This case report represents the first-time use of 4DCT to localize parathyromatosis. Parathyromatosis is a rare but problematic cause of recurrent hyperparathyroidism. Ultrasound and 4DCT may represent the best imaging modalities for identification and perioperative management to remove all affected tissue without reseeding. (AACE Clinical Case Rep. 2019;5:e384-e387)
Case Report PARATHYROMATOSIS: A RARE CASE OF RECURRENT HYPERPARATHYROIDISM LOCALIZED BY FOUR-DIMENSIONAL COMPUTED TOMOGRAPHY Abraham E Wei, DO1; Matthew R Garrett, MD2; Ankur Gupta, MD, FACE1 ABSTRACT Objective: To present a rare case of parathyromatosis Methods: We present the clinical, laboratory, and imaging findings, along with a review of the literature Results: A 33-year-old man with a history of right upper parathyroid adenoma removal years prior due to hyperparathyroidism was admitted for severe hypercalcemia (15.6 mg/dL; normal, 8.5 to 10.5 mg/dL) with elevated plasma parathyroid hormone (PTH) (882 pg/mL; normal, 15 to 65 pg/mL) Ultrasound, computed tomography (CT), sestamibi, and positron emission tomography scans were unremarkable; however, a four-dimensional CT (4DCT) of the neck showed an area of increased signal enhancement and hypervascularity without discrete nodule in the posterior right thyroid region The patient underwent parathyroid surgical exploration with right hemithyroidectomy and compartment neck dissection to remove the affected tissue PTH levels dropped to 208 pg/mL postoperatively; calcium decreased but remained elevated at 12.7 mg/dL Pathology revealed the presence of several small nodular foci of atypical hyperplastic parathyroid tissue in the right thyroid and soft tissue in the left central neck compartment consistent with parathyromatosis Submitted for publication May 14, 2019 Accepted for publication August 8, 2019 From 1Wright State University Boonshoft School of Medicine, Dayton, Ohio, and 2Southwest Ohio Ear, Nose, and Throat Specialists, Dayton, Ohio Address correspondence to Dr Abraham Wei, Wright State University Internal Medicine Residency, Wyoming Street, Dayton, OH 45419 E-mail: Abraham.wei@wright.edu DOI: 10.4158/ACCR-2019-0225 To purchase reprints of this article, please visit: www.aace.com/reprints Copyright © 2019 AACE Conclusion: This case report represents the first-time use of 4DCT to localize parathyromatosis Parathyromatosis is a rare but problematic cause of recurrent hyperparathyroidism Ultrasound and 4DCT may represent the best imaging modalities for identification and perioperative management to remove all affected tissue without reseeding (AACE Clinical Case Rep 2019;5:e384-e387) Abbreviations: CT = computed tomography; 4DCT = four-dimensional computed tomography; PTH = parathyroid hormone INTRODUCTION Parathyromatosis is a rare condition of multiple nests of hyperfunctioning parathyroid tissue It is likely either the result of spillage and seeding of parathyroid tissue around an operative area during parathyroid surgery or the change in embryologic foci of parathyroid tissue that become hyperplastic with physiologic stimuli (1) Preoperative diagnosis and subsequent treatment can be difficult Imaging is important for identification and perioperative management to remove all affected tissue without reseeding This case report describes the diagnostic challenges for this condition as well as the first-time use of four-dimensional computed tomography (4DCT) in the diagnosis of parathyromatosis CASE REPORT A 33-year-old man first presented at 28 years of age with epigastric pain and was found to have serum calcium of 18.1 mg/dL (normal, 8.5 to 10.5 mg/dL) and an elevated plasma parathyroid hormone (PTH) level of 1,199 pg/mL (normal, 14 to 72 pg/mL) Computed tomography (CT) of the neck revealed a cm nodule posterior to the superior e384 AACE CLINICAL CASE REPORTS Vol No November/December 2019 Copyright © 2019 AACE Copyright © 2019 AACE Parathyromatosis and Imaging, AACE Clinical Case Rep 2019;5(No 6) e385 right lobe of the thyroid gland and the patient underwent a right upper parathyroidectomy Repeat labs weeks later showed normalization of calcium at 9.2 mg/dL and of PTH at 64 pg/mL (Table 1) Pathology was consistent with an atypical parathyroid adenoma described as neoplastic parathyroid cells in trabecular arrangement with interspersing fibrovascular bands without mitosis nor evidence of vascular or perineural invasion Five years later, the patient developed abdominal pain, nausea, and vomiting for days and was admitted for an elevated serum calcium of 15.6 mg/dL (normal, 8.5 to 10.5 mg/dL) with