This case highlights several unusual features of a very rare disease of the parathyroid gland—parathyroid cancer—documented to be a causative factor in less than 1% of cases of hyperparathyroidism [1,2,3]. Compared with patients with parathyroid adenomas, patients with parathyroid carcinomas are more likely to have symptoms, a neck mass, bone and kidney disease, marked hypercalcemia, very high serum parathyroid hormone (PTH) concentrations and, subsequently, high urinary calcium losses [1, 7]. In this patient, although the preoperative parathyroid hormone level was inexorably high at 2105 pg/mL (16–87), the 24 h urine calcium was not as high (155 mg/day) as expected in association with these levels of PTH [9,10,11], given a reasonably sufficient (840 mL) 24 h urine collection. The relatively low 24 h urine calcium could in part be explained by the reduction of renal function (creatinine clearance of 50 mL/min). The serum calcium levels were not as high as reported in the literature for parathyroid cancers [1, 7, 9]. The initial level was 10.8 mg/dL {2.7 mmol/L}. The highest level documented was 15.1 mg/dL{3.775 mmol/L}, that too only after she had been placed on calcium and vitamin d supplementation by an orthopedic surgeon, whom she had presented to for her bone pains. The orthopedic surgeon had probably been treating her as a regular case of primary osteoporosis, without a complete evaluation and consideration for the initial mildly elevated calcium of 10.8 mg/dL {2.7 mmol/L}. The possibility exists that her baseline vitamin D level, unfortunately not assessed prior to institution of parental vitamin d, may have been low. This may have led to the relatively lower baseline levels of calcium than expected in the context of parathyroid carcinoma. Unmasking of primary hyperparathyroidism subsequent to vitamin D replacement has been reported in the literature [10].
Ultrasonography of our patient revealed a 1.8 × 1.2 cm hypo echoic, though well-circumscribed solid lesion, with no calcifications or lymphadenopathy, at lower pole of the right lobe of the thyroid. Cetani et al. in their review state that mass size > 3 cm, marked hypoechogenicity, a lobulated non homogenous pattern, calcifications and degenerative changes may raise the suspicion of parathyroid cancer [1, 12]. Another unusual feature of this patient’s presentation was that the first sestamibi scan was negative. The repeat scan (Fig. 2) (requested from a different radiologic centre) showed some tracer retention over the upper and lower poles of right lobe of thyroid, which co related with findings obtained on ultrasonography. The latter had revealed a mass lesion at the lower pole of the right lobe of the thyroid, though no malignant characteristics, such as calcifications, degenerative changes or irregular halo sign [1, 12] had been reported. Although both scans were planar, the negative scan had been done using a low energy general purpose collimator (LEGP), while the repeat scan was done using a low-energy high resolution collimator (LEHR). The discrepancy between the results of the two sestamibi scans could have been due to these different techniques employed. Sestamibi scan does not distinguish a parathyroid adenoma from a parathyroid carcinoma [11]. Considering the phenomenally raised parathormone levels, however, a hot nodule had been anticipated. The majority of cases of parathyroid cancer reported in the literature have described a dramatic lighting up of the lesion on the sestamibi scan, with a sensitivity of 85–100%, and specificity of 100% [13]. In our case, there was subtle tracer retention over upper and lower poles of right lobe of thyroid, with intensity of retention higher over the inferior pole. A pin- hole collimator technique to obtain a magnified, higher resolution image focused on the neck, was not available at either Institute at that time. There has been a case reported in the literature of false negative scintigraphy in parathyroid carcinoma with associated brown tumours (term discussed below) [13].
