INTRODUCTION
Primary hyperparathyroidism (PHPT) is caused by the autonomous production of parathyroid hormone (PTH) by 1 or more of the 4 parathyroid glands and is characterized by hypercalcemia and inappropriately normal or elevated PTH.[
1] PHPT predominates among women (female to male ratio, 3 to 4:1) and is usually postmenopausal.[
2]
PHPT has a wide spectrum of clinical presentations; most patients are asymptomatic; however, there may be classic manifestations of PHPT in the kidney (hypercalciuria, nephrolithiasis, renal disease) and bone (osteoporosis, fractures, cystic fibrous osteitis), nonclassical manifestations at the cardiovascular, neurological or gastrointestinal level, and even extreme states such as parathyroid crisis, which represents a severe emergency.[
1] A constitutional syndrome is a rare and underreported manifestation.
Parathyroidectomy (PTX) is the only curative approach in PHPT.[
1] Most patients with PHPT have single adenomas (80%) or hyperplasia (15%-20%); parathyroid carcinoma (PC) is reported in <1%.[
2] Among patients with adenoma, atypical parathyroid adenoma (APA) may be found at a low frequency. The incidence of APA ranges from 0.5% to 4.4%.[
3]
APA represents a diagnostic challenge for endocrinologists, surgeons, and pathologists because it is an intermediate form of parathyroid neoplasm of uncertain malignant potential, with atypical histological features that require differential diagnosis with PC.[
3,
4] This manuscript describes the clinical, biochemical, imaging, and histopathological features of 2 cases of PHPT with parathyroid crisis as a presentation of APA in a tertiary referral center in Mexico City.
DISCUSSION
We report 2 diagnostically challenging cases of PHPT by APA presenting as a parathyroid crisis. A parathyroid crisis is a rare manifestation of PHPT (1%-2%) and is characterized by severe hypercalcemia (>14 mg/dL) with multiorgan involvement, including renal failure, gastrointestinal symptoms, metabolic encephalopathy, and cardiac dysrhythmia, as well as other manifestations, such as proximal muscle weakness, neuropsychiatric syndrome with decreased ability to concentrate, depression and normochromic anemia.[
5]
In our cases, the first patient had muscular, gastrointestinal and neuropsychiatric manifestations, with normochromic anemia and an interesting finding of constitutional syndrome. The constitutional syndrome includes the presence of fatigue, anorexia, and unintentional weight loss [
6] and is a rare and underreported manifestation in PHPT.
On the other hand, our second patient had renal (‘acute on chronic kidney disease’), muscular, gastrointestinal and neuropsychiatric manifestations.
Classically, parathyroid crisis has been associated with the presence of PC; however, cases of typical parathyroid adenoma,[
7] hyperplasia,[
5] and, less frequently, APA has been reported.[
3,
4]
The presence of parathyroid crisis, serum calcium levels >14 mg/dL, and very high serum PTH concentrations (>500 ng/dL) in our patients suggested the possibility of parathyroid neoplasia initially making the diagnosis of PC vs. APA a challenge.
PC is the rarest cause of PHPT (<1%).[
8] The pathophysiological mechanisms of APA are unclear, but it has been proposed that it may share molecular mechanisms with PC.[
9] APA has higher rates of symptomatic hypercalcemia and fragility fracture, higher preoperative serum calcium, higher 24-hr urinary calcium and higher pre and postoperative PTH than typical adenoma.[
4] The clinical and biochemical differences between APA and PC are nil, making differential diagnosis difficult without histopathological analysis.[
10]
It has been reported that the differences between APA and PC by imaging studies are minimal: parathyroid adenomas are generally solid, hypoechoic lesions with well-defined margins and dimensions usually not >2 cm. In contrast, PCs are lesions with irregular and poorly defined margins, large dimensions (>2-3 cm), and increased vascularity.[
11] In our cases, we observed ultrasonographic patterns that included features of both, which is an interesting research topic for future studies in patients with APA.