an elevated PTH level of 882 pg/mL (normal, 15 to 65 pg/mL) Physical exam was only significant for mild epigastric tenderness on deep palpation Serum creatinine was also noted to be elevated at 1.6 mg/dL (normal, 0.5 to 1.4 mg/dL) attributed to poor fluid intake by the patient Urinary calcium was noted to be high at 530 mg/24 hours (normal, 50 to 150 mg/24 hours) and serum 25-hydroxyvitamin D was low at 21 ng/mL (normal, >30 ng/mL) Intravenous normal saline given during the hospital stay improved serum creatinine to baseline level of 1.0 mg/dL Serum calcium continued to remain high and greater than 14 mg/dL Cinacalcet 30 mg twice-a-day was then initiated Ultrasound of the neck, technetium-sestamibi scan with single photon emission CT, CT soft tissue neck with contrast (Fig A) were all unremarkable CT chest/abdomen/pelvis with contrast and positron emission tomography (PET) scan did not show any evidence of ectopic tumors or distant metastasis A 4DCT of the neck was then obtained that showed an area of increased signal enhancement and hypervascularity without a discrete nodule in the posterior right thyroid region near the site of prior parathyroid adenoma removal (Fig C) The patient then underwent parathyroid surgical exploration with right hemithyroidectomy, and intraoperative frozen section analysis showed the presence of abnormal parathyroid tissue intimately involved with the right thyroid lobe Intraoperative biopsies of right inferior, left superior, and left inferior parathyroid appeared normal and were not hyperplastic Central compartment neck dissection was completed without additional abnormal parathyroid tissue identified Postoperatively, calcium level decreased but remained elevated at 12.7 mg/dL Cinacalcet, which had been held before surgery, was restarted Three days after surgery, serum calcium improved and stabilized at 9.9 mg/dL and PTH improved to 174 pg/mL The patient was subsequently discharged Pathology showed the presence of several small nodular foci of atypical hyperplastic parathyroid tissue without invasive growth in the right thyroid and soft tissue in the left central neck compartment consistent with parathyromatosis DISCUSSION Parathyromatosis is a rare cause of recurrent hyperparathyroidism consisting of multiple nodules of benign hyperplastic and hyperfunctioning parathyroid tissue after spillage and seeding of parathyroid tissue during parathyroid surgery Another cause of parathyromatosis describes embryonic rests of parathyroid tissue that undergo hyperplasia under the influence of physiological stimuli such as end-stage renal disease Our patient’s past operative report on his parathyroid adenoma removal makes no mention of spillage of parathyroid tissue, but this can still be a possible cause of his parathyromatosis Otherwise, this may be some form of disorder which allows local cells to differentiate into parathyroid cells Epidemiologic data reveal parathyromatosis affects people across a wide age range from 19 to 87 years old with the majority being female or having end-stage renal disease, which makes our patient different Table Patient Laboratory Values First presentation (parathyroid adenoma with parathyroidectomy) Event Calcium (mg/dL, normal 8.5-10.5 mg/dL) PTH (pg/mL, normal 14-72 pg/mL) day after surgery 9.0 NR On admission prior to surgery days after surgery (discharge day) weeks after surgery Second presentation years after first presentation (parathyromatosis with hemithyroidectomy) 18.1 8.8 9.2 1,199 NR 64 Event Calcium (mg/dL, normal 8.5-10.5 mg/dL) PTH (pg/mL, normal 15-65 pg/mL) day after surgerya 12.7 NR On admission prior to surgery days after surgery days after surgery (discharge day) Abbreviations: NR = not reported; PTH = parathyroid hormone Values in bold are out of normal range aStarted oral cinacalcet 30 mg twice a day 15.6 10.0 9.9 882 NR 174 e386 Parathyromatosis and Imaging, AACE Clinical Case Rep 2019;5(No 6) A B C D Copyright © 2019 AACE Fig A, Regular CT with contrast B, 4DCT without contrast C, 4DCT arterial phase with contrast enhancement in right posterior thyroid (red arrow) where previous parathyroid adenoma was located and resected D, 4DCT 90-second delay (venous) phase CT = computed tomography; 4DCT = four-dimensional computed tomography from most cases (2,3,4) Parathyromatosis is often refractory to surgical intervention due to incomplete removal and reseeding of hyperplastic parathyroid tissue (2) Mortality from complications of parathyromatosis can be high with one case series reporting a mortality rate of 40% (5) Successful imaging of