From the neurologic and renal stand point the patient had been well preserved. There had been no manifestations of altered sensorium, even at the stage when her serum calcium had reached a level of 15.1 mg/dL {3.775 mmol/L}. Ultrasonography of her kidneys had revealed normal sized kidneys with intact corticomedullary differentiation, no nephrocalcinosis and a single small renal stone. In most cases of parathyroid carcinoma, central nervous system and renal manifestations are apparent at the time of diagnosis [1, 4]. In the case of this patient, the disease, though remaining undiagnosed for 5 years, seems to have involved predominantly the skeletal system, leading to severe osteoporosis. Her shortened fingers on physical examination were indicative of pharyngeal tuft resorption. The low Z scores of ≤− 2.0 at the spine, hip and forearm were highly suggestive of a secondary cause of osteoporosis. The bone mineral density at the forearm (T score − 4.5) was lower than at the spine (T score − 2.9) Table 2. This is in keeping with the fact that the parathormone has a greater impact on cortical bone (distal forearm and hip) than the spine, which consists of cancellous bone [12]. Correspondingly, a follow up dexa scan 2 years after the parathyroidectomy revealed a significant improvement in bone mineral density at all the sites, though a slower improvement was observed at the forearm (Table 2). This was likely related to the prolonged preoperative exposure to high levels of parathormone at the cortical bones of the forearm. The lytic lesions of the bones in primary hyperparathyroidism result from excess osteoclast activity leading to a collection of osteoclasts intertwined with fibrous tissue and undermineralized woven bone. Haemosiderin accumulation gives rise to the brown disclouration—hence originated the label of “brown tumours” for these lytic lesions [2, 12]. Correspondingly, as evident in this lady’s case, these lesions were originally interpreted as metastases or myeloma lesions radiologically. Both these conditions, though important differentials to consider, result in PTH-independent hypercalcemia, versus the PTH- dependant hypercalcemia ensuing from primary hyperparathyroidism.
Long-standing hypercalcemia resulting from autonomous parathormone production leads to suppression of the remaining parathyroid glands. Following parathyroidectomy, recovery of function has been variable, ranging from hours to a couple of weeks. In many cases, oral calcium supplementation alone adequately restores calcium levels. In some situations, as was the case in our patient, more severe hypocalcemia ensues, requiring intravenous calcium supplementation. As a result of PTH suppression, the 1-alfa hydroxylation of vitamin D, at the renal tubular level, is concurrently reduced. This necessitates supplementation with the active form of vitamin d. This condition has been described as the “hungry bone syndrome”, usually found to occur 3–5 days following parathyroidectomy. The reason for its development is thought to be due to significant increases in osteoblastic function, bone formation and deposition of calcium and phosphorus in previously deprived bones [2, 14, 15]. Our patient had a long-standing history of primary hyperparathyroidism, phenomenally elevated PTH levels, marked hypercalcemia and elevated alkaline phosphatase levels (indicating high bone resorption). She also had radiologic signs of osteitis fibrosa cystica (Fig. 1). These hallmarks very likely led to development of the typical hungry bone syndrome in this case. Concomitant with her long-standing history of hyperparathyroidism, the lytic lesions on her follow-up bone scintigraphy, done 3 months following parathyroidectomy, did not show any significant improvement.
A number of important lessons can be learned from this case. In the setting of bone pains and hypercalcemia, the parathormone level, along with a vitamin D assessment and renal function tests, should have been checked when the patient had first presented to the general practitioner back in 2004. This would have differentiated between parathyroid-dependant and parathyroid-independent hypercalcemia, and may have avoided an exhaustive work up for multiple myeloma. The patient had previously undergone bone marrow examinations on two occasions, both showing a normal result. The physicians may have been misguided by the only two differentials suggested on the MRI Lumbosacral spine report: “Multiple Myeloma versus metastasis.” In both these conditions, parathyroid levels are suppressed in the setting of hypercalcemia. Unfortunately, the parathormone level and relevant testing, including vitamin D and renal function tests, were only requested 5 years down the line when the patient first presented to the Endocrinologist. This led to an unacceptable delay in the diagnosis. It is unclear why the first sestamibi scan was requested, without a prior parathyroid hormone level assessment, at the time when the patient was following up elsewhere for her condition.
In the setting of hypercalcemia, parathyroid hormone level assessment is a must, to differentiate between the parathyroid dependant and independent causes of high serum calcium, thereby encouraging a comprehensive pathway to the work-up of the cause of the hypercalcemia. The Parathyroid carcinoma is a very rare cause of hypercalcemia that can present in several ways and which needs to be considered in the differentials of primary hyperparathyroidism, particularly in the setting of high parathyroid hormone levels.
