Two synchronous paraneoplastic endocrine syndromes in a 53-year-old male with broadly metastatic widely invasive Hürthle cell carcinoma.

Summary: Unlike medullary thyroid carcinomas, follicular cell-derived thyroid malignancies have rarely been associated with paraneoplastic endocrine syndromes. An ultrarare case of a middle-aged man with heavily treated broadly metastatic radioactive iodine-refractory widely invasive Hürthle cell carcinoma (HCC) of the thyroid with two synchronous paraneoplastic endocrine syndromes, T3 thyrotoxicosis and hypercalcemia of malignancy, is discussed here. The levothyroxine-induced T3 thyrotoxicosis was a gradual process that became more noticeable as the tumor burden, refractory to different modalities of therapy, expanded. The 1,25-dihydroxyvitamin-D-mediated hypercalcemia, on the other hand, developed in a manner of weeks, as it usually happens. It is important to emphasize that in patients with metastatic Hürthle cell and follicular carcinomas of the thyroid, on TSH suppressive therapy, the unexplained and progressive decline in FT4 and rise in FT3 levels, resulting in an elevated FT4/FT3 ratio, could be an indication of augmented type 1 (D1) and/or type 2 (D2) deiodinase expression in tumoral tissue, causing an increased conversion from the prohormone T4 into the active metabolite T3 via outer ring deiodination. Learning points: Albeit extremely rare, some patients with thyroid cancer can present with more than one concomitant paraneoplastic syndrome. Although medullary thyroid carcinoma is the thyroid malignancy that is usually associated with paraneoplastic endocrine syndromes, follicular cell-derived thyroid cancers have been rarely described as being the culprit. In patients with metastatic Hürthle cell and follicular thyroid carcinomas, the unexplained and progressive decline in FT4 and rise in FT3 levels could be an indication of augmented type 1 (D1) and/or type 2 (D2) deiodinase expression in tumoral tissue, causing an increased conversion from T4 into T3 leading to T3 thyrotoxicosis.

Hypoglycemia From Metastatic Meningeal Solitary Fibrous Tumor Occurring Over Two Decades After Initial Diagnosis.

Despite multiple intracranial and extracranial relapses associated with a widely metastatic meningeal solitary fibrous tumor (formerly classified as hemangiopericytoma), a 66-year-old type 2 diabetic man was first diagnosed with paraneoplastic hypoglycemia 23 years after the original diagnosis and 12 years after the onset of extracranial metastatic disease. An enlarging mass entirely replacing the left kidney measuring 11.6 × 10 × 28 cm, which had not been locally treated before, was considered to be the putative source of IGF-2 excess. The insulin-like effects of IGF-2 not only ameliorated his long-standing type 2 diabetes mellitus, but also caused spontaneous fasting hypoglycemia. The physiopathology, clinical manifestations, diagnostic approach, and treatment of non-islet cell tumor hypoglycemia are briefly discussed here. Palliative tumor debulking improved the hypoglycemia by day 11 after radiation therapy and glucose monitoring with continuous glucose monitoring system (Dexcom G6) facilitated the patient's management and gave him peace of mind.

Aldosterone- and cortisol-cosecreting adrenal adenoma, ovarian hyperthecosis and breast cancer.

SUMMARY: We describe a 56-year-old postmenopausal woman with hypertension, hypokalemia and severe alopecia who was found to have a 4.5-cm lipid-poor left adrenal mass on CT scan performed to evaluate her chronic right-sided abdominal pain. Hormonal studies revealed unequivocal evidence of primary aldosteronism and subclinical hypercortisolemia of adrenal origin. Although a laparoscopic left adrenalectomy rendered her normotensive, normokalemic and adrenal insufficient for 2.5 years, her alopecia did not improve and she later presented with facial hyperpigmentation acne, worsening hirsutism, clitoromegaly, and an estrogen receptor-positive breast cancer. Further testing demonstrated markedly elevated serum androstenedione and total and free testosterone and persistently undetectable DHEAS levels. As biochemical and radiologic studies ruled out primary adrenal malignancy and obvious ovarian neoplasms, a bilateral salpingo-oophorectomy was undertaken, which revealed bilateral ovarian hyperthecosis. This case highlights how the clinical manifestations associated with hyperaldosteronism and hypercortisolemia masqueraded the hyperandrogenic findings. It was only when her severe alopecia failed to improve after the resolution of hypercortisolism, hyperandrogenic manifestations worsened despite adrenal insufficiency and an estrogen receptor-positive breast cancer was found, did it becomes apparent that her symptoms were due to ovarian hyperthecosis. LEARNING POINTS: As cortisol cosecretion appears to be highly prevalent in patients with primary aldosteronism, the term 'Connshing' syndrome has been suggested. The associated subclinical hypercortisolemia could be the driver for the increased metabolic alterations seen in patients with Conn syndrome. The identification of these dual secretors before adrenal venous sampling could alert the clinician about possible equivocal test results. The identification of these dual secretors before unilateral adrenalectomy could avoid unexpected postoperative adrenal crises. Hyperfunctioning adrenal and ovarian lesions can coexist, and the clinical manifestations associated with hypercortisolemia can masquerade the hyperandrogenic findings.

