Medullary Thyroid Carcinoma Associated with Germline RETK666N Mutation.

BACKGROUND: Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RETK666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown. METHODS: The clinical features, genetic data, and family information of eight index MTC patients with a germline RETK666N variant were assessed. RESULTS: Four probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma. CONCLUSIONS: From this case series, the largest such experience to date, it is concluded that the RETK666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, "at risk" individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

Bone Metastases and Skeletal-Related Events in Medullary Thyroid Carcinoma.

CONTEXT: Bone metastases (BM) can lead to devastating skeletal-related events (SREs) in cancer patients. Data regarding medullary thyroid carcinoma (MTC) with BM are lacking. OBJECTIVE: We evaluated the natural history of BM and SREs in MTC patients identified by a cancer center tumor registry. SETTING: The study was conducted at a tertiary cancer center. PATIENTS AND MAIN OUTCOME MEASURES: We retrospectively reviewed the charts of MTC patients with BM who received care from 1991 to 2014 to characterize BM and SREs. RESULTS: Of 1008 MTC patients treated, 188 were confirmed to have BM (19%), of whom 89% (168 of 188) had nonosseous distant metastases. Median time from MTC to BM diagnosis was 30.9 months (range 0-533 mo); 25% (45 of 180) had BM identified within 3 months of MTC diagnosis. Median follow-up after detecting BM was 1.6 years (range 0-23.2 y). Most patients (77%) had six or more BM lesions, most often affecting the spine (92%) and pelvis (69%). Many patients (90 of 188, 48%) experienced one or more SREs, most commonly radiotherapy (67 of 90, 74%) followed by pathological fracture (21 of 90, 23%). Only three patients had spinal cord compression. Patients with more than 10 BM lesions were more likely to experience SREs (odds ratio 2.4; P = .007), with no difference in 5-year mortality after MTC diagnosis between patients with (31%) and without SREs (23%) (P = .11). CONCLUSIONS: In this large retrospective series, BM in MTC was multifocal, primarily involving the spine and pelvis, supporting screening these regions for metastases in at-risk patients. SREs were common but spinal cord compression was rare. Antiresorptive therapies in this population should be investigated further with prospective trials.

Role of salvage targeted therapy in differentiated thyroid cancer patients who failed first-line sorafenib.

CONTEXT: Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. OBJECTIVE: The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. DESIGN: This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. PATIENTS: The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). PATIENTS who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). OUTCOME MEASURES: Progression-free survival, best response, and median OS were measured. RESULTS: Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3). CONCLUSIONS: Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.

Approach and safety of comprehensive central compartment dissection in patients with recurrent papillary thyroid carcinoma.

BACKGROUND: Despite the generally favorable prognosis of patients with papillary thyroid cancers, 10-year recurrence rates for patients with stage I to III disease is greater than 20%, with central compartment recurrences common among these recurrent sites. METHODS: This study is a retrospective analysis of consecutive patients treated by a single surgeon over an 18-month period of time terminating in 2003. RESULTS: Sixty-three patients underwent a comprehensive dissection of levels VI and VII for papillary thyroid carcinoma during this period. There was a female predominance of 2:1, with 48% of patients being greater than 45 years of age. The median number of lymph nodes identified was 16 (range, 3-52), with 7 (1-20) lymph nodes pathologically involved. Permanent hypoparathyroidism was present on presentation in 13% of patients and developed in an additional 5% following surgery. Although recurrent laryngeal paralysis was present on presentation among 8 (13%) of patients, no patients experienced paralysis of documented functioning recurrent laryngeal nerves or necessitated tracheotomy. Postoperative thyroglobulin levels were reduced to nondetectable in 71% of the informative cases. Over 60% of patients were discharged on their first postoperative day. CONCLUSION: Bilateral paratracheal and superior mediastinal dissection is an oncologically safe procedure exhibiting minimal morbidity when performed among experienced individuals despite multiple prior surgical procedures or existing vocal cord paralysis.

Breast cancer: relationship between menopausal symptoms, physiologic health effects of cancer treatment and physical constraints on quality of life in long-term survivors.

