Incidental Solitary Adrenal Metastasis as the Initial Manifestation of a Solid Variant of Papillary Thyroid Carcinoma, With Emphasis on Pathologic Diagnosis and Clinical Management.

Objective: Distant metastases from papillary thyroid carcinoma (PTC) are relatively rare and may be associated with a poor prognosis. The adrenal gland is a highly unusual site of metastasis in the natural course of PTC. Herein, we describe a case of an incidentally detected metastatic solid variant of PTC in the adrenal gland of an asymptomatic patient as the initial presentation. Case Report: A 67-year-old male patient was evaluated for a 4.7-cm adrenal incidentaloma discovered during a workup for nephrolithiasis. Biochemical evaluation revealed a nonfunctioning adrenal mass. The patient underwent adrenalectomy, which revealed metastatic PTC. A subsequent thyroid ultrasound revealed an isthmic nodule. Fine needle aspiration of the nodule was cytologically suspicious for a follicular neoplasm, and gene expression analysis revealed an HRAS c.182A>G sequence variation. The patient subsequently underwent total thyroidectomy, which revealed a 1.2-cm solid variant of PTC in the thyroid isthmus. Postoperatively, the patient underwent radioactive iodine ablation. Discussion: Our case illustrates an exceedingly rare and challenging situation-a metastatic solid variant of PTC in the adrenal gland of a patient with no prior history of PTC. When confronted with a PTC in the adrenal gland in the absence of a previously identified primary tumor, our experience suggests that the next step in management should be total thyroidectomy followed by radioactive iodine ablation. Conclusion: A solid variant of PTC is a rare cause of an incidentally detected adrenal lesion. Multidisciplinary care team coordination is essential for accurate diagnosis and treatment plan formulation.

Intrathyroidal parathyroid glands: small, but mighty (a Napoleon phenomenon).

BACKGROUND: Intrathyroidal parathyroid adenomas (ITPAs) are a rare entity. The aim of this study is to describe the experience of 2 endocrine surgery centers and to distinguish characteristics of intrathyroidal parathyroid adenoma and nonintrathyroidal parathyroid adenomas. METHODS: We included patients who had undergone operations for primary hyperparathyroidism who had intrathyroidal parathyroid adenomas. Patients with single intrathyroidal parathyroid adenomas were also compared to age- and sex-matched controls with nonintrathyroidal parathyroid adenomas. RESULTS: Of 4,868 patients who underwent parathyroidectomy between January 2002 and June 2011, we identified 53 (1%) patients with intrathyroidal parathyroid adenoma. Sestamibi and ultrasound scans correctly identified the adenoma in 35 (70%) and 11 (61%) cases, respectively. Single adenomas were identified in 44 (83%) patients, double adenomas in 4 (8%) patients, and hyperplasia in 5 (9%) patients. Lobectomy was performed in 17 (32%) patients; enucleation was used in 36 (68%) patients. Cure was achieved in all patients and no patients experienced a recurrence. Patients with single intrathyroidal parathyroid adenomas had significantly smaller glands than patients with nonintrathyroidal parathyroid adenomas (325 ± 47 vs 772 ± 61 mg; P < .0001); however, no significant difference was identified between the groups with regard to demographics, symptoms, preoperative laboratory values, or outcomes. CONCLUSION: Single intrathyroidal parathyroid adenomas are smaller than nonintrathyroidal parathyroid adenomas, but patients with intrathyroidal parathyroid adenomas present with similar laboratory values and symptoms. Recognition of this rare entity can lead to a successful surgical outcome.

Three-gene molecular diagnostic model for thyroid cancer.

