Jeffrey F. Moley

Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer.

BACKGROUNDnAfter initial operations for medullary thyroid cancer (MTC), reoperation with removal of metastatic disease confined to the neck may benefit some patients. The identification of distant metastases precludes the possibility of curative reoperation.nnnMETHODSnForty-one patients with hypercalcitoninemia after initial surgical treatment for MTC underwent laparoscopic (n = 36) or open (n = 5) examination and biopsy of the liver. Thirty-seven of these patients underwent imaging by computed tomography (CT), magnetic resonance imaging (MRI) of the liver, or both, and 17 underwent selective venous catheterization (SVC) with measurement of hepatic and peripheral vein stimulated calcitonin levels.nnnRESULTSnLiver metastases were found in eight patients, seven by laparoscopy and one by open examination. Seven of these patients had normal CT or MRI scans of the liver. Laparoscopy or open liver examination revealed metastases in 2 of 11 patients with elevated hepatic vein-peripheral vein stimulated calcitonin ratios (greater than 1.3). Metastases appeared as small (less than 5 mm), bright white nodules on the surface of the liver.nnnCONCLUSIONSnDirect examination and biopsy of the liver by laparoscopy may show small deposits of metastatic MTC in patients with normal CT and MRI scanning.

Evaluation of fluorodeoxyglucose-positron emission tomographic scanning and its association with glucose transporter expression in medullary thyroid carcinoma and pheochromocytoma: A clinical and molecular study

BACKGROUNDnImaging of metastatic sites of medullary thyroid carcinoma (MTC) is successful in less than 60% of cases of residual or recurrent disease. Positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (FDG) takes advantage of the fact that malignant tumors are capable of increased uptake and use of glucose, which is mediated by the members of the glucose transporter family of proteins (GLUT 1 through GLUT 5).nnnMETHODSnFDG-PET images of 10 patients with recurrent or persistent MTC after primary operation were compared with images by computed tomography or magnetic resonance imaging. Identified metastatic lesions were assessed by intraoperative findings and pathology reports. Expression of GLUT 1 through GLUT 5 was examined by Western blot analysis of tumor tissue from eight of the patients evaluated and an additional panel of 10 MTCs and seven pheochromocytomas.nnnRESULTSnFDG-PET identified 31 foci of FDG accumulation in 10 patients, and 16 of these metastatic sites were resected and confirmed by histologic analysis. Only 11 foci were demonstrated by computed tomographic or magnetic resonance imaging. None of the glucose transporters examined displayed significant expression. Two pheochromocytomas were successfully imaged by FDG-PET.nnnCONCLUSIONSnFDG-PET imaging can be useful in the localization of cervicomediastinal MTC metastases and pheochromocytoma. The increased glucose uptake in these tumors, as evidenced by FDG-PET, does not appear to be attributable to the expression of the glucose transporter proteins GLUT 1 through GLUT 5.

Absence of TP53 alterations in pheochromocytomas and medullary thyroid carcinomas

The role of the TP53 gene in the development of inherited and sporadic pheochromocytomas and medullary thyroid carcinomas (MTC) has not been clarified because of conflicting reports and limitations in the assays used to detect mutations. To determine the frequency of TP53 alterations in these tumors, 22 pheochromocytomas and 29 MTCs were screened for loss of heterozygosity (LOH) on 17p with four markers. Single‐strand‐conformation‐variant (SSCV) analysis of exons 4–9 of the TP53 gene was performed in 20 of the pheochromocytomas and in 22 of the MTCs. The expression of p53 was determined by immunohistochemistry in 19 pheochromocytomas and in 17 MTCs using two antibodies (D01 and D07) on frozen and paraffin‐embedded tissues. Four of the 22 pheochromocytomas and none of the MTCs showed LOH on 17p. No mutations were detected in any of the tumors screened by SSCV analysis. Immunohistochemical staining of frozen and paraffin‐embedded tumor sections did not show p53 overexpression in any of the tumors examined. Our findings indicate that mutations in the TP53 gene are an uncommon event in the tumorigenesis of pheochromocytomas and medullary thyroid carcinomas. Genes Chromosom. Cancer 20:24–29, 1997.

