Atypical parathyroid adenomas as a rare cause of primary hyperparathyroidism - in an academic institution experience

BACKGROUND Primary hyperparathyroidism (PHPT) is caused by benign and malignant conditions. Most commonly by typical adenoma/single gland disease (PA) - this is 80-85% cases of PHPT. Parathyroid hyperplasia or multiple gland disease accounts for 10-15% of cases of PHPT. Atypical parathyroid adenoma (APA) and carcinoma (PC) - very rare conditions - are both responsible for PHPT in approximately 0,5 - 1,5% of cases. OBJECTIVES To estimate occurrence of atypical parathyroid adenoma, parathyroid carcinoma and parathyroid hyperplasia along with characterize them based on their etiology, clinical presentation, diagnosis and treatment METHODS We performed a retrospective study and enrolled 1,019 patients with primary hyperparathyroidism undergoing parathyroidectomy at academic Department of General and Endocrine Surgery between 1983 and 2018. RESULTS Out of 1,019 cases of primary hyperparathyroidism, 850 (83.4%) cases were due to typical parathyroid adenoma (PA), 135 (13.2%) cases were due to parathyroid hyperplasia, 29 (2.8%) cases were due to parathyroid carcinoma (PC), and 5 (0.5%) cases were due to atypical parathyroid adenoma (APA).

Do patients with atypical parathyroid adenoma need a close follow-up?

Context Atypical parathyroid adenomas (APAs) are neoplasms with uncertain malignant potential but lack unequivocal histological signs of malignancy. Objective To retrospectively evaluate the clinical and biochemical profiles of patients with APA, the outcome after parathyroidectomy (PTX), and the presence of CDC73 germline and somatic mutations. Design Monocentric study on consecutive patients undergoing PTX for primary hyperparathyroidism (PHPT) between June 2000 and December 2020. Patients Fifty-eight patients with a confirmed histopathological diagnosis of APA. Age and sex-matched controls with parathyroid adenoma (PA) were also included. Results Fifty-four patients had sporadic PHPT and four familial isolated hyperparathyroidism (FIHP). Thirty-four patients (59%) had a symptomatic disease. Serum calcium and PTH levels were significantly higher in symptomatic compared to asymptomatic patients (P=0.048 and 0.008, respectively). FIHP patients were younger than the sporadic counterpart (30±17yr vs. 55±13 yrs). APA patients had significantly higher serum calcium and PTH levels and lower 25(OH)D concentration, BMD and T-score at 1/3 distal radius compared to those with PA. Four of 56 APA patients displayed a CDC73 germline mutation. No somatic CDC73 mutation was identified in 24 tumor specimens. The mean follow-up after surgery was of 60±56.4 months. All but six patients (90%), five with apparently sporadic PHPT and one with FIHP, were cured after surgery. Conclusions The large majority of patients with APA, despite a moderate/severe phenotype, have a good prognosis. Germline CDC73 mutation-positive patients had a higher rate of persistent/recurrent disease. CDC73 gene alterations do not seem to have a relevant role in the tumorigenesis of sporadic APA.

Clinical Behaviors of Atypical Parathyroid Adenomas

Background: Atypical parathyroid adenoma is a rare entity that share some pathology features of parathyroid carcinoma such as fibrosis. Little is known about the clinical behavior of atypical parathyroid adenomas. Pathologically, it is defined as a hypercellular parathyroid lesion with intratumoral banding fibrosis, mitotic figures, trabecular growth and presence of tumor in the surrounding capsule but lacks unequivocal evidence of invasion, such as invasion to peritumoral vessels, perineural invasion and surrounding structures. Methods: A retrospective study of 15 consecutive patients with atypical parathyroid adenoma treated at a single center between 2010 and 2020 was performed. Patient demographics, clinical characteristics, biochemical profile, indications for surgery, preoperative localization studies, intraoperative findings, histopathological characteristics, disease recurrence or persistence and survival were collected. Results: 7 of 15 were female with a median age of 62 (IQR: 52–67). Five of the 15 patients (33%) were re-operative. No patients presented with palpable neck mass. Presentations were consistent with usual primary hyperparathyroidism. Average calcium on presentation was 11.2, and average PTH was 199. One patient had known MEN1 syndrome and one patient had family history of hyperparathyroidism but had negative genetic testing. Most patients 12/15 had correctly localizing imaging pre-operatively with the other 3 having equivocal or non-localizing studies. Two patients did not have biochemical resolution of hyperparathyroidism, both were re-operative. Of the patients with biochemical cure, 6 did not have follow up beyond 6 months, and 7 patients had long term follow up with persistent biochemical resolution and no recurrence of disease for a median of 4 years (IQR: 3.75–9.25). On review of pathology, no patients had invasive features and all patients had presence of thick fibrous bands or capsule. Conclusion: Patients with atypical adenoma have good response to surgery and low recurrence rates. Reoperation with associated scarring and fibrous bands can confound pathological findings. Our experience shows that patients found to have atypical parathyroid adenoma at their primary operation with resulting biochemical cure can be followed long-term with seemingly indolent and nonaggressive behavior.

