We present a rare case of a rapidly progressive GPA in an elderly woman who was initially admitted with extremely high levels of serum calcium and PTH as well as a rapidly deteriorating level of consciousness accompanied by the development of severe psychiatric disorders.

GPAs and PCs are both very rare entities. Their preoperative and pathological diagnosis is challenging, particularly in the absence of invasion of adjacent structures and distant metastases [3, 5, 7, 8]. The signs and symptoms of severe hypercalcemia are common to both PC and GPA. Clinical features due to infiltration of vital organs by tumor mass are rare in PC [9]; in most cases it is an indolent, slow growing but tenacious malignant tumor [6]. It is reported that the classical target organs of PTH, the kidney and skeleton, are affected with greater frequency and severity in PC. Bone pain and pathological fractures occur in 34–73% of cases, while renal pathology, such as polyuria, nephrolithiasis, and renal colic, is frequent in 32–70% [7, 10]. Of note, in our case, the main symptoms, apart from bone pain, nephrolithiasis, and kidney failure, were psychiatric disorders (depression, dementia, and organic psychosis), which developed in quite a short period. Concerning demographics, the age and the female: male ratio are higher in PA than in PC. However, there is a considerable overlap. It is reported that the average age of occurrence of PC is in the fifth decade, while our patient was in her 70s [5, 9].

Most patients with PC present with severe hypercalcemia (65–75%), generally above 14 mg/dl or 3–4 mg/dl above the upper limit of normal, while PTH levels are usually 5 to 10 times higher than normal. In a review by Obara et al., in two-thirds of 133 patients, mean serum calcium was 15.0 mg/dl (range 10.0–24 mg/dl) and serum PTH levels > 5 times the upper limit of the normal range [6]. Concerning PAs, most authors have reported a positive correlation between adenoma weight and the biochemical abnormalities. Indeed, a cohort of 378 PHPT cases showed a significant positive correlation of both preoperative calcium and PTH values with adenoma dimensions and weight [11]. Similarly, a retrospective study by Leong et al. confirmed these findings and suggested that PTH might be a better predictor of PA weight than serum calcium levels in patients with PA [12]. By contrast, in a recent systematic review of 65 patients with GPAs with hypercalcemia (mean 14.06 mg/dl, range: 10.4–23) and increased PTH levels (> 14 times above the upper limit of the normal reference), no correlation between the GPA size or weight and PTH levels was found [13]. In any case, in general, the symptoms of hypercalcemia are more frequent and severe in PC than in PA [5]. Of note, a study by Spanheimer et al. showed that GPAs are more frequently asymptomatic than non-giant PA despite higher levels of calcium and PTH [14].

Concerning our patient, the initial serum calcium concentration was notably elevated at 24.3 mg/dl along with a PTH level 41 times above the upper normal limit with symptoms indicating hypercalcemic crisis, which is not usual even in giant adenomas. A hypercalcemic crisis is a life-threatening endocrine emergency characterized by extremely high serum calcium concentration (> 14 mg/dl) with concomitant multiorgan dysfunction (gastrointestinal and neurological symptoms, acute renal failure, and cardiac rhythm abnormalities) [15]. Our patient exhibited renal and neurological dysfunctions, expressed as markedly elevated creatinine levels and impaired consciousness. Thus initially, in the present case, the clinical and biochemical profile raised a strong suspicion of PC.

To our knowledge, this is the first case reported in the literature of GPA with such high levels of serum calcium and PTH. Another exceptional case of a GPA mimicking PC and measuring 6.5 cm with milder preoperative hypercalcemia of 12.5 mg/dl and PTH of 2.747 pg/ml was published in 2020 [16]. The differential diagnosis of these entities is based on the clinical features and the laboratory findings. Preoperative fine-needle aspiration (FNA) is not recommended because cytology cannot distinguish between benign and malignant disease. In the case of PC, there have also been reports of tumor seeding along the biopsy tract [17, 18]. Imaging modalities such as neck ultrasound, CT scan, magnetic resonance imaging (MRI), and 99mTc-MIBI (sesta-MIBI) scintigraphy are mandatory in order to locate the tumor and metastatic lesions. In our patient, a neck CT scan demonstrated a large heterogenous solid lesion of 2 × 3.3 cm below the right inferior pole of thethyroid gland extending into the upper mediastinum.

