J Bone Miner Metab (2012) 30:367–372 DOI 10.1007/s00774-011-0344-y
CASE REPORT
Parathyroid carcinoma presenting as normocalcemic hyperparathyroidism Alfredo Campennı` • Rosaria M. Ruggeri • Alessandro Sindoni • Salvatore Giovinazzo • Enrico Calbo • Antonio Ieni • Letterio Calbo Giovanni Tuccari • Sergio Baldari • Salvatore Benvenga
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Received: 26 April 2011 / Accepted: 11 December 2011 / Published online: 14 January 2012 Ó The Japanese Society for Bone and Mineral Research and Springer 2012
Abstract Parathyroid carcinoma (PC) is a rare malignancy, with an indolent but progressive course. Long-term survival is largely dependent on the extent of the primary surgical resection. Hence, pre- or intraoperative suspicion of malignancy is of great importance. We describe the case of a 62-year-old woman with a 2-year history of asthenia and mental depression. Her past medical history was significant for osteoporosis. A diagnosis of primary normocalcemic hyperparathyroidism was established and the patient underwent surgery. PC was suspected intraoperatively because of the size and appearance of the parathyroid mass (a grayish, lobulated 3.5 cm mass). Thus, aggressive surgery (en bloc resection) was performed, along with bilateral neck exploration. Pathological examination of the specimens confirmed the suspicion of PC, demonstrating vascular invasion and extracapsular infiltration into adjacent soft tissue. Immunohistochemical staining revealed an elevated Ki-67 score (8.43%; cut-off value 5%). The mean A. Campennı` (&) A. Sindoni S. Baldari Unita` di Medicina Nucleare, Dipartimento di Scienze Radiologiche, Padiglione E, piano terra, Policlinico Universitario ‘‘G. Martino’’, University of Messina, v. Consolare Valeria, 98125 Messina, Italy e-mail:
[email protected] R. M. Ruggeri S. Giovinazzo S. Benvenga Department of Clinical and Experimental Medicine and Pharmacology, Section of Endocrinology, University of Messina, Messina, Italy E. Calbo L. Calbo Department of Human Pathology, Section of Surgery, University of Messina, Messina, Italy A. Ieni G. Tuccari Department of Human Pathology, Section of Anatomic Pathology, University of Messina, Messina, Italy
area of silver-stained nucleolar organizer regions (AgNOR) was high (4.972 lm2), indicating an elevated proliferation rate. Serum calcium and parathyroid hormone levels normalized postoperatively, and the patient’s 5-year outcome was good. The present case provides evidence that parathyroid malignancy cannot be excluded a priori based on normocalcemic hyperparathyroidism, emphasizing the variability in clinical presentation. Moreover, Ki-67 expression and AgNOR analysis confirmed their additional value in complementing the histological evaluation of a parathyroid malignant mass. Keywords Parathyroid Normocalcemia Parathyroid carcinoma AgNOR Ki-67
Introduction Parathyroid carcinoma (PC) is an uncommon endocrine malignancy, with about 800 cases reported worldwide [1– 5]. It accounts for 0.005% of all cancers [4] and about 1% of cases of primary hyperparathyroidism [1–3]. This rare tumor is often difficult to diagnose preoperatively, thus limiting the efficacy of surgical cure [5]. The typical features of PC are represented by signs and symptoms of severe hypercalcemia, with renal and bone involvement in up to 80–90% of patients [1–3]. A palpable neck mass has been reported in 30–76% of patients with PC [1–3]. Although such clinical features may suggest malignancy, the distinction between benign and malignant disease is often difficult on clinical ground. Even the histology of PC can be equivocal or frankly misleading. Thus, it is common that the diagnosis of PC is made a posteriori, when local recurrence or distant metastases occur [1–3].
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As better outcomes are associated with complete resection of the tumor at the time of initial surgery, it is of great importance to consider PC in the differential diagnosis of hyperparathyroidism. Here we report a case of PC which presented in the form of a mild, normocalcemic hyperparathyroidism, demonstrating the variability in clinical presentation of this malignancy.
