Long-Term Outcomes for Patients with Multiple Endocrine Neoplasia Type 1 and Duodenopancreatic Neuroendocrine Neoplasms.

BACKGROUND: Liver metastasis from duodenopancreatic neuroendocrine neoplasms (DP-NENs) is a major cause of mortality in multiple endocrine neoplasia type 1 (MEN1) patients, yet much of their natural history is unknown. METHODS: This longitudinal, retrospective cohort study analyzed all MEN1 patients with imageable functional (F) and nonfunctional (NF) DP-NENs (1990-2021) for liver metastasis-free survival (LMFS) and overall survival (OS). RESULTS: Of 138 patients, 85 (61.6%) had imageable DP-NENs (28 F, 57 NF), and the mean largest tumor size was 1.8 ± 1.4 cm. Multifocality was present in 32 patients (37.7%). Surgery was performed for 49 patients (57.7%). During an 11-year median follow-up period (IQR, 6-17 years), 23 (27.1%) of the patients had liver metastasis, and 19 (22.4%) patients died. Death was attributed to liver metastasis in 60% of cases. The patients with F-DP-NENs versus NF-DP-NENs more often had liver metastasis (46.4% vs. 15.8%; p = 0.002) but had similar 10-year LMFS (80.9 vs. 87.0%; p = 0.44) and OS (82.7 vs. 94.3%; p = 0.69). The patients with NF-DP-NENs had surgery when their tumors were larger (p < 0.001). Tumor size was not associated with liver metastasis (p = 0.89). The average growth rate was 0.04 cm/year (SE, 0.02 cm/year; p = 0.01) during active surveillance for NF-DP-NENs (n = 38). Liver metastasis developed in four patients with tumors smaller than 2 cm. The risk of liver metastasis was independent of surgery (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.21-2.93; p = 0.72) and death (HR, 0.51; 95% CI, 0.08-3.06; p = 0.46). CONCLUSIONS: Although the observed outcomes in this study were better than historical data, small NF-DP-NENs still developed liver metastasis and liver metastasis remains a major cause of death. These results suggest that size as a sole criterion for surgery may be insufficient to predict tumor behavior.

The Clinical Utility of Molecular Testing in the Management of Thyroid Follicular Neoplasms (Bethesda IV Nodules).

OBJECTIVE: FN present a management quandary as they are often benign but may also be aggressive TC. Consensus recommendations have historically advised thyroidectomy for definitive diagnosis. Although MT have robust benefit in hypothetical cost analyses, under current management guidelines a real-time study of their clinical utility in FN is awaited. We investigate if MT use for FN directs appropriate thyroidectomy for TC while triaging to surveillance nodules that are likely benign. METHODS: Data were analyzed for 389 consecutive patients managed from 11/14 to 9/19 for 405 FN, excluding oncocytic neoplasms. TC was defined as same-nodule histologic malignancy. When obtained, MT was performed using ThyroSeq (TS) v2 or 3. RESULTS: With a mean nodule size of 2.7 ±â€Š1.3 cm, MT was used in 89% and was positive in 39%. When MT was positive, thyroidectomy was more often utilized (91% v. MT- 27%; P < 0.001) and more likely for histologic TC (70% vs 16%, P < 0.001). With preoperative MT, all American Thyroid Association intermediate, high-risk, and medullary TC were positive whereas all MT- malignancies were low-risk. With TSv3, ultrasound surveillance was more likely for MT- FN (90% vs TSv2 65%, P < 0.001), and occurred for a total of 174 MT- FN. With mean follow-up of 24.6 months, 82% remained stable in size. CONCLUSIONS: MT use for FN increased the surgical yield of cancer by 4-fold, identified all potentially aggressive malignancies, and allowed apparently safe nonoperative surveillance for >80% of MT-negative patients. Thyroid nodule MT optimizes patient outcomes sufficiently to justify its incorporation into routine practice.