these small nodules of hyperplastic parathyroid tissue and obtaining a preoperative diagnosis is difficult, but it enhances the chances of surgically removing all involved tissue In a case series of 10 patients, only 40% of patients were successfully diagnosed with parathyromatosis preoperatively (3) Ultrasound can sometimes detect scattered hypoechoic, vascular small nodules in thyroid tissue suggesting the diagnosis (6) CT, sestamibi, and PET scans can reveal findings of parathyromatosis but are often negative (2) In our patient, all these modalities failed to localize parathyromatosis We then obtained a 4DCT to localize the affected tissue and optimize perioperative management and surgical resection 4DCT may be a popular imaging option to localize and diagnose parathyromatosis in the future 4DCT is a relatively new imaging modality first introduced in 2006 that is utilized in the diagnosis and characterization of suspected parathyroid adenoma as well as for brain aneurysms, arterial-venous malformations, musculoskeletal conditions such as joint instability, and internal impingement (7) Intravenous contrast is given and CT scans are obtained at specific time-points corresponding to venous and arterial circulations which enhances the quality of the images In a study of 45 patients who previously underwent parathyroidectomy, sensitivity for localization of hyperfunctioning parathyroid tissue for reoperation was 88% for 4DCT compared to 54% for sestamibi imaging (8) The enhanced capability to image abnormal hypervascular tissues with 4DCT makes it a good diagnostic test of choice for localizing parathyromatosis Pathology of parathyromatosis often reveals multiple nests of hyperplastic parathyroid cells with a lack of real capsule of the parathyroid tissue and without lymphvascular invasion that is seen in an adenoma or cancer (9) Definitive treatment is surgical removal of all offending tissue; however, it is difficult to identify and remove all the disseminated tiny nodules of hyperplastic parathyroid tissue that often adhere closely to scar tissue thereby hindering excision Even the more aggressive measure of total thyroidectomy does not ensure cure as parathyromatosis tissue can remain in surrounding muscular or fat tissue (3) Many cases are often refractory to or incompletely cured with surgery, such as in our case where postoperative PTH and serum calcium levels remained elevated, indicating incomplete removal of all affected parathyromatosis tissue Without localization via 4DCT, less parathyromatosis tissue would have been removed or more tissue seeding might have occurred if blind surgical manipulation was done, likely leading to worse outcomes After failed surgical intervention, suppression of PTH production with the calcium mimetic cinacalcet is the pharmacologic treatment of choice Bisphosphonates may also be added to both decrease calcium levels and to minimize the deleterious effect of PTH on the bone, especially if there is concern for concomitant osteopenia or osteoporosis (2) Several cases also successfully used vitamin D analogs (e.g., paricalcitrol, doxercalciferol) to further inhibit PTH synthesis and parathyromatosis activity, although at a cost of increasing serum calcium level (6,10) Even with phar- Copyright © 2019 AACE Parathyromatosis and Imaging, AACE Clinical Case Rep 2019;5(No 6) e387 macologic interventions, parathyromatosis activity may not be controlled Ideally, this condition should be prevented in the first place by avoiding rupture of the parathyroid capsule during parathyroidectomy CONCLUSION This case represents the first reported use of 4DCT to localize parathyromatosis tissue 4DCT is very sensitive in detecting hypervascular hyperparathyroid tissue This may become a popular imaging modality to localize and diagnose parathyromatosis However, parathyromatosis may be refractory to surgical and pharmacologic interventions in several cases DISCLOSURE The authors have no multiplicity of interest to disclose REFERENCES Reddick RL, Costa JC, Marx SJ Parathyroid hyperplasia and parathyromatosis Lancet 1977;1:549 Hage MP, Salti I, El-Hajj Fuleihan 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G Parathyromatosis: a rare yet problematic etiology of recurrent and persistent hyperparathyroidism Metabolism 2012; 61;762-775 Matsuoka S, Tominaga Y, Sato T, et al Recurrent renal hyperparathyroidism. .. hyperparathyroidism caused by parathyromatosis World J Surg 2007;31:299-305 Fernandez-Ranvier GG, Khanafshar E, Jensen K, et al Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis? Cancer