Case report A 62-year-old woman was referred to our endocrinology unit with a 2-year history of asthenia and mental depression. Her past medical history was significant for hypertension, which was treated with angiotensin receptor antagonists at standard doses, and osteoporosis (T-score of -2.6 at the lumbar spine and femoral neck, under bisphosphonates treatment). Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry. BMD measurements expressed as a percentage compared with young healthy individuals were converted to T-scores (SD values from the mean for a sex-matched young reference population), and osteoporosis was diagnosed according to the World Health Organization (WHO) classification. She denied prior neck irradiation and familial history of parathyroid and/or thyroid diseases. On physical examination, there was a palpable right thyroid mass and no lymph nodes. Neck ultrasonography (US) showed an enlarged thyroid and several nodules (from 4 to 35 mm in diameter) bilaterally. The 35-mm nodule was seen to be hypoechoic and hypervascularized by color Doppler (abnormal peri- and intranodular blood flow) and well separated from the lower pole of the right thyroid lobe, suggesting a parathyroid mass (Fig. 1a). Biochemical data of the patient are summarized in Table 1. She had elevated serum intact parathyroid hormone (PTH) (104.7 pg/ml; normal values (nv) 12–62) with normocalcemia (10.2 mg/dl; nv 8.2–10.4; ionized calcemia 5.0 mg/
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dl, nv 4.2–5.4), hypophosphatemia (2.1 mg/dl; nv 2.8–4.5), hypercalciuria and hyperphosphaturia (499 mg/24 h, nv 100–300 and 2.9 g/24 h, nv 0.8–2.0 g/24 h, respectively). Serum creatinine and creatinine clearance were normal, as were serum calcitonin, free T4, free T3 and thyroid stimulating hormone (TSH) (Table 1). Chest X-ray disclosed no abnormalities. Parathyroid dual-phase planar scintigraphy, after intravenous administration of 370 MBq 99mTcmethoxyisobutylisonitrile (99mTc-MIBI), revealed a single focus of sestamibi accumulation in the inferior right parathyroid gland (Fig. 1b). All findings were consistent with normocalcemic primary hyperparathyroidism associated with a large multinodular goiter. No skeletal (pain, fractures), abdominal (constipation, gastritis) or renal symptoms (nephrocalcinosis, lithiasis) were noted. Because of the reduction in bone density, the patient underwent radio-
Table 1 Serum and urinary biochemical data at admittance Analyte (unit of measure) Calcemia (mg/dl) Ionized calcemia (mg/dl) Sodium (mmol/L)
Patient’s value 10.2 5.0 143
Normal range 8.2–10.4 4.2–5.4 130–148
Potassium (mmol/L)
4.7
3.5–5.2
Magnesium (mg/dl)
2.5
1.5–3.8
Chlorine (mg/dl) Creatinine (mg/dl) Urea nitrogen (mg/dl) Albumin (g/dl) Total proteins (g/dl)
102 0.6 36 4.16 7.6
98–110 0.5–1.4 10–50 3.5–5.0 6–8.2
Alkaline phosphatase (U/L)
340
PTH (pg/ml)
104.7
12–62
2.1
2.8–4.5
Phosphatemia (mg/dl)
0–270
25(OH) vitamin D (ng/ml)
40.3
20–100
1,25(OH)2 vitamin D (ng/ml) Osteocalcin (ng/ml)
30.8 17.2
20–120 1.60–17.4
Calcitonin (pg/ml) FT3 (pg/ml)
\ 2.0 3.72
0–12 2–4.4
FT4 (pmol/l)
19.4
12–22
TSH (uIU/ml)
1.7
0.25–4.2
Urine
Fig. 1 Images of pre-surgery echography and 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy scan, demonstrating an enlarged parathyroid gland (a) and an area of abnormal tracer uptake in a position consistent with the right inferior parathyroid gland (b)
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Creatinine clearance (ml/min)
112
74–125
Calcium (mg/24 h)
499
100–300
Fractional excretion of calcium
0.05
Phosphorus (g/24 h)
2.9
Fractional excretion of phosphate
0.013
Sodium (mmol/l)
99
0.8–2.0 50–200
Potassium (mmol/l)
34
30–90
OH-proline (mg/24 h)
52.8
14–45
Boldface values indicate abnormality