BACKGROUND: The preoperative diagnosis of thyroid nodules primarily depends upon fine needle aspiration (FNA) cytology. However, up to 25% of FNA samples have associated "suspicious or indeterminate", but not diagnostic cytologic reports, resulting in difficulty deciding appropriate clinical management for these patients. We hypothesize that the use of molecular markers as an adjunct to FNA cytology can improve the distinction of benign from malignant nodules that have associated suspicious or indeterminate cytology. METHODS: Using microarray analysis, we previously identified and reported on 75 genes useful in the distinction of benign versus malignant thyroid nodules. In the present study, we have further validated the expression of 14 of these markers in a large number of thyroid samples by immunohistochemistry (IHC) analysis of 154 thyroid tumors and quantitative real-time RT-PCR (QRT-PCR) analysis of 95 FNA samples. Of the 154 tumors analyzed by IHC, 44 samples (29%) had associated suspicious or indeterminate FNA cytology. RESULTS: Receiver operating characteristic using three-gene model, (HMGA2, MRC2, and SFN) analysis for the detection of malignant nodules resulted in areas under the curve (AUCs) of≥0.95 (80% sensitivity; 100% specificity) and≥0.84 (71% sensitivity; 84% specificity) for the IHC data in tumors, and QRT-PCR data in FNA samples, respectively. CONCLUSIONS: Our results suggest that a three-gene model for the cytological diagnosis of indeterminate thyroid nodules is both feasible and promising. Implementation of this as an adjunct to thyroid cytology may significantly impact the clinical management of patients with suspicious or indeterminate thyroid FNA nodules.

Preoperative thyroid ultrasound is indicated in patients undergoing parathyroidectomy for primary hyperparathyroidism.

BACKGROUND: Primary hyperaparathyroidism (pHPT) is often accompanied by underlying thyroid pathology that can confound preoperative parathyroid localization studies and complicate intra-operative decision making. The aim of this study was to examine the utility of preoperative thyroid ultrasonography (US) in patients prior to undergoing parathyroidectomy for pHPT. METHODS: An Institutional Review Board approved prospective study was undertaken from January 2005 through July 2008. All patients with pHPT meeting inclusion criteria (n=94) underwent preoperative thyroid ultrasound in addition to standard (99m)Tc-sestamibi scintigraphy for parathyroid localization. Demographics, operative management and final pathology were examined in all cases. RESULTS: Fifty-four of the 94 patients (57%) were noted to have a thyroid nodule on preoperative US, of which 30 (56%) underwent further examination with fine needle aspiration biopsy. Alteration of the operative plan attributable to underlying thyroid pathology occurred in 16 patients (17%), with patients undergoing either total thyroidectomy (n=9) or thyroid lobectomy (n=7). Thyroid cancer was noted in 33% of patients undergoing thyroid resection, and 6% of all patients with HPT. CONCLUSIONS: The routine utilization of preoperative thyroid ultrasound in patients prior to undergoing parathyroid surgery for pHPT is indicated. The added information from this non-invasive modality facilitates timely management of co-incidental, and sometimes malignant, thyroid pathology.

Long-term outcome in patients with primary hyperparathyroidism who underwent minimally invasive parathyroidectomy.

BACKGROUND: Minimally invasive parathyroidectomy (MIP) has become a well-accepted treatment for selected patients with primary hyperparathyroidism (PHPT). However, few studies have evaluated long-term outcomes for this operative approach. We therefore chose to examine both the long-term symptom resolution and biochemical cure following MIP for PHPT. METHODS: A total of 460 PHPT patients who underwent a MIP between 2004 and 2009 were successfully mailed a questionnaire that assessed preoperative and postoperative Parathyroidectomy Assessment of Symptoms (PAS) scores, most recent calcium and parathyroid hormone (PTH) levels, and information about any reoperation for PHPT. Long-term evaluation of symptomatic and biochemical cure was performed. RESULTS: A total of 200 patients (43.5%) responded to our correspondence. The mean age of the patients was 58.7 ± 11.9 years, 74.5% were female, and 78.5% were Caucasian. The mean follow-up was 37 ± 19 months. The mean PAS scores fell by 117 ± 14 at long-term follow-up after MIP (P < 0.0001). All 13 symptoms comprising the PAS score diminished, of which ten did so significantly (P < 0.01). There was a significant drop in the mean serum calcium (preop. 11.1 mg/dl, postop. 9.6 mg/dl; P < 0.0001) and PTH (preop. 130.9 pg/ml, postop. 45.7 pg/ml; P < 0.0001) at long-term follow-up. Five patients (2.5%) developed recurrent disease (calcium > 10.5 mg/dl), and one (0.5%) underwent a reoperation for persistent disease and was subsequently cured. CONCLUSIONS: This study demonstrates that MIP has long-term benefits in terms of excellent symptom resolution and a high biochemical cure rate (97%) in selected patients who have PHPT, preoperative localization with sestamibi scans, and assessment of intraoperative PTH level.