Technology-Enabled Outreach to Patients Taking High-Risk Medications Reduces a Quality Gap in Completion of Clinical Laboratory Testing.

Clinical laboratory quality improvement (QI) efforts can include population test utilization. The authors used a health care organization's Medical Data Warehouse (MDW) to characterize a gap in guideline-concordant laboratory testing recommended for safe use of antirheumatic agents, then tested the effectiveness of laboratory-led, technology-enabled outreach to patients at reducing this gap. Data linkages available through the Kaiser Permanente Colorado MDW and electronic health record were used to identify ambulatory adults taking antirheumatic agents who were due/overdue for alanine aminotransferase (ALT), aspartate aminotransferase (AST), complete blood count (CBC), or serum creatinine (SCr) testing. Outreach was implemented using an interactive voice response system to send patients text or phone call reminders. Interrupted time series analysis was used to estimate reminder effectiveness. Rates of guideline-concordant testing and testing timeliness in baseline vs. intervention periods were determined using generalized linear models for repeated measures. Results revealed a decrease in percentage of 3763 patients taking antirheumatic agents due/overdue for testing at any given time: baseline 24.3% vs. intervention 17.5% (P < 0.001). Among 3205 patients taking conventional antirheumatic agents, concordance for all ALT testing was baseline 52.8% vs. intervention 65.4% (P < 0.001) among patients chronically using these agents and baseline 20.6% vs. intervention 26.1% (P < 0.001) among patients newly starting these agents. The 95th percentiles for days to ALT testing were baseline 149 vs. intervention 117 among chronic users and baseline 134 vs. intervention 92 among new starts. AST, CBC, and SCr findings were similar. Technology-enabled outreach reminding patients to obtain laboratory testing improves health care system outcomes.

AMYLOID GOITER AS THE FIRST RECOGNIZABLE MANIFESTATION OF IMMUNOGLOBULIN LIGHT CHAIN AMYLOIDOSIS.

OBJECTIVE: Clinically apparent thyroid enlargement due to massive amounts of amyloid deposition, known as amyloid goiter, is rare. Endocrinologists should become familiar with this manifestation of systemic amyloidosis, which may be diagnosed by Congo red staining of the specimen obtained by fine-needle aspiration. METHODS: We describe a 70-year-old man who presented with a slowly enlarging goiter. It was asymptomatic, predominantly left-sided, nontoxic, and multinodular with atypia of undetermined significance (Bethesda System category III) by cytology. The goiter tested negative using the ThyraMIR miRNA Gene Expression Classifier kit (eviCore Healthcare, Bluffton, SC). RESULTS: Left thyroid lobectomy produced a 220-g specimen with nodular hyperplasia and prominent amyloid deposition confirmed by Congo red staining. Liquid chromatography tandem mass spectrometry detected a peptide profile consistent with light chain amyloid deposition of the lambda type, formerly called primary amyloidosis. In retrospect, he had been diagnosed with restrictive cardiomyopathy, cardiac conduction system disease, coronary artery disease, non-nephrotic range proteinuria, and chronic kidney disease, which had been attributed to his longstanding type 2 diabetes mellitus. Extensive workup subsequently demonstrated cardiac amyloidosis and monoclonal gammopathy of unknown significance, consistent with light chain amyloidosis. CONCLUSION: Amyloid goiter should be included in the differential diagnosis of enlarging goiters with Bethesda System category III cytology in patients with monoclonal gammopathy of uncertain significance, clinical manifestations of systemic amyloidosis, or known diagnosis of monoclonal cell dyscrasia.

Identifying Preanalytic and Postanalytic Laboratory Quality Gaps Using a Data Warehouse and Structured Multidisciplinary Process.