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guided surgery to remove the parathyroid mass, along with a bilateral neck exploration to exclude the presence of parathyroid hyperplasia. An enlarged, grayish and lobulated right parathyroid measuring 3.5 9 1.2 cm was surgically removed (Fig. 2), along with the multinodular goiter (subtotal thyroidectomy) and lateral cervical lymph nodes. Pathological examination of the specimens revealed a parathyroid carcinoma associated with a benign colloid goiter (Fig. 2). The parathyroid tumor had a nodular shape and was separated from the surrounding tissue by a grayish, fibrous capsule. From the corresponding formalin-fixed paraffin-embedded tissue blocks, a microscopic examination was carried out on 4-lm thick sections. The neoplastic proliferation was arranged in a trabecular and cordonal pattern surrounded by a dense fibrous capsule; the capsule appeared discontinuous for the presence of proliferating neoplastic solid cell nests. At higher magnification, the neoplastic elements showed round to ovoid, enlarged nuclei, prominent nucleoli and clearly demarcated cytoplasm. Some areas of the tumor consisted of neoplastic cells with abundant, clear to oxyphilic cytoplasm with occasionally binucleated and giant nuclei. Vascular invasion and extracapsular infiltration into adjacent soft tissue were also appreciable (Fig. 2b, c). On a parallel section, mounted on silane-coated glass, the expression of the cell cycle-associated antigen Ki-67, a marker for proliferative growth fraction, was assessed by immunohistochemistry using the monoclonal antibody MIB-1 (Dako Cytromation, Copenhagen, Denmark; working dilution 1:200), after an antigen retrieval pretreatment by three cycles 9 5 min (0.01 M citrate buffer, pH 6.0) in a microwave oven. An elevated Ki-67 score (8.43%; cut-off value 5%) was recorded, thus indicating aggressive behaviour. Moreover, to determine the proliferation rate, a standardized silverstained nucleolar organizer regions (AgNOR) analysis was also performed, as previously reported [6]. The mean area (in lm2) of AgNORs per nucleus (NORA) was evaluated by means of an image analyzer and specific software. By AgNOR technique, our parathyroid specimen showed an adequate and homogeneous staining intensity throughout the whole section; the mean NORA value was 4.972 lm2. Immunohistochemistry for PTH was also performed using the monoclonal antibody anti-PTH (Dako Cytromation; working dilution 1:50). Such immunohistochemistry showed an intense but inhomogeneous distribution of PTH immunostaining throughout the tumor, probably due to functional heterogeneity of tumor cells that synthesized PTH (Fig. 3). Two small sub-centimetric lateral cervical lymph nodes on the right showed features of focal metastatic infiltration from the parathyroid carcinoma.
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Fig. 2 Post-surgery excised parathyroid mass (a) and the corresponding H&E-stained section showing the neoplastic cells arranged in a trabecular and cordonal pattern (9100 magnification); the capsular invasion is indicated by a black arrow (b). c The vascular invasion by tumor cells (arrow), which are almost completely surrounded by CD34 positive endothelial cells
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Fig. 3 Immunohistochemistry for PTH demonstrated an intense but inhomogeneous staining throughout the whole section (a magnification 9180). Note the usual and characteristic pseudoglandular distribution of PTH immunostaining at high magnification (b magnification 9360)
After surgery, serum calcium decreased to 8.6 mg/dL. On the 6th postoperative day, the patient was discharged uneventfully with a serum PTH level of 28.4 pg/mL, and calcemia of 8.7 mg/dL. Both levels have remained essentially unchanged during the 5-years of follow-up, with no evidence of recurrent disease by US, 99mTc-MIBI scintigraphy and computed tomography total body scan.
