Feasibility of Intraoperative Parathyroid Hormone Monitoring in Minimally Invasive Surgery

Background and Objectives There has been a long debate on whether intraoperative parathyroid hormone (IOPTH) monitoring is mandatory or not in the excision of a single abnormal parathyroid gland. The aim of this study is to suggest a new criteron of IOPTH monitoring. Subjects and Method We retrospectively analyzed 31 patients who underwent parathyroidectomy from 2005 to 2019. Patients had IOPTH not measured and those with secondary hyperparathyroidism were excluded. IOPTH was measured preoperatively (EX00), at 10 minutes (EX10) and 20 minutes (EX20) after the excision and analyzed. We determined the surgery as a ‘successful excision of lesion (SEOUL)’ when it met the following criteria: criterion 1) the level of EX10 or EX20 decreased under the upper normal or under upper limit of parathyroid hormone (65 pg/mL); criterion 2) EX20 decreased below 50% of EX00 and less than 195 pg/ mL (3 times the upper normal limit); criterion 3) multiglandular disease. Results Twenty-five patients among 31 patients were included this study (M:F=8:17). Twenty- two patients were suspected of single lesion and three patients of multiple lesions on preoperative images (99mTc-sestamibi scan, neck CT, and PET-CT). IOPTH of EX00, EX10, and EX20 were 488.92±658.74, 121.36±134.73, and 92.44±111.55 pg/mL, respectively. Sixty-four percent patients (16/25) met the criterion 1. Six patients (24%) successfully excised a lesion meeting the criterion 2. Three patients had multiglandular disease, meeting the criterion 3. Conclusion Our new criteria suggest when we could stop the procedure. If the level of IOPTH does not meet the SEOUL criteria, it means that there might be more lesions.

Treatment-Resistant Hypercalcemia Secondary to Ectopic PTH Hypersecretion From Disseminated Ovarian Cancer

Background: Hypercalcemia of malignancy (HCM) can present secondary to hypersecretion of parathyroid hormone (PTH)-related protein (PTHrP) from malignant tumors, but rare cases of HCM have also been documented due to inappropriate PTH secretion from ectopic neoplasms. Here, we report an unusual case of HCM due to hypersecretion of PTH from a disseminated mucinous ovarian adenocarcinoma. Case Presentation: A 45-year-old female presented with confusion, constipation, fatigue, and abdominal pain two weeks after total abdominal hysterectomy with bilateral salpingo-oophorectomy and suboptimal debulking of a newly discovered left ovarian mucinous adenocarcinoma with metastasis to the bladder, parametrium, vagina, right ovary, and rectosigmoid. Subsequent CT revealed numerous bilateral pulmonary nodules, hilar adenopathy, liver lesions, and abdominal adenopathy. On exam, she was tachycardic and hypertensive with diaphoresis, dry mucous membranes, respiratory distress, guarded abdominal tenderness, and altered mental status. Her labs were significant for a serum calcium of 21.7 mg/dL, creatinine of 1.93 mg/dL, ferritin of 2,379 ng/mL, leukocytosis of 21.9 bil/L, PTH of 1,061 pg/mL, and PTHrP of 29 pmol/L. Ectopic PTH secretion was highly suspected after negative parathyroid ultrasound. Pamidronate (60 mg IV), calcitonin (200 U IM), and fluid resuscitation were unable to normalize her serum calcium, resulting in the need for dialysis and subsequent continuous renal replacement therapy. Further intervention with denosumab (120 mg SQ), etelcalcetide (5 mg IV), and cinacalcet (60 mg PO) was also attempted. Serum calcium began to decline, but repeat PTH resulted greater than 2,500 pg/mL. Unfortunately, the patient died just one week into her hospital course from septic shock and multi-organ system failure. Discussion: Hypercalcemia of malignancy typically arises from tumor secretion of PTHrP, cytokine release from osteolytic metastases, or tumor production of calcitriol. In cases of hypercalcemia due to excess PTH secretion, primary parathyroid etiologies are typically considered while ectopic PTH-secreting tumors are rare. PTH staining of biopsy specimens and total body sestamibi scan may prove useful in the early detection and treatment of these tumors, but HCM offers a poor prognosis with mean survival of 2 to 3 months and in-hospital mortality of 6.8%. Currently, there are only three cases in the reported literature of ectopic PTH-induced hypercalcemia related to ovarian cancer. To our knowledge, this is the fourth reported case. Conclusion: Ectopic PTH-secreting tumors carry a poor prognosis and should be considered in cancer patients presenting with PTH-associated hypercalcemia. Biopsy staining for PTH and total body sestamibi scan may assist in the early detection of these tumors, but current treatment strategies offer suboptimal outcomes.