Novel Findings on SPECT-CT Tc-99 Sestamibi Imaging for Primary Hyperparathyroidism.

BACKGROUND: The addition of SPECT-CT to Tc-99 sestamibi has become a valuable tool for parathyroid localization in primary hyperparathyroidism (PHP). However, the enhanced sensitivity of this test can lead to unexpected and significant findings. We sought to identify the frequency and types of nonparathyroid detections by SPECT-CT. MATERIALS AND METHODS: With institutional approval, we reviewed all SPECT-CT studies performed for PHP between October 2012 and August 2018 for incidental nonparathyroid abnormalities. The electronic medical record was referenced to determine the type of lesion confirmed by additional evaluation. RESULTS: Among 2413 studies, 652 patients (27%) had 677 (28%) nonparathyroid findings. The most common were thyroid nodules (331/677, 49%), including 47 (6.9%) malignancies to date: 40 papillary thyroid cancers (11 microcarcinomas), five follicular thyroid cancers, one medullary carcinoma, and one noninvasive follicular thyroid neoplasm with papillary-like features. One hundred and seventy-seven patients had pulmonary nodules (26%), of whom nine were diagnosed with primary lung lesions (6 non-small-cell cancers, one small-cell cancer, one carcinoid, and one pulmonary sequestration). SPECT-CT revealed 14 patients (2.1%) with breast abnormalities, including three cancers. Nine patients (1.3%) demonstrated metastatic diseases within the lungs (4), bones (3), and mediastinum (2). One patient was diagnosed with follicular lymphoma. Two intracranial tumors were also identified, as well as dysplastic Barrett's esophagitis (1), hiatal hernia (20, 3%), and aortic aneurysm (13, 1.8%). In all, 72/677 (10.6%) PHP patients exhibited premalignant or malignant nonparathyroid SPECT-CT findings. CONCLUSIONS: In patients undergoing localization for PHP with Tc-99 sestamibi SPECT-CT, nonparathyroid findings are frequent (27%) and can lead to newly diagnosed malignant or premalignant lesions in at least 3% of patients to date.

Clinical and Biochemical Features of Pheochromocytoma Characteristic of Von Hippel-Lindau Syndrome.

BACKGROUND: Approximately 30% of patients with apparent sporadic pheochromocytoma (Pheo) may later prove to have an inherited predisposition syndrome, most commonly Von Hippel-Lindau (VHL) disease. Our aim was to compare the clinical and biochemical features of Pheo in VHL to those in sporadic disease to identify differences that may be used to guide management and surveillance of Pheo in VHL patients. METHODS: Data of all patients who had adrenalectomy for histologic Pheo from 2000 to 2018 (QIIRB1749) were retrospectively reviewed. VHL patients were diagnosed by standard clinical criteria and/or genetic testing. Patients were classified as having sporadic Pheo (sPheo) if they had no family/personal history consistent with an associated genetic disorder and/or had negative testing for VHL, MAX, MEN1, NF1, RET and SDHAF2/B/C/D/A mutations. RESULTS: Of 175 patients, 38 (22%) had VHL and 137 (78%) had sPheo including 27 (20%) with negative genetic testing. Compared to sPheo, VHL Pheo patients were younger (mean 25.9 vs. 51.2 years, p < 0.001), less symptomatic (55% vs. 72%, p = 0.074), less hypertensive (46% vs. 64%, p = 0.043) and were more likely to have normal plasma metanephrines (85% vs. 25%, p < 0.001). VHL-related Pheos were smaller (median 2.8 cm vs. 4.4 cm, p < 0.001) but more often multifocal (>1 adrenal Pheo) (16% vs. 0%, p < 0.001). Recurrence >6 months from initial resection was common in VHL (40% vs. 0%, p < 0.001), median time to recurrence 15 years, (range 1-38 years). CONCLUSIONS: Compared to those with sporadic Pheo, patients with VHL are more likely to be young, asymptomatic and normotensive and to have small, multifocal, normetanephrine-secreting tumors. Because recurrence is common in VHL and arises up to 38 years later, continued surveillance is advised.

