disease, with RCCs comprising 50%. Most thyroid metastases (80%) present within 3 years of primary tumor resection, but with RCC they can occur as late as 19 years. The diagnosis of metastatic disease should be suspected in patients with even a remote history of cancer, especially RCC, and an FNA revealing clear cell or spindle cell carcinoma. Contrary to previous reports, long-term survival can be achieved after resection of the metastatic tumor. Furthermore, thyroidectomy may also palliate/prevent the potential morbidity of tumor recurrence in the neck.

Hurthle cell neoplasms of the thyroid : are there factors predictive of malignancy?

OBJECTIVE To determine if any preoperative or intraoperative factors can reliably predict malignancy in patients with Hürthle cell neoplasms. SUMMARY BACKGROUND DATA Most experienced surgeons recommend total thyroidectomy for Hürthle cell carcinomas and reserve thyroid lobectomy for Hürthle cell adenomas. However, delineation between Hürthle cell adenoma versus carcinoma often cannot reliably be made either before or during surgery. METHODS Medical records from 57 consecutive patients who underwent thyroid resections for Hürthle cell neoplasms between October 1984 and April 1995 at The Johns Hopkins Hospital were analyzed to determine if any factors were predictive of malignancy. RESULTS Of the 57 patients with Hürthle cell neoplasms, 37 had adenomas and 20 had carcinomas, resulting in a 35% prevalence of malignancy. Patients with adenomas did not differ from those with carcinoma with respect to age, sex, or history of head and neck irradiation. However, patients with Hürthle cell carcinomas had significantly larger tumors (4.0 +/- 0.4 cm vs. 2.4 +/- 0.2 cm, p < 0.005). Furthermore, although the incidence of malignancy was only 17% for tumors 1 cm or less and 23% for tumors 1 to 4 cm, tumors 4 cm or greater were malignant 65% of the time (p < 0.05). Both fine-needle aspiration and intraoperative frozen section analysis had low sensitivities in the detection of cancer (16% and 23%, respectively). With up to 9 years of follow-up, there has been no tumor-related mortality. CONCLUSIONS These data demonstrate that the size of a Hürthle cell neoplasm is predictive of malignancy. Therefore, at the time of initial exploration for large Hürthle cell neoplasms (>4 cm), definitive resection involving both thyroid lobes should be considered because of the higher probability of malignancy.

Nonrandom Distribution of Aberrant Promoter Methylation of Cancer-Related Genes in Sporadic Breast Tumors

Purpose: In an effort to additionally determine the global patterns of CpG island hypermethylation in sporadic breast cancer, we searched for aberrant promoter methylation at 10 gene loci in 54 primary breast cancer and 10 breast benign lesions. Experimental Design: Genomic DNA sodium bisulfate converted from benign and malignant tissues was used as template in methyl-specific PCR for BRCA1, p16, ESR1, GSTP1, TRβ1, RARβ2, HIC1, APC, CCND2, and CDH1 genes. Results: The majority of the breast cancer (85%) showed aberrant methylation in at least 1 of the loci tested with half of them displaying 3 or more methylated genes. The highest frequency of aberrant promoter methylation was found for HIC1 (48%) followed by ESR1 (46%), and CDH1 (39%). Similar methylation frequencies were detected for breast benign lesions with the exception of the CDH1 gene (P = 0.02). The analysis of methylation distribution indicates a statistically significant association between methylation of the ESR1 promoter, and methylation at CDH1, TRβ1, GSTP1, and CCND2 loci (P < 0.03). Methylated status of the BRCA1 promoter was inversely correlated with methylation at the RARβ2 locus (P < 0.03). Conclusions: Our results suggest a nonrandom distribution for promoter hypermethylation in sporadic breast cancer, with tumor subsets characterized by aberrant methylation of specific cancer-related genes. These breast cancer subgroups may represent separate biological entities with potential differences in sensitivity to therapy, occurrence of metastasis, and overall prognosis.

The Accuracy of Combined Cytopathologic and Flow Cytometric Analysis of Fine-Needle Aspirates of Lymph Nodes

We studied flow cytometry in 156 fine-needle aspirations (FNAs) of lymph nodes performed between June 1993 and September 1998. Information from flow cytometry was combined with cytomorphologic evaluation, and the diagnosis determined by using combined modalities was compared with tissue biopsy results or clinical follow-up. In 74 cases, a combined cytopathologic-flow cytometric diagnosis of lymphoma was made; histologic material was available for 52 patients; in no case was a benign process found. The lymphoma grade assigned agreed with histopathologic findings in 45 of 48 cases with a specific cytologic diagnosis. Treatment was initiated on the basis of the FNA alone for 17 of 52 patients with a history of lymphoma and in 22 additional patients with no follow-up biopsy. Among 71 cases in which the diagnosis using both modalities was benign, the only false-negative was 1 case of Hodgkin disease. Of the 156 cases, 11 were considered atypical or suggestive of lymphoma; biopsies from 8 of 10 patients revealed lymphoma. A combination of flow cytometry and cytomorphology of cells obtained by FNA of lymph nodes can distinguish between benign and malignant lymphoid infiltrates and support a diagnosis of lymphoma that permits definitive therapy in most cases.