Predictive factors of malignancy in pediatric thyroid nodules.

BACKGROUND: Studies suggest that while most pediatric thyroid nodules are benign, there is a higher rate of malignancy than in adults. We investigate clinical factors that may predict malignancy in pediatric thyroid nodules. METHODS: A retrospective review of 207 pediatric thyroidectomies was conducted over 15 years at 2 tertiary hospitals. Analyses examined predictive values of 16 clinicopathologic factors associated with cancer. Positive predictive values (PPVs) of fine-needle aspiration biopsy specimens (FNABs) were analyzed independently. RESULTS: Malignancy occurred in 41% of patients. After excluding missing data, malignancy was more likely with family history of thyroid cancer (34.2% vs 17.7%; P = .111), palpable lymphadenopathy (34.2% vs 2.9%; P = .001), and hypoechoic nodules (52.2% vs 19.2%; P = .016). Palpable lymphadenopathy indicated greater than 2-fold increased risk for malignancy (relative risk, 2.18; 95% confidence interval, 1.56-3.05). PPVs of FNAB results were 0.94 for malignancy, 0.63 for suspicious for malignancy, and 0.55 for indeterminate lesions. PPV for benign FNAB to be benign on final pathology was 0.71. CONCLUSION: While malignancy is associated with family history of thyroid cancer and hypoechoic lesions, palpable lymphadenopathy had the greatest risk. When compared to adults, a benign FNAB in children is not as accurate and the likelihood that an indeterminate nodule is cancer is greater.

Tumor size and presence of calcifications on ultrasonography are pre-operative predictors of lymph node metastases in patients with papillary thyroid cancer.

BACKGROUND AND OBJECTIVES: Lymph node metastases in papillary thyroid cancer (PTC) are common and their presence can significantly alter the treatment for patients with PTC. We therefore sought to identify pre-operative predictors of lymph node metastases in patients with PTC. METHODS: A thyroid tumor database was queried to identify patients with a pre-operative diagnosis of PTC and underwent thyroidectomy between January 2006 and August 2009. One hundred and three patients who had a pre-operative ultrasound and had lymph nodes surgically resected were identified. Clinical factors and tumor ultrasound characteristics were recorded. The pre-operative ultrasound results, type of operation, and final pathology results were also recorded. RESULTS: Of the 103 patients, 74 (72%) were women and 29 (28%) were men with an age range of 15-78 years (median age of 43). Of the ultrasound characteristics evaluated only calcifications (P = 0.007) and size (P = 0.003) were statistically associated with positive cervical lymph nodes. None of the other demographic or clinical factors were significantly associated with lymph node metastases. CONCLUSIONS: Thyroid nodule size and presence of calcifications on ultrasound were found to have a statistically significant association with lymph node metastases in patients with PTC. This information could be used to guide the surgical management of these patients.

Postoperative hypocalcemia after thyroidectomy for Graves' disease.

BACKGROUND: It is believed that patients who undergo thyroidectomy for Graves' disease are more likely to experience postoperative hypocalcemia than patients undergoing total thyroidectomy for other indications. However, no study has directly compared these two groups of patients. The aim of this study was to determine whether there was an increased incidence or severity of postoperative hypocalcemia in patients who underwent thyroidectomy for Graves' disease. METHODS: An institutional review board-approved database was created of all patients who underwent thyroidectomy from 1998 to 2009 at the Johns Hopkins Hospital. There were a total of 68 patients with Graves' disease who underwent surgery. Fifty-five patients who underwent total thyroidectomy were randomly selected and served as control subjects. An analysis was conducted that examined potential covariates for postoperative hypocalcemia, including age, gender, ethnicity, preoperative alkaline phosphatase level, size of goiter, whether parathyroid tissue or glands were present in the specimen, and the reason the patient underwent surgery. Specific outcomes examined were calcium levels on postoperative day 1, whether or not patients experienced symptoms of hypocalcemia, whether or not Rocaltrol was required, the number of calcium tablets prescribed upon discharge, whether or not postoperative tetany occurred, and calcium levels 1 month after discharge. RESULTS: Each outcome was analyzed using a logistic regression. Graves' disease patients had a significantly (p-value < 0.001) higher odds of greater number of calcium tablets prescribed upon discharge. Further, 6 of 68 patients with Graves' disease and no patient in the control group were readmitted with tetany (p = 0.033). There was a trend, though not significant, toward patients with Graves' disease having a higher prevalence of hypocalcemia the day after thyroidectomy and 1 month later. CONCLUSIONS: Patients with Graves' disease are more likely to require increased dosages of calcium as well as experience tetany postoperatively than patients undergoing total thyroidectomy for other indications. This suggests that patients operated upon for Graves' disease warrant close followup as both inpatients and outpatients for signs and symptoms of hypocalcemia.