Atypical Parathyroid Adenoma in a Young Man

Patient is a 38-year-old man who developed sudden onset of pain in the upper left arm while carrying a case of water. The pain recurred periodically over the next few months. He presented to the emergency department where imaging showed a pathologic fracture in the proximal left humerus through a lytic lesion. Laboratory testing showed: calcium 13.8 mg/dL (8.5–10.1 mg/dL), 25-OH vitamin D 8 ng/mL (31–100 ng/mL), parathyroid hormone 1583.1 pg/mL (18.5–88 pg/mL). Neck ultrasound showed a complex nodule in the left neck measuring 4.2 x 1.7 x 2.5 cm. Subsequent biopsy of the left arm lesion showed a Brown tumor. The patient was referred to endocrinology. There was concern for parathyroid carcinoma given the elevated parathyroid hormone and large neck lesion. Technetium-99m sestamibi scan showed a 4.1 x 2.6 x 2.5 cm mass posterior to the left thyroid lobe. He subsequently underwent left hemithyroidectomy and parathyroidectomy. Pathology revealed a 3.1 cm parathyroid mass with scattered fibrous bands, foci of prominent nucleoli and foci of sheet-like trabecular and spindled architecture. It was without necrosis, lymphovascular invasion, perineural invasion, increased mitotic activity, atypical mitoses or invasion into adjacent structures. Thus, it was classified as an atypical parathyroid adenoma. Primary hyperparathyroidism is the third most common endocrine disorder, but fewer than 2% occur as a result of an atypical parathyroid adenoma. Patients with an atypical parathyroid adenoma tend to have a more dramatic clinical presentation compared to those with classic adenoma. We see higher calcium and parathyroid hormone levels. Atypical parathyroid adenomas are classified as such due to other features which place the lesion at a higher risk for malignant behavior including higher mitotic activity, adherence to adjacent structures, banding fibrosis and a growth pattern that is either solid or trabecular. In contrast to parathyroid carcinoma, atypical parathyroid adenomas do not show invasion into the surrounding tissues or lymphatic/vascular vessels, and there should be no evidence of metastatic disease. The exact definition of an atypical parathyroid adenoma varies among institutions, and recognition of the defining features (or lack thereof) necessitates an experienced endocrine pathologist. Due to their uncertain malignant potential, patients with an atypical parathyroid adenoma should undergo routine surveillance for recurrence. Routine follow-up of calcium, parathyroid hormone and imaging is indicated to detect for recurrence. A CDC73 germline mutation is associated with recurrence compared to CDC73-negative patients. Parafibromin expression is also thought to play a role although studies so far have had discrepant results.

Benign, Malignant or Something in Between: A Rapidly Developing Atypical Parathyroid Adenoma

Introduction: Although Primary Hyperparathyroidism (PHPT) is the third most common endocrine disorder, parathyroid carcinoma and atypical parathyroid adenoma are the rarest of endocrine tumours. The true incidence of atypical parathyroid adenomas has been elusive to endocrinologists since it is not possible to differentiate clinically between parathyroid carcinoma and atypical parathyroid adenomas before histological analysis. Atypical parathyroid adenoma represents a group of an intermediate form of parathyroid neoplasms with uncertain malignant potential. The majority of patients present with hypercalcaemia, however the development of atypical adenoma in patients with known PHPT is extremely rare. Clinical Case: A 78-year-old gentleman presented at the emergency department with lethargy and slurred speech which had started 1 week ago. Blood tests revealed severe hypercalcaemia. (Ca 4.98 mmol/L, PTH 114.2 pmol/L). The patient had a background of primary hyperparathyroidism which was diagnosed due to incidental mild hypercalcaemia (Ca 2.71 mmol/L, PTH 17.57 pmol/L, 25OH-vitamin D3 55 nmol/L). 2 weeks prior to presentation to the Emergency Department calcium and PTH levels were stable. On clinical examination, he was found mildly confused with no other clinical findings. No precipitating factors were identified. Hydration with IV crystalloids commenced and bisphosphonate IV was given. In view of PHPT Cinacalcet was added to treatment (30 mg BD). While the calcium levels seemed to improve initially, (lowest level achieved Ca 3.05 mmol/L) a week later they started to rise gradually. Hypercalcaemia proved refractory to medical treatment despite concomitant use of aggressive hydration, increased cinacalcet dose, second intravenous bisphosphonate, and intravenous calcitonin. Neck U/S revealed a probable parathyroid adenoma measuring 2cm axially at the inferior pole of the left thyroid lobe. In view of the severity and refractory nature of hypercalcaemia, a PET CT was requested which identified an 18 mm soft tissue mass in the left lower neck posterior to the left thyroid lobe with moderate to intense FDG uptake. There was no evidence of increased uptake elsewhere. The patient required 2 sessions of haemodialysis to maintain calcium levels around 3.5 preoperatively. He underwent parathyroidectomy with histological findings in keeping with atypical parathyroid adenoma. Gradual reduction of calcium levels was noted post-operatively with the lowest on day 10 (1.99) when he was started on oral calcium supplementation. The patient remains under follow-up with normal calcium levels 6 months postoperatively while remains on calcium and vitamin D3 supplements. Conclusion: To our knowledge, this is the only case of a patient with known primary hyperparathyroidism and mild hypercalcaemia, to develop severe parathyroid crisis with refractory to medical management hypercalcaemia within 2 weeks. Prompt surgical intervention remains of paramount importance in the management of these patients. They should have lifelong follow up in the view of uncertain malignant potential of the atypical parathyroid adenoma.