Rare Case of Severe Hypercalcemia Secondary to Atypical Sestamibi Negative Parathyroid Cystic Adenoma

Primary hyperparathyroidism (PHPT) is defined as excessive secretion of parathyroid hormone (PTH) originating from the parathyroid gland. The most common cause is a single parathyroid adenoma which is typically solid. Cystic parathyroid adenomas (CPA) are the cause of about 1–2% of cases of primary hyperparathyroidism. It is known that cystic parathyroid adenomas are a result of degeneration of an existing parathyroid adenoma. SestaMIBI is an imaging study based on uptake of radioactive technetium99 and used to localize parathyroid adenomas. We describe an unusual case of severe hypercalcemia secondary to 99mTc sestaMIBI negative atypical parathyroid cystic adenoma. A 56-year-old male presented to our facility with nausea and vomiting. His past medical history included hypertension and hepatitis C with no history of fractures or kidney disease. Physical examination was normal. Upon admission the patient was afebrile with blood pressure of 170/120 mmHg and heart rate of 62 bpm. Chemistry showed Calcium of 14.5 mg/dL (8.6–10.2mg/dL), phosphorus 2.2 (2.7–4.5) mh/dL, magnesium 1.8 (1.7–2.6)mg/dL, intact PTH of 375 (15–65) pg/mL, PTH-related peptide <2.0 pmol/L(<2 pmol/L), 25-OH vitamin D of 19 ng/ml (30–80), Creatinine 1.22 (0.7–1.2)mg/dL, alkaline phosphatase 95 (40–129) units/L. He was started on aggressive hydration, calcitonin 4 units/kg, 4 mg of IV Zolendroninc acid. Neck sonogram revealed a large, complex, predominantly anechoic lesion with solid vascular components and thick internal septations in the inferior and medial aspect of the right thyroid lobe measuring 3 x 2 x 5.5 cm. Findings were confirmed with CT of the neck. Since Sestamibi scan (planar and SPECT/CT) did not show uptake in parathyroid glands, the cyst was thought to be of thyroid origin. Fine needle aspiration was not able to detect cellular material, but PTH was >100 pg/ml on the FNA sample. Otolaryngology service was consulted for parathyroidectomy. During the surgical treatment, the right upper parathyroid gland was removed with no changes in serum PTH. Next, the cystic lesion was removed with normalization of serum PTH (from 218 pg/ml to 35.2 pg/ml respectively). Intraoperative frozen section analysis was read as a cystic parathyroid adenoma. The final pathology report revealed cystic parathyroid tissue favoring parathyroid adenoma with focal atypia. Hypercalcemia resolved. Conclusions: Atypical cystic parathyroid adenomas are a rare cause of PHPT. 90% of parathyroid cysts are nonfunctional. Above mention is a case of a patient presenting with hypercalcemic crisis secondary to cystic parathyroid adenoma, which posed a diagnostic challenge as both neck ultrasound and 99mTc sestaMIBI scan were inconclusive. These findings should trigger suspicion for functional parathyroid lesions. Cystic components should be evaluated for PTH levels and if significantly elevated should be treated as a parathyroid adenoma.