The surgical management of medullary thyroid cancer.

Medullary thyroid cancer (MTC), accounts for approximately 5% to 10% of all thyroid cancers. Significant advances in the understanding of the biology and clinical outcomes of MTC have been made over the last decade, culminating most recently in the publication of treatment guidelines by the American Thyroid Association that follow an evidence-based approach that is summarized in this presentation. Prognosis, genetic testing, surgical technique, and re-operation are also discussed.

An unusual case of recurrent hyperparathyroidism and papillary thyroid cancer.

OBJECTIVE: To report an unusual occurrence of recurrent hyperparathyroidism due to papillary thyroid carcinoma. METHODS: We describe the clinical history, physical examination findings, laboratory values, imaging findings, and pathologic findings of a woman who developed recurrent hyperparathyroidism 13 years after successful parathyroidectomy. RESULTS: A 59-year-old woman presented to our clinic with recurrent primary hyperparathyroidism. In 1994, she presented with nephrolithiasis and underwent resection of a right superior parathyroid adenoma that resulted in clinical and biochemical cure. Her clinical course had been followed at periodic intervals, and she had been symptom-free and normocalcemic. In 2007, she again developed nephrolithiasis and was documented to have recurrent hyperparathyroidism. Imaging studies suggested a parathyroid adenoma near the right inferior pole of the thyroid. The patient had reoperative neck exploration. No obvious parathyroid adenoma was found and a right thyroid lobectomy was performed, which resulted in normalization of intraoperative intact parathyroid hormone levels, and the incision was closed. Final pathology demonstrated no parathyroid adenoma, but instead, a 1-cm papillary thyroid carcinoma that stained positive for parathyroid hormone. More than 6 months after surgery, she remains clinically and biochemically cured. CONCLUSIONS: Recurrent hyperparathyroidism occurs secondary to multiple causes. This case demonstrates the challenge a surgeon faces in managing recurrent disease and highlights a rare phenomenon of papillary thyroid cancer causing recurrent hyperparathyroidism.

Evaluation for concomitant thyroid nodules and primary hyperparathyroidism in patients undergoing parathyroidectomy or thyroidectomy.

BACKGROUND: Previous investigators have reported the incidence of thyroid nodules in patients with primary hyperparathyroidism; others have noted the incidence of primary hyperparathyroidism in patients who underwent thyroidectomy. It is well known that both of these entities coexist. In this article, we present a single-center experience with the incidence of concomitant thyroid nodular disease and primary hyperparathyroidism in patients who underwent parathyroidectomy or thyroidectomy. METHODS: From May 2006 to December 2007, 526 patients underwent thyroidectomy, parathyroidectomy, or both. Operations were performed by surgeons in the Johns Hopkins Endocrine Surgery Section after screening preoperatively for concomitant thyroid nodular disease or primary hyperparathyroidism. RESULTS: Among the 200 patients who underwent a parathyroidectomy, 102 (51.0%) were found to have thyroid nodular disease. Six percent of these 200 patients also had a thyroid malignancy. Of the 326 patients who were primarily seen for thyroid disease, the incidence of primary hyperparathyroidism was 3.1%. CONCLUSION: By implementing a comprehensive approach to patients who present with thyroid disease or primary hyperparathyroidism, concomitant pathology may be elucidated preoperatively. This approach will facilitate the detection of otherwise unsuspected thyroid cancer and hyperparathyroidism as well as prevent unnecessary reoperative surgery.