Ectopic Atypical Parathyroid Adenoma Presenting With Pancreatitis

Background: Atypical Parathyroid Adenoma (APA) and parathyroid carcinomas (PC) are rare parathyroid tumors (<1%) causing primary hyperparathyroidism. We present a case of ectopic APA in the left anterior mediastinum. Case: A 38 year old male with hyperlipidemia admitted for acute pancreatitis noted to have calcium level of 13.4 mg/dl (8.6–10.3mg/dl) in the absence of family history of hypercalcemia or kidney stones. He was treated with zoledronic acid, intravenous fluids and calcitonin for hypercalcemia. Pancreatitis resolved with fluid management. Calcium on discharge was 9.9 mg/dl. 8 week follow-up labs showed PTH of 420 pg/ml (14–64 pg/ml), calcium 10.2 mg/dl, phosphorus 1.9 mg/dl (2.5–4.5 mg/dl), vitamin D 19 ng/ml (30–100 ng/ml), 24-hour urinary calcium 115 mg/24 hour (55–300 mg/24 hour) and calcium to creatinine ratio 0.41. Hence diagnosis of primary hyperparathyroidism was made but given the degree of calcium and PTH elevation there was a concern for PC. Ultrasound of the neck demonstrated no abnormality. Sestamibi scan showed irregular focal accumulation of radiotracer in the left upper mediastinum suggestive of mediastinal ectopic parathyroid adenoma (EPA). CT chest with contrast showed a 3.9 x 2.2 x 3.4cm lobulated, heterogenous, hypodense, minimally enhancing mass in the left anterior prevascular space. Diagnosis of EPA was made and he underwent left video assisted thoracic surgery. Operative findings showed a multilobular mass at the level of the aortic arch between vagus and phrenic nerves. Intraoperative PTH went from 1124 pg/ml pre-incision to 160 at 15-minute post-excision. Postoperative calcium was 9.6 mg/dl and PTH 51 pg/ml. Final pathology showed 3.7 x 2.5 x 2cm, hypercellular parathyroid with prominent fibrous band and parafibromin retention compatible with APA. Discussion: APA is an intermediate form of parathyroid neoplasm with uncertain malignant potential, showing atypical histological features without evidence of invasive growth. This poses a diagnostic challenge of PC as the histopathological features overlap and requires an expert pathologist to make the diagnosis. Inactivating CDC73 mutations, encoding parafibromin, is the most common genetic abnormality. Loss of parafibromin has been seen in 100% cases of PC and predicts poor prognosis. Due to rarity of the disease there are no clear guidelines on follow up. Based on literature, annual follow up is suggested with biochemical testing and imaging for the first 5 years after surgery and every 2–3 years thereafter due to 3% recurrence rate and potential progression to PC. Cetani et al in 2019 reported 672 cases of APA, only 3 were ectopic in the mediastinum thus making our case rare. APA is a rare entity as biochemical profile and histopathological features overlap with PC and can be misdiagnosed. Greater awareness of APA may improve capture of cases, allowing the development of guidelines to recognize and treat it.

Genetic Alteration Profiles and Clinicopathological Associations in Atypical Parathyroid Adenoma

Genomic aberrations associated with atypical parathyroid adenoma (AA) are poorly understood. Thus, herein, we sought to expand our current understanding of the molecular basis of atypical parathyroid adenomas. We analyzed 134 samples that had been surgically obtained from parathyroid tumors, including parathyroid carcinomas, atypical parathyroid adenomas, and parathyroid adenomas. The tumors were harvested from formalin-fixed, paraffin-embedded tissues. Fifteen tumor-related genes from recently published genome sequencing data were subjected to targeted sequencing analysis, and an average sequencing depth of 500x was achieved. Sixteen (16/50, 32%) AA tumors harbored at least one of the following genomic alterations: CDC73 (12, 24%), EZH2 (4, 8%), HIC1 (1, 2%), and CDKN2A (1, 2%). Our study identified, for the first time, a relatively high frequency of genomic alterations in patients with AA in a Chinese population. This suggests that AA arises de novo, rather than developing from a parathyroid adenoma. Altogether, these findings will improve our understanding of the malignant potential of parathyroid tumors at the molecular level.