Complete Hepatic Resection of Metastases from Leiomyosarcoma Prolongs Survival

Although liver resection has been shown to prolong survival in selected patients with metastases from colorectal cancer, the benefit for other metastatic tumors is unproved. To determine whether hepatic resection has a role in the management of metastatic leiomyosarcoma, medical records from 11 consecutive patients who underwent resection of isolated metastases from leiomyosarcoma between 1984 and 1995 were reviewed. All liver resections were for leiomyosarcomas originating in the viscera (n = 6) or retroperitoneum (n = 5). The average disease-free interval was 16 months. Five of 11 primary tumors were classified as low grade, whereas six were high grade. Hepatic resections included lobectomy or extended lobectomy (n = 4), segmentectomy and/or wedge resection (n = 5), and complex resection (n = 2). There were no operative deaths. Median survival of all patients after liver resection was 39 months. Patients who underwent complete resection of hepatic metastases (n = 6) had a significantly longer survival than those who had incomplete resections (n = 5) (P = 0.03, log-rank test). Furthermore, five of six patients who underwent complete resection are alive after hepatectomy with a median follow-up of 53 months. Therefore, in selected patients with isolated liver metastases from visceral and retroperitoneal leiomyosarcomas, complete resection of hepatic metastases results in prolonged survival.

Differences in Ablation Size in Porcine Kidney, Liver, and Lung After Cryoablation Using the Same Ablation Protocol

OBJECTIVE The purpose of our study was to assess the variation in size of acute necrosis and the variation in thermal map measured during cryoablation in multiple organs using the same ablation protocol for each organ. MATERIAL AND METHODS Eight female pigs underwent one cryoablation per organ of kidney, lung, and liver performed with open surgery with a 2.4-mm cryoprobe. A 12- and 8-minute double-freeze cycle was used. Intratissue temperatures were monitored using 16-gauge thermometers spaced at 5.0-mm increments from the cryoprobe. The comparison of results among tissues was performed using the multiple analysis of variance. The -20 degrees C thermal diameter was correlated with tissue damage. The kidneys, lungs, and liver were removed and examined histologically for a pathologic complete coagulative necrosis zone. RESULT A single 2.4-mm cryoprobe had a mean ice ball diameter in kidney, lung, and liver of 38.5 +/- 4.7, 35.5 +/- 3.6, and 32.5 +/- 2.7 mm, respectively. A mean -20 degrees C thermal diameter was achieved at 24.07 +/- 1.38 mm in kidney, 12.76 +/- 3.0 mm in lung, and 8.8 +/- 3.7 mm in liver by means of regression analysis. The acute pathologic complete coagulative necrosis zone size was 21.0 +/- 1.56 mm (kidney), 11.6 +/- 1.48 mm (lung), and 8.0 +/- 1.20 mm (liver). CONCLUSION The inherent characteristics of different organs manifest different ablation zone sizes during cryoablation despite the same ablation protocol being used. This information should be factored into planning for ablation procedures.

Positron emission tomography in the detection and management of sarcomatous transformation in neurofibromatosis.

Benign neurofibromas undergo sarcomatous transformation in approximately 5% of patients with neurofibromatosis type I. The clinical and radiologic diagnosis of sarcomatous change remains difficult. Positron emission tomography with F-18 fluorodeoxyglucose is a method to assess increased glucose metabolism in malignant tissue such as sarcomas. In this case report, positron emission tomography accurately distinguished malignant from benign neurofibromas. The technique may be useful as a noninvasive screening tool for malignant transformation of neurofibromas.

Granulocytic sarcoma (chloroma) of the sacrum: initial manifestation of leukemia

Abstract We present an unusual case of a granulocytic sarcoma (chloroma) of the sacrum which predated the initial clinical manifestation of acute myelogenous leukemia. Although granulocytic sarcomas occur in up to 9.1% of cases of acute myelogenous leukemia they usually present concurrently with the leukemic presentation. Although granulocytic sarcomas can involve several different organ systems, bone is the most common site.