A diagnostic predictor model for indeterminate or suspicious thyroid FNA samples.

BACKGROUND: The management of patients with thyroid fine-needle aspiration (FNA) specimens that are neither benign nor malignant still remains problematic. Efforts to improve their management have focused on identifying risk factors that predict malignancy. This study seeks to identify clinical and tumor characteristics that predict thyroid malignancy among patients with indeterminate or suspicious FNA and to develop a diagnostic predictor model. METHODS: The records of 639 patients with an indeterminate or suspicious thyroid FNA between January 1995 and April 2005 were reviewed. Patient and tumor characteristics were evaluated for their potential to predict malignancy in the final surgical histopathology. A diagnostic predictor model was designed based on statistically significant predictors. Patients seen between April 2005 and April 2007 were used to validate the model. RESULTS: Patient age, nodule size, and FNA cytopathology were identified as risk factors. Patients at extremes of age were at increased risk. Patients 50 years of age had the lowest risk of malignancy. For patients less than age 50, the risk increased 3% for each year decrease in age (p = 0.001). After 50, the risk increased 3.4% for each year increase in age (p = 0.016). Nodules 2.5 cm had the lowest likelihood of malignancy. For smaller nodules, the risk increased 53% per cm decrease in size (p < 0.001). For larger nodules, the risk increased 39% per cm increase (p < 0.001). Patients with FNA cytology suspicious for papillary thyroid carcinoma had the greatest risk of malignancy (p < 0.001). CONCLUSIONS: A predictor model was created using the variables age, nodule size, and FNA cytology to predict thyroid malignancy.

Identification of genes differentially expressed in benign versus malignant thyroid tumors.

PURPOSE: Although fine-needle aspiration biopsy is the most useful diagnostic tool in evaluating a thyroid nodule, preoperative diagnosis of thyroid nodules is frequently imprecise, with up to 30% of fine-needle aspiration biopsy cytology samples reported as "suspicious" or "indeterminate." Therefore, other adjuncts, such as molecular-based diagnostic approaches are needed in the preoperative distinction of these lesions. EXPERIMENTAL DESIGN: In an attempt to identify diagnostic markers for the preoperative distinction of these lesions, we chose to study by microarray analysis the eight different thyroid tumor subtypes that can present a diagnostic challenge to the clinician. RESULTS: Our microarray-based analysis of 94 thyroid tumors identified 75 genes that are differentially expressed between benign and malignant tumor subtypes. Of these, 33 were overexpressed and 42 were underexpressed in malignant compared with benign thyroid tumors. Statistical analysis of these genes, using nearest-neighbor classification, showed a 73% sensitivity and 82% specificity in predicting malignancy. Real-time reverse transcription-PCR validation for 12 of these genes was confirmatory. Western blot and immunohistochemical analyses of one of the genes, high mobility group AT-hook 2, further validated the microarray and real-time reverse transcription-PCR data. CONCLUSIONS: Our results suggest that these 12 genes could be useful in the development of a panel of markers to differentiate benign from malignant tumors and thus serve as an important first step in solving the clinical problem associated with suspicious thyroid lesions.

Unusual case of metastatic neuroendocrine tumor.

OBJECTIVE: To report a rare case of metastatic growth hormone (GH)-secreting pituitary carcinoma causing acromegaly. METHODS: We present a case report and review the available literature on this topic. RESULTS: A 68-year-old woman presented with persistent acromegaly after treatment for a GH-secreting pituitary adenoma. Evaluation of long-standing cervical adenopathy revealed findings consistent with a metastatic neuroendocrine tumor. Further work-up revealed additional thyroid, parathyroid, and cervical masses. After operative treatment including total thyroidectomy, subtotal parathyroidectomy, partial thymectomy, and right modified radical neck dissection, the patient's symptoms diminished, and her GH levels approached the normal range. Surgical pathology findings were consistent with a GH-secreting pituitary carcinoma metastatic to the cervical lymph nodes, multinodular thyroid hyperplasia with a focus of papillary microcarcinoma, and parathyroid hyperplasia. CONCLUSION: Overall, pituitary carcinomas are extremely rare. To date, about 100 cases have been reported in the world's literature, and of these, only 19 cases originated from GH-secreting cells. Our examination of the symptoms, signs, diagnosis, and treatment of our patient, in comparison with the previously reported cases, should enhance awareness of this unusual disease process.