Retropharyngeal Parathyroid Glands: Important Differences.

INTRODUCTION: In primary hyperparathyroidism (PHPT), parathyroid ectopia is seen in up to 22% leading to more difficult surgery. We aimed to determine the rate and characteristics of retropharyngeal (RP) parathyroid glands. METHODS: A prospective database was queried for patients with sporadic PHPT who had surgery from 1997 to 2016. The data of RP patients were compared to those who had surgery for sporadic PHPT over the same time period with hyperfunctioning parathyroids in anatomically normal positions (N). RESULTS: RP glands occurred in 47/3006 (1.6%) patients and were more common at reoperative than initial surgery (5.5 vs 1.4%, p < 0.01). RP patients had prior failed surgery more often than N patients (17 vs 3.1%, p < 0.01). Preoperative calcium levels (p = 0.06), PTH levels (p = 0.15), and mean gland weights (p = 0.07) were similar among groups. For RP glands, ultrasound imaging was negative in all but one patient, while 99mTc-sestamibi accurately indicated a posterior midline position in only 13/47 (28%) and was negative in 21%. All RP glands were anatomically superior. RP patients more often required > 1 post-resection intraoperative PTH level (36 vs 21%, p = 0.02). Failure due to persistent PHPT was more likely in RP patients (4.7 vs 2.1%, p = 0.2). CONCLUSION: In PHPT, hyperfunctioning RP glands are seen in 1.6% of cases and often associated with initial failure (17%). At reoperation, RP ectopia is 4X more common. RP glands are associated with a high rate of negative imaging, but imaging results suggestive of a midline abnormality can guide exploration. The RP space should be evaluated prior to ending an otherwise unfruitful surgery.

Clinical Predictors of Malignancy in Patients with Pheochromocytoma and Paraganglioma.

BACKGROUND AND PURPOSE: Factors associated with malignancy in patients with pheochromocytoma (adrenal tumors, Pheo) and paraganglioma (extra-adrenal, PGL) are not well-defined and all patients require lifelong surveillance. The primary aim of our study was to determine genetic and clinical variables associated with malignancy in patients with Pheo/PGL. METHODS: Single institution retrospective review was performed of all patients who underwent surgery (1/95-1/15) for Pheo/PGL. Malignancy was defined as histology-confirmed distant metastasis, lymph nodal involvement, or tumor bed recurrence. RESULTS: A total of 157 Pheo/PGL patients (44 malignant, 113 benign) with mean follow-up of 87 months were included. Compared with patients with benign Pheo/PGL, patients with malignant Pheo/PGL were younger (median 42 vs 50 years, p = 0.014), had larger tumors (median 6.5 vs 4 cm, p < 0.001) and had PGL (63.6 vs 4.4%, p < 0.001). Genetic testing was performed in 60 patients and was positive in 38 (63%). Although positive genetic results were equally likely in malignant vs benign Pheo/PGL (76 vs 54%, p = 0.1), all 11 patients with germline SDHB mutations had malignant disease. In multivariable analysis, younger age, larger tumor size, and PGL were associated with malignancy (p < 0.05). Pheo patients with negative genetic testing and negative family history who developed metachronous metastases all had primary tumors ≥4 cm in size. CONCLUSIONS: Patients who are young, have larger tumors, positive genetic testing (especially SDHB) or have PGL require long-term follow-up. Patients with negative genetic testing or family history and Pheo <4 cm have a lower risk of malignancy, and de-escalated long-term surveillance may be appropriate follow-up.

Tumor genotype determines phenotype and disease-related outcomes in thyroid cancer: a study of 1510 patients.

OBJECTIVES: To correlate thyroid cancer genotype with histology and outcomes. BACKGROUND: The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management. METHODS: We reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy. RESULTS: Papillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (70%); the most common mutations were BRAFV600E (644/1039, 62%), and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall cell variant (58%), with frequent extrathyroidal extension (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02). CONCLUSIONS: In this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.