CONTEXT.­: The laboratory total testing process includes preanalytic, analytic, and postanalytic phases, but most laboratory quality improvement efforts address the analytic phase. Expanding quality improvement to preanalytic and postanalytic phases via use of medical data warehouses, repositories that include clinical, utilization, and administrative data, can improve patient care by ensuring appropriate test utilization. Cross-department, multidisciplinary collaboration to address gaps and improve patient and system outcomes is beneficial. OBJECTIVE.­: To demonstrate medical data warehouse utility for characterizing laboratory-associated quality gaps amenable to preanalytic or postanalytic interventions. DESIGN.­: A multidisciplinary team identified quality gaps. Medical data warehouse data were queried to characterize gaps. Organizational leaders were interviewed about quality improvement priorities. A decision aid with elements including national guidelines, local and national importance, and measurable outcomes was completed for each gap. RESULTS.­: Gaps identified included (1) test ordering; (2) diagnosis, detection, and documentation, and (3) high-risk medication monitoring. After examination of medical data warehouse data including enrollment, diagnoses, laboratory, pharmacy, and procedures for baseline performance, high-risk medication monitoring was selected, specifically alanine aminotransferase, aspartate aminotransferase, complete blood count, and creatinine testing among patients receiving disease-modifying antirheumatic drugs. The test utilization gap was in monitoring timeliness (eg, >60% of patients had a monitoring gap exceeding the guideline recommended frequency). Other contributors to selecting this gap were organizational enthusiasm, regulatory labeling, and feasibility of a significant laboratory role in addressing the gap. CONCLUSIONS.­: A multidisciplinary process facilitated identification and selection of a laboratory medicine quality gap. Medical data warehouse data were instrumental in characterizing gaps.

Primary high-grade calcitonin-negative neuroendocrine carcinoma of the thyroid: a very rare cancer.

Most medullary thyroid carcinomas (MTCs) are low grade and produce calcitonin. There are some calcitonin-negative MTCs that produce only calcitonin gene-related peptide (CGRP). Rarely, MTCs are negative for calcitonin and CGRP peptides, but contain their corresponding mRNAs. Primary thyroid neuroendocrine neoplasms other than MTCs are extremely rare. We describe a primary high-grade neuroendocrine carcinoma that was negative for CGRP and calcitonin at both the protein and mRNA levels. A 42-year-old woman presented with a rapidly enlarging thyroid mass replacing most of the left lobe and isthmus. A computed tomography-guided core-needle biopsy was performed. The tumor was composed of sheets of small-to-medium sized epithelial cells. The cells were immunoreactive for pancytokeratin, synaptophysin, CD56 and thyroid transcription factor-1, but negative for CK7, CK20, CD45, CD99, ERG, chromogranin A, thyroglobulin, calcitonin, CGRP and carcinoembryonic antigen. The Ki-67 proliferation index was ~90%. In situ hybridization was negative for calcitonin mRNA. The patient was initially diagnosed as having a small cell carcinoma. She was treated with cisplatin and etoposide (VP16), followed by radiation therapy. Given the excellent clinical course, the tumor was reviewed and reclassified as a high-grade neuroendocrine carcinoma (non-small-cell type). Heretofore, only a few other similar high-grade neuroendocrine tumors with negative markers of C-cell derivation have been reported. In our case, the patient is cancer free five years after diagnosis, but in the other cases, the outcome was poor. LEARNING POINTS: There are neuroendocrine carcinomas of the thyroid that do not produce calcitonin or calcitonin gene-related peptide.This category of calcitonin-negative neuroendocrine carcinomas is heterogeneous, consisting of low- and high-grade tumors.The high-grade neuroendocrine carcinomas of the thyroid are rare and generally have a poor prognosis. They are divided into small cell and non-small cell or large cell types.

Human papillomavirus detection with genotyping by the cobas and Aptima assays: Significant differences in HPV 16 detection?

BACKGROUND: The primary high-risk human papillomavirus (hrHPV) assays in the United States are the cobas (Roche) and the Aptima (Hologic). The cobas assay detects hrHPV by DNA analysis while the Aptima detects messenger RNA (mRNA) oncogenic transcripts. As the Aptima assay identifies oncogenic expression, it should have a lower rate of hrHPV and genotype detection. METHODS: The Kaiser Permanente Regional Reference Laboratory in Denver, Colorado changed its hrHPV assay from the cobas to the Aptima assay. The rates of hrHPV detection and genotyping were compared over successive six-month periods. RESULTS: The overall hrHPV detection rates by the two platforms were similar (9.5% versus 9.1%) and not statistically different. For genotyping, the HPV 16 rate by the cobas was 1.6% and by the Aptima it was 1.1%. These differences were statistically different with the Aptima detecting nearly one-third less HPV 16 infections. With the HPV 18 and HPV 18/45, there was a slightly higher detection rate of HPV 18/45 by the Aptima platform (0.5% versus 0.9%) and this was statistically significant. CONCLUSION: While HPV 16 represents a low percentage of hrHPV infections, it was detected significantly less by the Aptima assay compared to the cobas assay. This has been previously reported, although not highlighted. Given the test methodologies, one would expect the Aptima to detect less HPV 16. This difference appears to be mainly due to a significantly increased number of non-oncogenic HPV 16 infections detected by the cobas test as there were no differences in HPV 16 detection rates in the high-grade squamous intraepithelial lesions indicating that the two tests have similar sensitivities for oncogenic HPV 16.