Laparoscopic resection of a paraganglioma of the organ of Zuckerkandl in a patient with a carotid body tumor.

Paragangliomas of the organ of Zuckerkandl are rare tumors with only several case reports noted in the literature. Synchronous paraganglioma occur sporadically, and on occasion, in association with several genetic syndromes. Paraganglioma of the organ of Zuckerkandl with synchronous carotid body paraganglioma is described herein. Traditionally, surgical resection of abdominal paraganglioma involved an exploratory laparotomy. In this manuscript, we describe one of the first reported laparoscopic resections of this tumor and review the literature on multiple paragangliomas and their associated genetic syndromes.

25-hydroxyvitamin D deficiency is a risk factor for symptoms of postoperative hypocalcemia and secondary hyperparathyroidism after minimally invasive parathyroidectomy.

BACKGROUND: Patients with primary hyperparathyroidism who undergo minimally invasive parathyroidectomy (MIP) may have postoperative symptoms of hypocalcemia or secondary hyperparathyroidism. This study sought to identify factors predictive of these events. METHODS: Between 1998 and 2004, 190 patients with primary hyperparathyroidism underwent MIP with excision of a single adenoma. Age, gender, race, prior head and neck surgery, use of preoperative thyroid hormone or calcium-channel blockers, preoperative levels of calcium, 25-hydroxyvitamin D (25[OH]D) and intact parathyroid hormone (iPTH), the presence of osteopenia or osteoporosis, intraoperative iPTH levels, and adenoma weight were evaluated by univariate analysis as predictors of postoperative symptoms of hypocalcemia and secondary hyperparathyroidism. RESULTS: None of the following were predictors of postoperative symptoms of hypocalcemia: age, gender, race, prior head and neck surgery, preoperative medications, preoperative calcium and iPTH levels, osteopenia or osteoporosis, intraoperative iPTH levels, or adenoma weight. However, patients with postoperative symptoms of hypocalcemia had significantly lower preoperative 25[OH]D levels (P = .01). Further, higher preoperative iPTH levels (P < .01) and lower preoperative 25[OH]D levels (P = .05) were associated with secondary hyperparathyroidism postoperatively. CONCLUSIONS: A low preoperative 25[OH]D level is associated with postoperative symptoms of hypocalcemia and secondary hyperparathyroidism in patients undergoing MIP. One might consider instituting empiric calcium supplementation postoperatively in patients with low 25[OH]D levels.

A six-gene model for differentiating benign from malignant thyroid tumors on the basis of gene expression.

BACKGROUND: Thyroid nodules are common; fine-needle aspirations commonly are read as indeterminate, necessitating surgery to exclude carcinoma. We developed a 6-gene array-based predictor model to diagnose benign versus malignant thyroid lesions. In this study, we verified whether quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using this model reliably can differentiate benign from malignant thyroid nodules. METHODS: Molecular profiles of benign (follicular adenomas, hyperplastic nodules) and malignant tumors (papillary thyroid carcinomas, follicular variants of papillary thyroid carcinomas) were analyzed using qRT-PCR from our 6-gene model (kit, Hs.296031, Hs.24183, LSM7, SYNGR2, C21orf4). The gold standard was standard pathologic criteria. A diagnosis-predictor model was built by using the training samples and was then used to predict the class of 10 additional samples analyzed as unknowns. RESULTS: Our predictor model using 47 training samples correctly predicted 9/10 unknowns. One sample diagnosed as benign by standard histologic criteria was diagnosed as malignant by our model (sensitivity 75%; specificity, 100%; positive predictive value, 100%; negative predictive value, 85.7%). CONCLUSIONS: Molecular diagnosis with our 6-gene model can differentiate between benign and malignant thyroid tumors with high sensitivity and specificity. In combination, these genetic markers may be a reliable test to preoperatively diagnose the malignant potential of thyroid nodules.