Adrenal Imaging Features Predict Malignancy Better than Tumor Size.

INTRODUCTION: In adrenal tumors, size ≥ 4 cm has been an indication for adrenalectomy due to concern for malignancy. We compared mass size to imaging features (ImF) for accuracy in diagnosing adrenal malignancy. METHODS: Data were retrieved for 112 consecutive patients who had adrenalectomy from January 2011 to August 2014. ImF was classified as nonbenign if HU > 10 on unenhanced CT scan or if loss of signal on out-of-phase imaging was absent on chemical-shift MRI. Indications for resection included hormonal hypersecretion, nonbenign ImF, and/or size ≥ 4 cm. RESULTS: Of 113 resected adrenals, 37 % were functional. Histologic malignancy occurred in 18 % (20/113) and included 3 adrenocortical carcinomas (ACC), 1 epithelioid liposarcoma, 1 lymphoma, 1 malignant nerve sheath tumor, and 14 adrenal metastases. Patients with malignancies were older (mean age, 60 ± 13 vs. 51 ± 14 years, p = 0.01). Malignant tumors were larger on preoperative imaging (mean 5.3 ± 3.2 vs. 3.9 ± 2.4 cm, p = 0.03). All 20 malignant masses had nonbenign ImF. In predicting malignancy, the sensitivity, specificity, NPV, and PPV of nonbenign ImF was 100, 57, 100, and 33 %, respectively. Size ≥ 4 cm was less predictive with sensitivity, specificity, NPV, and PPV of 55, 61, 86, and 23 %, respectively. If size ≥ 4 cm had been used as the sole criterion for surgery, 45 % of malignancies (9/20) would have been missed including 8 metastases and an ACC. CONCLUSIONS: In resected adrenal tumors, the presence of nonbenign ImF is more sensitive for malignancy than mass size (100 vs. 55 %) with equivalent specificity. Regardless of mass size, adrenalectomy should be strongly considered when non-benign ImF are present.

A clinical algorithm for fine-needle aspiration molecular testing effectively guides the appropriate extent of initial thyroidectomy.

OBJECTIVE: To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate. BACKGROUND: Either TT or lobectomy is often needed to diagnose differentiated thyroid cancer. Determining the correct extent of initial thyroidectomy is challenging. METHODS: After implementing an algorithm for prospective MT of in-house fine-needle aspiration biopsy specimens, we conducted a single-institution cohort study of all patients (N = 671) with nonmalignant cytology who had thyroidectomy between October 2010 and March 2012, cytological diagnosis using 2008 Bethesda criteria, and 1 or more indications for thyroidectomy by 2009 American Thyroid Association guidelines. sTC was defined by histological differentiated thyroid cancer of 1 cm or more and/or lymph node metastasis. Cohort 2 patients did not have MT or had unevaluable results. In cohort 1, MT for a multigene mutation panel was performed for nonbenign cytology, and positive MT results indicated initial TT. RESULTS: MT guidance was associated with a higher incidence of sTC after TT (P = 0.006) and a lower rate of sTC after lobectomy (P = 0.03). Without MT results, patients with indeterminate (follicular lesion of undetermined significance/follicular or oncocytic neoplasm) cytology who received initial lobectomy were 2.5 times more likely to require 2-stage surgery for histological sTC (P < 0.001). In the 501 patients with non-sTC for whom lobectomy was the appropriate extent of surgery, lobectomy was correctly performed more often with routine preoperative MT (P = 0.001). CONCLUSIONS: Fine-needle aspiration biopsy MT for BRAF, RAS, PAX8-PPARγ, and RET-PTC expedites optimal initial surgery for differentiated thyroid cancer, facilitating succinct definitive management for patients with thyroid nodules.

The final intraoperative parathyroid hormone level: how low should it go?