AIMS AND OBJECTIVES: The purpose of this study is to describe the relationship between menopausal symptoms, physiologic health effects of cancer treatment and the physical contributors to quality of life in long-term survivors of breast cancer. BACKGROUND: The treatment of menopausal symptoms is hotly debated, especially for women with breast cancer. Common treatments for menopausal symptoms are considered to be contraindicated in women with breast cancer. DESIGN: This is a descriptive, cross-sectional study of long-term breast cancer survivors; a subset of a study that responded to a mailed survey targeting long-term cancer survivors treated at The University of Texas M.D. Anderson Cancer Center. METHODS: In 291 breast cancer patients information was available that included items that commonly relate to menopausal symptoms including hot flushes, painful sexual intercourse, inability to concentrate, fatigue and sleep disturbances. RESULTS: Ninety per cent were Caucasian American and the mean time since diagnosis was 16 +/- 8 years. All patients had been treated with surgery, (60%) with radiotherapy, (68%) with chemotherapy and (37%) with hormonal therapy. Forty-six per cent of the breast cancer survivors indicated that having breast cancer affected their overall health. Self-reported health effects were more common in those survivors who had received a combination of chemotherapy and radiotherapy. A menopausal quality of life score was determined using the items about hot flushes, ability to concentrate, painful sexual intercourse, fatigue, unhappiness and sleep disturbances. CONCLUSIONS: This study reminds us that breast cancer and menopause are independent issues. Quality of life parameters need to be rigidly defined and time sensitive. There are complex interactions between quality of life indicators and specific physiologic consequences of treatment. However, menopausal signs and symptoms may not be different for the breast cancer survivor and they should not be confused with the quality of life/psychosocial issues of the cancer survivor. RELEVANCE TO CLINICAL PRACTICE: Menopause is not a disease process but a normal developmental stage for women. It is important for nurses not only to understand the client needs of the menopausal woman, but also to be able to differentiate between quality of life issues related to menopause and to cancer treatment in order to provide holistic nursing care.

Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship.

HYPOTHESIS: Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC. DESIGN: Review of endocrine surgery database from 1951 through 2002. SETTING: Tertiary referral center. PATIENTS: Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918). MAIN OUTCOME MEASURES: Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism. RESULTS: RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations. CONCLUSION: Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.

Genotype-phenotype analysis in multiple endocrine neoplasia type 1.

HYPOTHESIS: Multiple endocrine neoplasia type 1 (MEN 1) syndrome is an autosomal dominant disorder caused by germline mutations in the MEN1 gene and characterized by multiple endocrine tumors, most notably in the parathyroid glands, pituitary, and pancreas. The syndrome demonstrates variable expressivity and considerable genetic heterogeneity. Patient data were examined for possible associations between genotype and phenotype. DESIGN: We reviewed recorded medical data from 1975 to 2001 on patients with MEN 1 and compared specific types and locations of MEN1 gene mutations with manifestations of the syndrome. PATIENTS AND RESULTS: We identified 109 affected patients from 24 MEN 1 kindreds. The phenotypic expression of MEN 1 in affected individuals included hyperparathyroidism in 74%, pancreatic endocrine tumors in 51%, and pituitary tumors in 35%. Twelve of 14 insulinomas occurred in patients with pituitary tumors. Mutation analysis was completed in 14 of 24 kindreds (80 of the 109 patients). Mutations were most common in exons 2 (31%), 9 (15%), and 10 (23%). All 21 patients with frameshift mutations (and known pancreatic endocrine tumor status) had such tumors. Pituitary tumors were associated with frameshift mutations in exon 2. CONCLUSIONS: The type and location of MEN1 mutations may be associated with the phenotypic expression of specific tumors. Such information may assist in the genetic counseling and surveillance of at-risk patients. A specific genotype-phenotype correlation is unlikely because of the heterogeneity of the mutations in the MEN1 gene.

Cancer survivors. Work related issues.

New and more effective treatments for cancer have resulted in individuals living longer with a better quality of life. Many more survivors are employed in the workplace. Cancer is no longer only an issue for survivors and their families; it has become an issue for the employer and the workplace. This article describes survey results of 4,364 long term cancer survivors in which they were asked to respond to items describing their ability to work, job discrimination, and quality of life. Thirty-five percent of survivors were working at the time they completed the survey, and 8.5% considered themselves unable to work. This research has shown that age, gender, ethnic group, and cancer type affected the working status of the survivors. Of survivors continuing to work, 7.3% indicated they had experienced job discrimination. The results indicate most cancer survivors do not perceive employment related problems, and are readily assimilated into the work force. Job discrimination and the ability to work is a quality of life issue.