Oregon Index of Endocrine Neoplasias (ORION)

Principal Investigator

Kresimira Milas

Study Purpose

There are two major components of this study. The first one is the clinical and outcome-based characterization of endocrine neoplasias retrospectively via chart reviews and the second one is the molecular characterization of endocrine neoplasias.


The ORegon Index of Endocrine Neoplasias (ORION) will help to establish a centralized resource that will aid in the identification, care, and study of individuals who develop benign and malignant endocrine tumors of the thyroid, parathyroid and adrenal glands, as well as of the neuroendocrine system. The spectrum of disorders includes, as an illustration, thyroid cancers, abnormally functioning thyroid glands, hyperparathyroidism and parathyroid tumors, adrenal gland tumors, neuroendocrine tumors of the pancreas and liver, and carcinoid tumors. The patients who would be indexed in ORION are all who have received or are currently receiving care at OHSU for these endocrine tumors and have been evaluated by multidisciplinary specialists who routinely collaborate in clinical practice – endocrine surgeons and otolaryngologists, endocrinologists, pathologists, oncologists, genetics specialists and scientists involved with neuroendocrine diseases. Included in the registry would be patients whose endocrine disorder is part of a hereditary syndrome. For example, thyroid cancer is a known component of the multiple endocrine neoplasia syndromes, Cowden syndrome, and familial adenomatous polyposis and other hereditary gastrointestinal polyposis conditions.

The unique significance of ORION is that it would represent the first such registry for the Northwestern region of the United States, including academic medical centers. The unique ability of OHSU to serve as the center of such a registry comes from OHSU’s role as a major tertiary referral center for endocrine tumors and from a critical mass of experts assembled at OHSU with national and international reputation for patient care and research in these areas.

The specific aims and benefits of ORION include, but are not limited, to the following:
• To provide a clinically relevant registry of patients with thyroid cancer, the #1 malignancy in the United States in terms of highest rates of increasing incidence
• To track endocrine cancer diagnosis and treatment outcomes
• To provide an organized way to follow patients with rare endocrine conditions and the need for complex operations
• To be a vehicle for translational clinical research, related to pathophysiology of endocrine disorders
• To be a vehicle for clinical research that may lead to improved patient care
• To be a source of information related to specialty-specific outcomes measures, standards of care, and innovative clinical practices
• To develop into the major index of information about endocrine tumors in Oregon

A secondary objective of this study is to examine specific clinical questions of significance as they arise in the care of patients with thyroid and parathyroid disease, leading to peer-reviewed publication of new knowledge.

At the present time, with the collaborators listed, the following studies are planned.

• Screening for Cowden Syndrome/ PTEN Mutation Hamartoma Tumor Syndrome (OHSU IRB #9686). This study was submitted separately and has received OHSU IRB approval. Please refer to the extensive protocol there for details. It is mentioned as part of ORION because it meets the criteria for inclusion, but was chronologically the first study we hoped to do at OHSU and thus submitted an early and separate IRB study number.

• Descriptive characterization of endocrine gland anatomy (evident during ultrasound exam and surgery of patients) and histology findings in patients with thyroid cancer and benign thyroid and parathyroid diseases. These are short, focused case presentations whose purpose is to communicate a practical clinical management pearls.
-Sonography of the Tubercle of Zuckerkandl
-Unusual Thyroid Anatomy and Lesions
-Review of Rare and Unusual Thyroid Cancer Histologies (Primary Thyroid Epithelial Tumors: Mucoepidermoid carcinoma,
Sclerosing mucoepidermoid carcinoma with eosinophilia, Squamous cell carcinoma, Mucinous carcinoma, Spindle cell tumor with thymus-like differentiation, Carcinoma with thymus-like differentiation, Ectopic
thymoma. Primary Thyroid Nonepithelial Tumors: Angiosarcoma, Teratoma, Malignant Smooth muscle tumors (leimyosarcoma), Malignant Peripheral Nerve Sheath tumors, Paraganglioma, Solitary fibrous tumor). Literature review and review of cases with such diagnosis at OHSU.
-Parathyroid gland sizes in patients with multiple endocrine neoplasia and double adenomas

• Thyroid cytopathology specimens initially classified as follicular neoplasm or suspicious for malignancy (Bethesda 3,4,5): Does pathology re-review at a tertiary center alter surgical management?
Despite the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) providing standardized diagnostic terminology for thyroid fine-needle aspiration (FNA), subjective interpretation and inter-observer discrepancies remain a challenge among pathologists. Other institutions have reported that management can change in up to 30% of patients (Olson, Zeiger et al J Clin Endocrinol Metab. 2013 Apr;98(4):1450-7). This study would quantify the frequency and magnitude of these discrepancies at OHSU, identify whether they lead to changes in surgical care, and determine features that predict discordant cytopathology reporting. Our methods would involve a review of thyroid cytopathology cases sent to OHSU for institutional consultation. The BSRTC classification made by the sending institution would be compared with that of our institution. We would perform ANOVA analysis to determine factors that may be associated with inter-institutional diagnostic differences. We would also calculate the thyroid malignancy rate when available from surgical histology of those patients who proceeded to have thyroidectomy.