BACKGROUND: In minimally invasive surgery for primary hyperparathyroidism (HPT), intraoperative parathyroid hormone (IOPTH) monitoring assists in obtaining demonstrably better outcomes, but optimal criteria are controversial. METHODS: The outcomes of 1,108 initial parathyroid operations for sporadic HPT using IOPTH monitoring from 1997 to 2011 were stratified by final post-resection IOPTH level. All patients had adequate follow-up to verify cure. RESULTS: With mean follow-up of 1.8 years (range 0.5-14.3 years), parathyroidectomy using IOPTH monitoring failed in 1.2 % of cases, with an additional 0.5 % incidence of long-term recurrence at a mean of 3.2 years (range 0.8-6.8 years) postoperatively. Operative success was equally likely with a final IOPTH drop to 41-65 pg/mL vs ≤40 pg/mL (p = 1). In the 76 patients with an elevated baseline IOPTH level that did not drop to ≤65 pg/mL, surgical failure was 43 times more likely than with a drop into normal range (13 vs. 0.3 %; p < 0.001). When the final IOPTH level dropped by >50 % but not into the normal range, surgical failure was 19 times more likely (3.8 vs. 0.2 %; p = 0.015). Long-term recurrence was more likely in patients with a final IOPTH level of 41-65 pg/mL than with a level ≤40 pg/mL (1.2 vs. 0; p = 0.016). CONCLUSIONS: Adjunctive intraoperative PTH monitoring facilitates a high cure rate for initial surgery of sporadic primary hyperparathyroidism. A final IOPTH level that is within the normal range and drops by >50 % from baseline is a strong predictor of operative success. Patients with a final IOPTH level between 41-65 pg/mL should be followed beyond 6 months for long-term recurrence.

The small abnormal parathyroid gland is increasingly common and heralds operative complexity.

BACKGROUND: Over decades, improvements in presymptomatic screening and awareness of surgical benefits have changed the presentation and management of primary hyperparathyroidism (PHPT). Unrecognized multiglandular disease (MGD) remains a major cause of operative failure. We hypothesized that during parathyroid surgery the initial finding of a mildly enlarged gland is now frequent and predicts both MGD and failure. METHODS: A prospective database was queried to examine the outcomes of initial exploration for sporadic PHPT using intraoperative PTH monitoring (IOPTH) over 15 years. All patients had follow-up ≥6 months (mean = 1.8 years). Cure was defined by normocalcemia at 6 months and microadenoma by resected weight of <200 mg. RESULTS: Of the 1,150 patients, 98.9 % were cured and 15 % had MGD. The highest preoperative calcium level decreased over time (p < 0.001) and varied directly with adenoma weight (p < 0.001). Over time, single adenoma weight dropped by half (p = 0.002) and microadenoma was increasingly common (p < 0.01). MGD risk varied inversely with weight of first resected abnormal gland. Microadenoma required bilateral exploration more often than macroadenoma (48 vs. 18 %, p < 0.01). When at exploration the first resected gland was <200 mg, the rates of MGD (40 vs. 11 %, p = 0.001), inadequate initial IOPTH drop (67 vs. 79 %, p = 0.002), operative failure (6.6 vs. 0.7 %, p < 0.001), and long-term recurrence (1.6 vs. 0.3 %, p = 0.007) were higher. CONCLUSIONS: Single parathyroid adenomas are smaller than in the past and require more complex pre- and intraoperative management. During exploration for sporadic PHPT, a first abnormal gland <200 mg should heighten suspicion of MGD and presages a tenfold higher failure rate.

Thyroid nodules (≥4 cm): can ultrasound and cytology reliably exclude cancer?