Histologically, PC are characterized by sheets or lobules of tumor cells with interspersed thick fibrous bands, a pattern of trabecular growth, mitotic figures/high mitotic index, cell pleomorphism, nuclear atypia, necrosis, invasion beyond the capsule and vascular invasion.[
3,
12] APA is a parathyroid tumor with surrounding fibrous tissue and some of the histological features of PC, but it is not sufficient to make a diagnosis of malignancy.[
8] Compared to PC, APA has a lower proportion of fibrous bands (77% vs. 100%), less cellular atypia (18% vs. 33%), less necrosis (12% vs. 17%), and less tissue infiltration (23% vs. 83%).[
10] These findings are compatible with what was observed in our patients. In the first case, cell pleomorphism, nuclear atypia, and vascular invasion were evidenced, while the second case showed cell pleomorphism and focal capsular invasion; in both cases, a giant adenoma (>4 cm) was evident.
APA is a challenge for the differential diagnosis of PC, and it could represent an early stage of a PC that is excised before the development of the molecular signature of malignancy responsible for the invasive properties.[
3] The importance of a proper diagnosis of APA lies in the prognosis. The prognosis in PC is poor, with a 5-year survival of 86.5%, while the 5-year survival in APA is 93.3% with a disease-free recurrence of 90.9%.[
13]
The relevance of these 2 cases lies in the clinical presentation of parathyroid crisis, highlighting in the first case the presence of constitutional syndrome, an extremely rare entity and unreported in PHPT, and the second case the alteration of renal function with acute deterioration of chronic kidney disease. Biochemically, we highlight the elevated levels of calcium and PTH, as well as imaging studies with characteristics of both PC and parathyroid adenoma. Furthermore, we highlight the heterogeneity of the clinical context of the patients: one patient with a previous normal renal function who developed HBS after PTX but with disease cure at 6 months post-surgery and another patient with impaired renal function attributed to long-standing recurrent nephrolithiasis, with a high probability of long-standing PHPT but with a risk factor for secondary hyperparathyroidism, who had persistent disease at 6 months after surgery.
The main reported clinical manifestations of APA are nephrolithiasis (approximately 30%) and osteoporosis (18%-22%), rarely presenting with parathyroid crisis [
3,
4]; however, information about outcomes in patients with APA is scarce, even null in specific populations such as cyclin-dependent kinase. This represents an interesting topic for future research.
When PC is suspected in patients with hypercalcemic crisis, en bloc resection (PTX, resection of the surrounding capsule and concurrent hemithyroidectomy) has been recommended. In the case of APA, there are no specific guidelines for the first-choice surgical approach. The most frequent initial surgery in APA is selective PTX (resection of affected parathyroid) (56%), followed by en bloc resection (24%).[
3] The cure rate of PHPT in APA is 96%, similar to that of typical adenoma, with a recurrence of 3% and persistence of 1% [
3]; however, information about the cure, persistence, or recurrence rate according to the type of surgery is still scarce. The factors associated with the persistence of PHPT in the specific context of APA have not yet been elucidated.
In our cases, it is important to note that in the patient with curative criteria (Case 1), en bloc resection was performed, while in the patient with persistent PHPT, selective PTX was performed, which raises the question: could the type of surgery be a determining factor in the successful outcome of PHPT in patients with APA?
Added to this is the possibility of having patients with complications of PHPT, such as long-standing nephrolithiasis and subsequent chronic kidney disease, which is a risk factor for persistent hyperparathyroidism, further justifying the need for more stringent and individualized surgical management by an expert surgeon.
It is important to consider that parathyroid surgery concurrent with thyroidectomy carries an 8-fold increased risk of complications compared to PTX alone, mainly hypocalcemia,[
14] which is consistent with our first cases, noting that this complication was transient. HBS is a rare but serious complication of PTX for PTH, characterized by profound and prolonged hypocalcemia. Risk factors for HBS include advanced age, very high preoperative serum calcium, alkaline phosphatase, and PTH levels, osteitis fibrosa cystica, and high volume and weight of the resected pathological parathyroid gland(s).[
15]
We propose that when PC or APA is suspected, surgical treatment (individualized and performed by an expert surgeon) should be more stringent to improve the patient’s prognosis, as histopathological analysis is decisive in diagnosing APA. APA should be closely monitored because of the likelihood of a premalignant stage of PC.[
13]