Novel Method in Performing PTH Washout for Localizing Parathyroid Adenoma: Case Report & an Institute Experience in Qatar

Introduction: Primary hyperparathyroidism (PHPT) is a common cause of hypercalcemia and mostly caused by benign solitary benign adenoma (80 to 85 %). Definite treatment is the surgical removal. The most commonly used diagnostic modalities are Sestamibi scan and neck ultrasound (US) which can be inconclusive in some cases. Parathyroid hormone (PTH) washout obtained with ultrasound guided FNA may be useful to accurately localize the adenoma. In our study we describe a novel method for PTH washout. Methods: First, blood samples are drawn from the patient’s peripheral vein and placed in two yellow top tubes (3 ml of blood in each tube). 1 ml of normal saline (NS) will be add to Tube # 1 (Control tube). The suspected parathyroid lesion aspirate is obtained via US guided FNA. It is washed in 1 ml of NS and added to tube #2 (PTH washout tube). Both tubes are sent to our local laboratory for PTH assay. The ratio of PTH in PTH washout tube to control tube (PTH W/C ratio) is calculated and considered positive if more than 2. Results: Total 16 patients (12 females and 4 males) underwent the PTH washout procedure. All patients had PHPT. Out of 16 patients, 13 had inconclusive Sestamibi scan while 3 patients didn’t have the scan due to pregnancy. PTH W/C ratio was positive in 13 patients (ruled in) and negative (ruled out) in 3 patients. All patients underwent parathyroid surgery. The operative findings and pathology report were consistent with PTH W/C ratio findings. i.e. parathyroid hypercellularity was found in all the 13 patients ruled in by PTH W/C ratio. Post-surgery, biochemical parameters normalized in all. Conclusion: PTH washout is an important tool in localizing parathyroid lesion in PHPT when Sestamibi scan cannot be done or if it is inconclusive. PTH W/C ratio can be performed with our novel method to accurately localize the PTH lesion and improve surgical outcome.

Calcium of 19mg/dL and Yet Asymptomatic

Lithium is a commonly used medication for Bipolar disorder. Lithium induced hyperparathyroidism is a rare disorder but leading cause of hypercalcemia in patients receiving Lithium treatment. Lithium may lead to exacerbation of pre-existing hyperparathyroidism or it may increase set point for calcium for PTH suppression. We present a case of 65 year old female presented with hypercalcemia of 19mg/dl. She was sent by PCP office for hypercalcemia. She did not have any complains and was completely asymptomatic. Her history includes hypertension, Bipolar disorder and Diabetes mellitus type 2. She has not been able to get her labs drawn because of COVID-19. She was only having Tele visits with Psychiatrist. Her mood and bipolar symptoms were under controlled. She denies any abdominal pain, headache, visual problems, polyuria, polydipsia, numbness or tingling. She was given IV fluids and calcium was monitored. Her PTH was 65mg/dl, CBC and metabolic panel normal otherwise. Her Sestamibi scan was negative for parathyroid adenoma. Her lithium level was 4mg/dl. Lithium was discontinued after Psychiatry consultation. Her calcium came down to 9mg/dl after aggressive fluid resuscitation. Her calcium, parathyroid and lithium levels were monitored for next 6 months. Given her asymptomatic course she was not started on any calcium lowering medication. Her lithium level normalizes after one year of abstinence. A patient who is started on Lithium therapy should be monitored for hypercalcemia, hyperparathyroidism and nephrogenic diabetes.