BACKGROUND: Whether a threshold nodule size should prompt diagnostic thyroidectomy remains controversial. We examined a consecutive series of patients who all had thyroidectomy for a ≥4 cm nodule to determine (1) the incidence of thyroid cancer (TC) and (2) if malignant nodules could accurately be diagnosed preoperatively by ultrasound (US), fine needle aspiration biopsy (FNAB) cytology and molecular testing. METHODS: As a prospective management strategy, 361 patients with 382 nodules ≥4 cm by preoperative US had thyroidectomy from 1/07 to 3/12. RESULTS: The incidence of a clinically significant TC within the ≥4 cm nodule was 22 % (83/382 nodules). The presence of suspicious US features did not discriminate malignant from benign nodules. Moreover, in 86 nodules ≥4 cm with no suspicious US features, the risk of TC within the nodule was 20 %. US-guided FNAB was performed for 290 nodules, and the risk of malignancy increased stepwise from 10.4 % for cytologically benign nodules, 29.6 % for cytologically indeterminate nodules and 100 % for malignant FNAB results. Molecular testing was positive in 9.3 % (10/107) of tested FNAB specimens, and all ten were histologic TC. CONCLUSIONS: In a large consecutive series in which all ≥4 cm nodules had histology and were systematically evaluated by preoperative US and US-guided FNAB, the incidence of TC within the nodule was 22 %. The false negative rate of benign cytology was 10.4 %, and the absence of suspicious US features did not reliably exclude malignancy. At minimum, thyroid lobectomy should be strongly considered for all nodules ≥4 cm.

Outcomes of subtotal parathyroidectomy for renal hyperparathyroidism.

BACKGROUND: Renal hyperparathyroidism due to end-stage kidney disease is associated with considerable morbidity, and when refractory is treated with parathyroidectomy. Recurrent renal hyperparathyroidism is a major surgical complication, yet initial target parathyroid remnant size and outcomes, including rates of recurrence are not well elucidated. METHODS: This is a single-institution retrospective cohort study of patients who underwent initial subtotal parathyroidectomy for renal hyperparathyroidism on dialysis, from 1990-2022. The subtotal parathyroidectomy was defined as resection of 3 parathyroid glands ± partial resection of the fourth gland leaving a remnant of ∼75-100 mg, and postresection intraoperative parathyroid hormone goal was 150-250 pg/mL. Clinical data were examined for outcomes. RESULTS: Among 204 patients who met inclusion criteria, 139 (68%) had follow-up data; 58% (80/139) were women and median age was 45 years. Surgical complications included 2 hematomas (1.4%), 1 recurrent laryngeal nerve injury (<1%), and no patient required readmission for intravenous calcium. Using a target remnant size of 75-100 mg, recurrent renal hyperparathyroidism was uncommon (14/139, 10%) and arose at a median interval of 58.6 months (range, 8-180). In cases of recurrence, the postresection intraoperative parathyroid hormone level was less likely to drop <250 pg/mL (40%, 4/10 vs nonrecurrence 65%, 80/123; P = .11) with a slightly lower median decrease (70% vs 81% in nonrecurrence, P = .8); however, neither were significant. Recurrence did not occur in the 19 patients who later received kidney transplantation (P = .2). CONCLUSION: In subtotal parathyroidectomy for renal hyperparathyroidism, use of a target 75-100 mg remnant size results in low complication rates. Durable cure appears to be more likely with renal transplantation.

4D SPECT/CT: A Hybrid Approach to Primary Hyperparathyroidism.

Our rationale was to review the imaging options for patients with primary hyperparathyroidism and to advocate for judicious use of 4-dimensional (4D) SPECT/CT to visualize diseased parathyroid glands in patients with complex medical profiles or in whom other imaging modalities fail. We review the advantages and disadvantages of traditional imaging modalities used in preoperative assessment of patients with primary hyperparathyroidism: ultrasound, SPECT, and 4D CT. We describe a scheme for optimizing and individualizing preoperative imaging of patients with hyperfunctioning parathyroid glands using traditional modalities in tandem with 4D SPECT/CT. Using the input from radiologists, endocrinologists, and surgeons, we apply patient criteria such as large body habitus, concomitant multiglandular disease, multinodular thyroid disease, confusing previous imaging, and unsuccessful previous surgery to create an imaging paradigm that uses 4D SPECT/CT yet is cost-effective, accurate, and limits extraneous radiation exposure. 4D SPECT/CT capitalizes on the strengths of SPECT and 4D CT and addresses limitations that exist when these modalities are used in isolation. In select patients with complicated clinical parameters, preoperative imaging with 4D SPECT/CT can improve accuracy yet remain cost-effective.