Sporadic and familial medullary thyroid carcinoma: state of the art.

Medullary thyroid cancer (MTC) accounts for 5% to 10% of all thyroid cancers. The high frequency of familial cases mandates screening and genetic testing. The aggressiveness and age of onset of familial MTC differs depending on the specific genetic mutation, and this should determine the timing and extent of surgery. Sporadic MTC can present at any age, and it is usually associated with a palpable mass and the presence of nodal metastases. Surgery is standard treatment for any patient presenting with resectable MTC. Further studies are needed to investigate the role of radiation therapy in the palliation and local control of postresection and advanced-stage MTC. New systemic therapies for metastatic disease are being investigated. Targeted molecular therapies, based on knowledge of the pathways affected by RET mutations, are being tested in multiple clinical trials.

SOFT-TISSUE SARCOMAS

Sarcomas of the soft tissues are challenging lesions for the surgical oncologist. Careful planning must be done at all stages of diagnosis and treatment, because every sarcoma is unique with respect to histologic type, size, and location. Pretreatment discussions in a multidisciplinary format are useful to ensure appropriate and effective management of these tumors.

“Cold” single-strand conformational variants for mutation analysis of the RET protooncogene

BACKGROUNDnRET protooncogene mutation analysis is a routinely performed predictive DNA test in kindreds affected by multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma (FMTC), and is a valuable diagnostic tool in newly diagnosed cases of medullary thyroid carcinoma (MTC).nnnMETHODSnWe tested the suitability of the recently introduced cold single-strand conformational variant (SSCV) technique, which promises rapid, simple, nonradioactive detection of sequence variants in the identification of germline and somatic RET mutations. A total of 11 different mutations in exon 10 (codons 609, 611, 618, and 620) and 6 mutations in exon 11 (codon 634) were studied.nnnRESULTSnConditions were optimized so that conformational variants were demonstrated for all mutations examined in a single setting for exons 10 and 11. A novel six base pair (bp) inframe deletion between cysteines 630 and 634 was detected in a sporadic MTC. This adds to the evidence that not only cysteine deletions and substitutions but also changes in the spacing between cysteine residues have a pathogenic effect.nnnCONCLUSIONSnOur results indicate that the cold SSCV method offers the advantages of simplicity, time savings, and nonradioactive detection for screening for RET sequence variants in hereditary and sporadic MTCs.

RET Proto-Oncogene and Its Role in Multiple Endocrine Neoplasia and Medullary Thyroid Cancer

The RET proto-oncogene encodes a transmembrane protein receptor tyrosine kinase, the function of which is unknown at present. The inclusion of a discussion of this gene in a book on hormones and cancer is appropriate because of the recently described association of mutations in RET and the hereditary cancer syndromes multiple endocrine neoplasia (MEN) type 2A, MEN 2B, and familial non-MEN medullary thyroid cancer (FMTC). In these disorders, which are inherited in an autosomal dominant fashion, individuals inherit a predisposition to medullary thyroid cancer (MTC), a malignancy of neuroendocrine cells (C-cells) that reside in the para-follicular areas of the thyroid gland. This trait is expressed with virtually 100% penetrance. MEN 2A, MEN 2B, and FMTC are clinically distinct diseases. (Schimke, 1984, Farndon et al., 1986). MEN 2A and MEN 2B are syndromes characterized by neoplasms involving more than one endocrine tissue or cell type. FMTC, on the other hand, is a nonsyndromic Mendelian trait characterized by the development of MTC in the absence of any other recognizable abnormalities (Table 1). Through DNA marker linkage studies, the gene(s) responsible for MEN 2A, MEN 2B, and FMTC were mapped to the same region of chromosome 10 (Mathew et al., 1987a; Simpson et al., 1987; Norum et al., 1990a; Lairmore et al., 1992).