A Challenging Diagnosis of Primary Hyperparathyroidism in an Adolescent Female

Background: Hypercalcemia secondary to primary hyperparathyroidism (PHPT) is less common in children than adults. Single parathyroid adenoma is commonly the cause of primary hyperparathyroidism in children. Clinical Case: We present a 15-year-old female with one-week history of abdominal pain despite taking over the counter antacids. Her initial work up by her primary care provider revealed serum calcium of 11.8 mg/dL (9.0–11.5) and creatinine of 0.8 mg/dL (0.4–1.2). A week later, she presented to the emergency department with same complaint. In ED, she was found to have hypercalcemia (12.8 mg/dl) with elevated parathyroid hormone (PTH) at 78.5 pg/mL (15–65). Her random urine calcium creatinine ratio was high at 2.1. Her 25OHD was 25 ng/mL (30–100). She had negative urine pregnancy test but had trace ketones, leukocyte esterase, blood and bacteria. CBC and CMP were otherwise unremarkable. She continued to complain abdominal pain with nausea, decrease appetite, fatigue, and general muscle weakness. There was no known family history of calcium or metabolic bone disorders. Her vital signs and physical exam were normal. Subsequent labs showed mild improvement of calcium between (11–12.3 mg/dL), PTH between 54.5 and 77 pg/mL, normal thyroid function. Ionized calcium was mildly elevated 6.0 mg/dL (4.5–5.3) but her repeat 25OHD was low at18 ng/mL. Serum phosphorus levels were relatively normal with lowest level of 2.5 mg/dL (2.7–4.5). Gliadin Deamidated IgA was detectable 15 U/mL (< 15.0 U/). Ultrasound of abdomen was significant for nonspecific mild hepatomegaly; kidneys were normal in size and appearance. Ultrasound of thyroid was significant for probably intrathyroid parathyroid, measuring 6 x 8 x 8 mm. Tc-Sestamibi scan did not confirm a parathyroid adenoma. Genetic testing for MEN-1 was negative. FHH- related genes (i.e. CASR) was positive for p.R990G variant resulting in a mild gain of function of the calcium-sensing receptor. Although previous Tc-Sestamibi scan was unremarkable, an over read of it raised a concern for questionable uptake in the left superior lobe. SPEC-CT demonstrated possible abnormal parathyroid tissue in the upper pole of the left thyroid. FNA of the left thyroid nodule confirmed likely intrathyroidal parathyroid adenoma. Subsequent follow up and treatment, including parathyroidectomy, was done by another institution. She underwent a left parathyroidectomy with normalization of serum calcium and PTH levels post operatively (10.1 mg/dl and 8 pg/mL, respectively) and has complete resolution of her previous abdominal and gastrointestinal symptoms. Conclusion: PHPT is uncommon in children and adolescents and is typically associated with a single parathyroid adenoma. High index of suspicion is key for early diagnosis of PHPT despite a negative Tc-Sestamibi initially.

Cushing’s Disease (CD) Due to ACTH-Secreting Pituitary Microadenoma Incidentally Discovered on a Sestamibi Scan for Primary Hyperparathyroidism