Sex differences in patients with primary hyperparathyroidism.

BACKGROUND: Differences in presenting symptoms of primary hyperparathyroidism and outcomes of parathyroidectomy between sexes have been described, but whether these can be assessed by perioperative use of a validated tool, such as the Pasieka Parathyroidectomy Assessment Score, is unknown. METHOD: All patients with primary hyperparathyroidism were asked to complete symptom assessment at the preoperative and postoperative visits. The assessment included a query for 13 Pasieka Parathyroidectomy Assessment Score parameters evaluated using a visual analog scale as described by Pasieka (summative score 0-1,300), and general quality of life and wellness. A review of a prospectively maintained database of primary hyperparathyroidism patients (January 2016-December 2019) was performed, and those who had a 6-month cure after initial parathyroidectomy were included. RESULTS: The study cohort was mostly women (77%, 541/701). The median preoperative Pasieka Parathyroidectomy Assessment Score was higher in women (155, 0-1,190) than in men (80.5, 0-855, P < .001), although there were similar rates of asymptomatic primary hyperparathyroidism (Pasieka Parathyroidectomy Assessment Score = 0, 12.5% vs 7%, P = .042). After curative parathyroidectomy, women reported a substantial reduction in symptomatology, with Pasieka Parathyroidectomy Assessment Score declining by 35% at initial postoperative visit (median, 155 vs 100, P < .001), further decreasing to 48% by 6 months (155 vs 80, P < .001). The Pasieka Parathyroidectomy Assessment Score in men did change but to a much smaller degree at both the initial postoperative visit (80.5 vs 70; P = .036) and at 6 months (80.5 vs 57.5; P = .048). CONCLUSION: When assessed with the Pasieka Parathyroidectomy Assessment Score, improvement in symptoms was clearly demonstrated for women after curative parathyroidectomy. Whether symptom improvement also occurs in men is less apparent but may be due to disparities in the development and validation of outcomes tools in general.

Normocalcemic hyperparathyroidism: Intervention to differentiate primary from secondary hyperparathyroidism.

BACKGROUND: Normocalcemic hyperparathyroidism can occur, but surgery should not be considered until common etiologies for secondary hyperparathyroidism are comprehensively excluded. Calcium deficiency is an underrecognized cause of normocalcemic parathyroid hormone elevation, and we aim to determine if the implementation of a preoperative calcium challenge can be used to reduce unnecessary parathyroidectomy. METHODS: Consecutive patients referred for parathyroidectomy (1/21-6/22) with normocalcemia (serum calcium <10 mg/dL) and concurrently elevated parathyroid hormone levels were routinely treated with supplemental calcium and vitamin D3, and follow-up laboratory studies were assessed. RESULTS: A total of 29/314 (9%) patients had normocalcemic parathyroid hormone elevation with mean calcium, parathyroid hormone, and vitamin D 25OH levels of 9.5 ± 0.3 mg/dL, 109.9 ± 34.9 pg/mL, and 42.7 ± 23.8 ng/mL respectively. Confounding factors included estimated glomerular filtration rate <60 in 2, loop diuretic use in 4, and prior gastric bypass or gastric sleeve surgery in 4. Follow-up biochemical evaluation was available in 27 (92%); results were unchanged in 7 patients (26%); normalization of parathyroid hormone levels with persistently normal calcium levels occurred in 15 (55%), thus confirming secondary hyperparathyroidism and hypercalcemia with elevated parathyroid hormone levels (classic primary hyperparathyroidism) was diagnosed in 5 (19%). Parathyroid exploration has been completed for 3 of 5 patients with classic primary hyperparathyroidism to date. CONCLUSION: A preoperative calcium challenge was prospectively initiated in normocalcemic patients with parathyroid hormone elevation, and there was high compliance (92%). Short-interval calcium supplementation revealed ∼50% to have resolved secondary hyperparathyroidism due to insufficient calcium intake, which avoided unnecessary surgery. In contrast, classic patients were unveiled in 20%, allowing for prompt and correct surgical intervention.