• Endocrine Surgery in The Pacific Northwest. Physician shortage, increasing surgical sub-specialization, and rural access-to-care barriers are national trends with significant implications for future healthcare delivery. Limited information exists regarding these trends for endocrine surgery, particularly in geographic areas of low population density as exist in some regions of Oregon and surrounding states that refer patients to OHSU. We would query the city/zip code/county of origin for patients undergoing thyroid and parathyroid surgery at OHSU and determine the source of referral (specialists vs. primary care physicians) and the local availability of endocrine surgeons and endocrinologists. We would analyze how those trends correlate with the complexity of disease in the referred patient, including the cancer stage and history of prior neck operations.

• Calculating an individual maxPTH to aid diagnosis of normocalemic primary hyperparathyroidism. Two recent studies have proposed that a nomogram to calculate maxPTH uniquely defines a patient-specific upper limit of normal for parathyroid hormone (PTH) based on the readily available variables of serum calcium, 25(OH) vitamin D, and patient age (Harvey et al Endocr Pract. 2012 Mar-Apr;18(2):124-31; Jin et al, Surgery. 2012 Dec;152(6):1184-92). This helps refine the diagnostic criteria for primary hyperparathyroidism (1°HPT) to identify atypical patients, in whom serum calcium, parathyroid hormone (PTH), or both are within the "normal" range. It proposes to distinguish patients with secondary hyperparathyroidism (2°HPT) from those with atypical 1°HPT, which affects up to 10% of patients making management challenging. We would review patients with the diagnosis of 1°HPT and 2°HPT and those who underwent parathyroid surgery to calculate maxPTH. We would determine whether the results of the reported nomogram are reproducible in another hospital system (OHSU) that uses different lab values for these tests. We would also calculate whether the nomogram correctly classified patients into each diagnosis.

• Correlation of molecular marker status in primary thyroid cancers to recurrence and survival rates during intermediate-term follow-up. Under OHSU-approved IRB # 4919 and 2844, thyroid cancer patients were studied with respect to the presence of genetic mutations in the primary tumor and their clinical presentation. We propose to perform chart review to determine thyroid cancer recurrence rates, disease-free and overall survival at the 5 –year follow-up mark. This would be done following permission of the PI of those IRB studies.

• Determining the Success of Parathyroid CT to Localize Abnormal Glands for Initial and Reoperative Parathyroidectomy. The prevalence of hyperparathyroidism, especially 1°HPT, has increased in recent decades due to improvements in diagnostic techniques and has led to higher frequency of parathyroidectomy. Consequently, there has been a proliferation of parathyroid imaging modalities and protocols, resulting in confusion about their indications and applications (Kuntsman, Udelsman et al J Clin Endocrinol Metab. 2013 Mar;98(3):902-12). OHSU has an extensive experience in parathyroid computed tomography (CT), as well as parathyroid ultrasound (US) and sestamibi (Mibi) imaging. We would calculate the sensitivity and specificity of parathyroid CT to correctly localize abnormal parathyroid glands, compare these rates to those of US and Mibi which all patients also undergo,, and determine whether parathyroid CT scan helps avoid the need for more invasive imaging procedures such as selective venous sampling.


There is increasing recognition that the responses of individual patients to specific cancer therapies vary by specific gene mutations. This has led to a need to genotype tumors for potential selection of therapeutic regimens and for prognostic purposes. For clinical trials, identifying subjects whose tumors have specific molecular characteristics prior to enrollment is challenging, as tumor genotyping requires a coordinated effort between clinicians, pathologists, and a centralized testing laboratory. The logistical and technical hurdles are considerable and may lead to enrollment delays of weeks to months – unacceptable to all parties concerned, especially the patients. For this reason, tumor genotyping is rarely used as an eligibility requirement and correlation of tumor genotype and treatment response is usually performed retrospectively. ORION will prospectively genotype tumors and create a registry of consented patients who may be potential candidates for future clinical trials. This registry will include molecular, clinicopathologic, staging and demographic information that can used to rapidly identify and recruit subjects for enrollment in future clinical trials and be available for future research studies.

The objective of ORION is to establish a registry of endocrine tumors which have been profiled for selected alternations in molecular constituents with a primary focus on detection of nucleotide and structural alterations in tumor DNA from existing clinical specimens. Patients will also be prospectively consented (or as a pilot, enrolled under waiver of consent but with notification and opt out opportunity) to profiling of their tumor and being listed in a registry for potential future clinical trials. In addition, tumors and mutation data may be associated with stored normal tissue, germline DNA, cells, blood, body fluids (such as bone marrow, cerebrospinal fluid, urine, pleural fluid, ascites fluid, and cyst fluid), other biological materials and associated clinical data.

Medical Condition(s)

All endocrine tumors involving the following organ systems: thyroid, parathyroid, adrenal, neuroendocrine pancreas/liver and carcinoids.

Eligibility Criteria

Any individual who is being seen at OHSU for a condition that involves any one of the following body systems:

neuroendocrine/ carcinoid

Any individual who has also been treated for these conditions specifically

kideny stones
osteoporosis or osteopenia
high calcium
underactive thyroid
overactive thyroid
thyroid cancer

Age Range

0 - 99

Healthy Volunteers Needed


Duration of Participation

Indefinite. The study has no end date and it’s value comes from being an ongoing, comprehensive, prospective process.

Minors Included



Enrique Leon, B.S. Genetics


Dr. Mira Milas
(503) 494-2277

Recruitment End


Compensation Provided


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