Introduction: MIBI scintigraphy is commonly being used for the preoperative localization of parathyroid adenomas. Multiple studies showed MIBI uptake in pituitary adenomas are likely due to higher metabolic activity. When hyperfunctioning pituitary adenomas were reported, both had CD [1,2]. We present the third case of increased pituitary uptake on a MIBI scan later confirmed as CD. CaseA 64-year-old Caucasian female s/p renal transplantation for RPGN who presented for evaluation of hypercalcemia. Evaluation confirmed primary hyperparathyroidism with persistently elevated PTH levels 74-108 pg/ml (11-68), serum calcium levels 10.0-10.4 mg/dl (8.4-10.3), albumin 4.1-4.3 g/dl (3.6-5.1), phosphorus 3.0-3.2 mg/dl (2.5-4.5), creatinine 0.94-1.07 mg/dl. 24-hour urine calcium 60 mg/day (35-250). Vitamin D-25 OH level was 37 ng/dL (30-100). A sestamibi scan showed uptake in the right lower parathyroid, the midsternal chest region and the pituitary gland. MRI of the pituitary revealed a 7mm cystic pituitary microadenoma in the right posterior pituitary. CD was confirmed by the findings of persistently elevated 8 AM serum cortisol levels of 28.4 and 24.2 mcg/dl (4-22), ACTH levels of 59 and 39 pg/ml (10-48), and an elevated plasma free cortisol of 1.43 mcg/dl (0.07-0.93). CT of the abdomen showed L adrenal thickening suggesting adrenal hyperplasia from CD. Plasma cortisol suppressed to 1.2 mg/dl following 1 mg of dexamethasone. 24 urine for free cortisol 26.7 mcg/day (4-50). The patient had no proximal muscle weakness, striae or Cushingoid facial features. She had no hyperglycemia or hypertension. Patient was diagnosed with an ACTH secreting pituitary microadenoma with mild CD and adrenal hyperplasia. Her DXA scan showed osteoporosis. Genetic testing for MEN1 mutation was negative. Patient did not wish surgery for either her hyperparathyroidism or her CD and is being evaluated for medical treatment of hypercortisolism. Conclusion: There are two prior case reports of an incidentally discovered pituitary adenoma on sestamibi scan later diagnosed as CD [1,2]. Corticotrophs may have a strong affinity for sestamibi. Our case is the first, to our knowledge, of pituitary MRI confirmation of the ACTH secreting pituitary incidentaloma initially suspected by pituitary uptake on a sestamibi scan in a patient with hyperparathyroidism. Reference1. Kuhadiya ND et al. Incidentally Discovered ACTH-Secreting Pituitary Adenoma on a Sestamibi Scan in a Patient With Hyperparathyroidism. AACE Clinical Case Reports. 2015;1(3):e152-5. 2. Gierach M et al. The case of Cushing’s disease imaging by SPECT examination without manifestation of pituitary adenoma in MRI examination. Nuclear Medicine Review. 2005;8(2):137-9.

Original Preoperative Localization Technique of Parathyroid Adenomas by 3-Dimensional Virtual Neck Exploration

Objective. Preoperative imaging in primary hyperparathyroidism (PHPT) is essential for planning of parathyroidectomy—particularly for selection of a minimally invasive approach. The objective of this cohort study was to evaluate the diagnostic precision of 3D virtual neck exploration (3D-VNE), to evaluate its impact on choice of surgical approach, and to document the correlation with long-term outcomes. Methods. 235 consecutive patients with PHPT were studied (January 2014 to December 2018), with 6-month follow-up. 220 patients had a preoperative computed tomography (CT), 172 of these had a 3D-VNE based on the CT, and 226 patients had a Tc-99m sestamibi scan. Results. Sensitivity of exact, per gland, adenoma localization was 57.09% (95% CI: 50.85–63.10%) for nonspecialized radiologist interpretation of CT scan, 58.17% (95% CI: 51.99–64.10%) for Tc-99m sestamibi scan, and 90.21% (95% CI: 85.21–93.64%) for 3D-VNE, and thereby favoring 3D-VNE compared to CT scan alone (OR 34.5, 95% CI: 9.19–290.56%, P < 2.2 × 10−16) and to Tc-99m sestamibi scan (OR 16.25, 95% CI: 6.05–61.42%, P = 3.1 × 10−15). Specificity was 87.38% for CT scan, 86.36% for 3D-VNE, and 90% for Tc-99m sestamibi scan ( P > .05). The cure rate was 100%. The long-term recurrence rate (RR) was 2.978%. The RR was 1.324% in the video-assisted parathyroidectomy group of 151 patients and 5.952% in the group of 84 patients with cervicotomy ( P = .0459). Conclusion. CT-based 3D-VNE proved to be the most accurate localizing study in PHPT and aided in selecting patients for targeted minimally invasive parathyroidectomy, which was associated with the lower recurrence rate. 3D-VNE could be proposed as a first-line imaging study in patients with PHPT.