Outcome and prognostic factors after adrenalectomy for patients with distant adrenal metastasis.

BACKGROUND: The purpose of this study was to describe a single-institution experience with adrenal metastasectomy and to elucidate factors that may bear prognostic significance. METHODS: This is a single-center, retrospective review of patients with adrenal metastasis who underwent adrenalectomy performed with curative intent between 2000 and 2012. The Kaplan-Meier method was used to evaluate overall survival from time of adrenalectomy to death or last follow-up. Primary endpoint was death from any cause. Clinical variables were examined for association with survival. RESULTS: The study included 62 patients with mean age of 60 (±12) years; 55 % (34 of 62) were male, 85 % (53 of 62) presented with isolated adrenal metastasis, and 82 % (51 of 62) had metachronous disease with median disease-free interval (DFI) of 22 months (range, 6-217 months). Non-small cell lung cancer (NSCLC) was the most common primary comprising 50 % of cases. Median survival for the study population was 30 months (range, 1-145 months) and 5-year survival was 31 %. Patients with NSCLC had significantly shortened survival compared with non-NSCLC with median and 5-year survival of 17 versus 47 months and 27 % versus 38 %, respectively (p = .033). Synchronous metastasis (p = .028) and DFI < 12 months (p = .038) were also associated with worse survival outcome, though male gender (p = .69) and oligometastatic disease (p = .62) were not. CONCLUSIONS: Adrenal metastasectomy resulted in median survival of 30 months and 5-year survival of 31 %. Shorter survival was associated with lung primary, short disease-free interval, and synchronous metastasis, but not with the presence of oligometastatic disease provided that the primary cancer and additional metastatic lesions were adequately controlled and amenable to resection.

BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer.

PURPOSE: This study was designed to examine whether available preoperative clinical parameters, including B-type Raf kinase (BRAF) V600E mutation status, can identify patients at risk for central compartment lymph node metastasis (CLNM). METHODS: Under an institutional review board-approved protocol, we conducted a single-center, retrospective review of all patients who had initial thyroidectomy for histologic papillary thyroid carcinoma (PTC) during 2010. The presence of CLNM was examined for correlation with available preoperative clinical parameters, including tumor size, gender, age, and BRAF mutation status. RESULTS: Cervical lymph node resection and molecular testing on FNAB or histopathologic specimen was performed on a consecutive series of 156 study patients with histologic PTC. Overall, CLNM was diagnosed in 37% and 46% were BRAF-mutation-positive. BRAF positivity was the only clinical parameter associated with CLNM (BRAF, p=0.002; tumor size≥2 cm, p=0.16; male gender, p=0.1; age≥45 years, p=0.3) and remained an independent predictor of CLNM on multiple logistic regression analysis (odds ratio (OR) 3.2, p=0.001). The PPV and NPV of BRAF positivity for CLNM was 50 and 74%, respectively. When restricting the analysis to the subset of 38 patients who had molecular testing performed preoperatively on FNAB, the PPV and NPV of BRAF positivity for CLNM was 47 and 91%, respectively, and BRAF positivity was still a significant predictor of CLNM on both univariate (OR 8.4, p=0.01) and multivariate (OR 9.7, p=0.02) analyses. CONCLUSIONS: Of the commonly used clinical parameters available preoperatively, the BRAF V600E mutation is the only independent predictor of CLNM in PTC and can be utilized to guide the extent of initial surgery.