Differentiating between an adenoma and PC is difficult as no specific imaging characteristics exist [19]. Features such as irregular margins, pathological lymph nodes, and invasion of the adjacent structures may be indicative of PC [7, 9].

Surgery remains the gold standard procedure for the treatment as well as for the final differential diagnosis of PC vs. GPA. Therefore, our patient underwent en bloc right lobe thyroidectomy, parathyroidectomy, and removal of the right recurrent laryngeal nerve due to apparently tumor infiltration. In the case of PC, en bloc dissection of the tumor together with the lateral thyroid lobe, ipsilateral parathyroid, and other adjacent tissues invaded by the tumor (such as paratracheal alveolar and lymphatic tissue, the thymus or some of the neck muscles, and the recurrent laryngeal nerve) is associated with the best prognosis [6, 20].

Histopathological distinction between benign and malignant parathyroid tumors is also difficult. Macroscopically PC presents as a firm, lobulated mass surrounded by dense fibrous tissue that invades or adheres to surrounding structures including the thyroid gland, the strap muscles, the recurrent laryngeal nerve, esophagus, and trachea [6]. GPAs tend to be bright reddish or brown, soft, and ovoid. However, up to 20% of GPAs and PCs can be misclassified if only these parameters are taken into account [21]. Microscopically, capsule, blood vessel and lymph invasion, stromal calcifications, fibrous trabeculae, enlarged nuclei, and strong mitotic activity are considered to be signs of malignancy according to the histopathological criteria of Shantz and Castleman [22]. Furthermore, the loss of staining for parafibromin, a protein coded by the HRPT2 gene (involved in the pathogenesis of PC), and increased values of Ki-67% are two additional elements indicating a PC in the majority of cases [5, 16]. Fortunately, in the present case, to our surprise, despite the hypercalcemic crisis with markedly elevated levels of calcium and PTH and the exceptionally firm tumor found during surgical excision, the histological examination established the diagnosis of a GPA measuring 5.4 cm x2.3 and weighting 11 g, with no atypias, positive parafibromin staining or negative Ki67 and p53 staining. In addition, there was partial cystic and hemorrhagic degeneration. Cystic transformation is an unusual presentation. Cystic parathyroid lesions are very uncommon, accounting for less than 0.01% of all neck masses [8, 23]. In our patient, focal areas of cystic degeneration of the gland were noted, probably due to the huge dimensions and longtime evolution of the disease. On the other hand, the unusually rapid onset of hypercalcemia with severe symptoms in this case could be attributed to a possible acute hemorrhage of the lesion.

Post-surgery restoration of normocalcemia is a clear sign that the entirety of hyperfunctioning tissue has been excised. During the early postoperative period, however, there should be strict monitoring of serum calcium level due to the risk of symptomatic hypocalcemia arising from HBS, as in our patient. Hypocalcemia due to HBS suggests that the surgery has been successful [9]. It is observed in 13–30% of parathyroid surgery cases [24] and some studies suggest the use of bisphosphonates prior to surgery in order to prevent this post-operative outcome [25]. The hypocalcemia of HBS may be rapid, severe (serum calcium concentration < 8.4 mg/dl), and prolonged and can be associated with hypophosphatemia and hypomagnesemia. It is exacerbated by low PTH levels following parathyroidectomy in patients with severe PHPT and preoperative high bone turnover. HBS treatment requires high doses of calcium (6 and 12 g/day) as well as active metabolites of vitamin D and replenishment of magnesium stores as needed. Intravenous calcium replacement may be temporarily necessary in severe forms of HBS, as observed in our case [24, 26].