Discussion A PC is an uncommon endocrine tumor, with a low malignant potential, but progressive and tenacious. It tends to recur locally at the operative site and to spread to contiguous structures in the neck, while distant metastases (lung, liver) occur less frequently and late in the course of the disease. Prognosis is largely dependent from the initial surgical approach, the only curative treatment being the complete resection of the primary tumor before metastatic spread. Incomplete resection results in a local recurrence rate of 50% with a disease-related mortality rate of 46% [2, 7]. In patients in whom the disease recurs, hypercalcemia and its complications may become life-threatening. Mortality is usually from complications of hypercalcemia or, less frequently, from systemic metastases. Hence, both preoperative suspicion and intraoperative recognition of malignancy are essential in order to obtain the best cure rate. Nevertheless, it still remains a challenge to differentiate between cancer-associated hyperparathyroidism and the much more common adenoma-associated hyperparathyroidism. Severe hypercalcemia (up to 24 mg/dL) and very high levels of PTH, which are considered the main indicators of malignancy because they are unusual in parathyroid adenomas [1, 3], are associated with kidney, bone, gastrointestinal
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and psychiatric symptoms more frequently than parathyroid adenomas [1–3, 5]. To date, the few cases of normocalcemic PC reported in the literature were non-functioning PCs [8, 9]. Here we describe a case of a PTH-secreting PC associated with normal values of serum calcium. Our patient only complained of asthenia and mood disturbances of a few years duration, without renal, skeletal and/or abdominal symptoms characteristic of a severe hyperparathyroid state, as expected in a case of parathyroid malignancy. Osteoporosis was the only noted skeletal alteration, but it had not been given much attention because of the postmenopausal age of the patient. It is now clear that normocalcemic hyperparathyroidism exists and is characterized by consistently normal calcium concentrations in the face of persistently abnormal PTH levels [10]. Here we report that a malignant parathyroid lesion may also present in this way. In a case reported by Messerer et al. [11] no biochemical data whatsoever are presented except to state that in a 60-year-old woman ‘‘serum ionized calcium level was normal and her intact PTH was elevated to three times the upper limit of normal’’. Furthermore, no cases of PC were presented in a cohort of 37 patients (29 being postmenopausal women) with normocalcemic hyperparathyroidism, most of whom were collected during evaluation of low bone mass [12]. Serum levels of calcium, PTH and 1,25-dihydroxycholecalciferol [1,25(OH)] vitamin D of our patient fell within the range of that cohort (9.0–10.4 mg/dl, 65–182 pg/ml and 20–54 ng/ml). The increased calciuria, phosphaturia and bone resorption markers (urinary OHproline, serum alkaline phosphatase) exclude that PTH was biologically inactivate and are consistent with the hypothesis put forward that normocalcemic hyperparathyroidism is the onset of a dynamically evolving symptomatic hyperparathyroidism [12]. Biphosphonate treatment may have contributed to normocalcemia in our patient. It is also well known that malignancy-associated hypercalcemia is often accompanied by low levels of the active form of vitamin D (1,25 OH-vitamin D). It may cause both decreased calcium absorption from the intestine and a relatively high renal calcium excretion, thus contributing to normacalcemia, even in the presence of high PTH. However, in our patient, serum levels of 25(OH) vitamin D and 1,25(OH) vitamin D were within normal range—even if in the lower part of the range—thereby, excluding vitamin D insufficiency as a cause of elevated PTH without abnormalities in serum levels of calcium (see Table 1). PC is often diagnosed late after surgery when local recurrence or metastases occur, but is curable when detected early (diagnosed/suspected pre-or intra-operatively); the present case stresses the need for increased appreciation of the variability in clinical patterns of presentation.
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In our patient, PC was suspected intraoperatively because of the finding of a lobulated parathyroid mass of 3.5 cm maximum diameter, surrounded by a fibrous, grayish-white capsule tenaciously adherent to adjacent tissues, which is the usual appearance of a parathyroid malignant mass [1, 2]. Thus, an aggressive (en bloc resection) surgery was performed, along with a bilateral neck exploration to exclude the presence of parathyroid hyperplasia, and the patient’s 5-year outcome was good. The surgical specimens were carefully examined in order to confirm the suspicion of malignancy. Histopathological diagnosis of PC is extremely challenging because features overlap with those of parathyroid adenoma, with up to 50% of patients with metastases having been initially diagnosed with benign disease [3, 13]. Some morphological parameters have been considered as signs of malignancy, such as the presence of thick fibrous bands within the tumor, capsular penetration, nuclear atypia and mitotic count [14–16]. However, these findings are present in only half of the cases of PC and may also be observed in parathyroid adenomas [15]. The only unequivocal features of parathyroid malignancy are invasion of vascular and/or adjacent soft tissues, and metastases [16]. Several immunohistochemical markers such as parafibromin, retinoblastoma protein, p53, and cyclin D1, have been sought for the recognition of parathyroid malignancy, but none of them appears to be specific and sensitive enough [17–23]. The proliferation marker Ki-67 has also been indicated as an adjunct tool, since PCs generally have a more intense immunostaining for Ki-67 than adenomas [21–23]. Although an overlap between benign and malignant parathyroid lesions exists [23], the current WHO guidelines concerning PCs suggest that tumors with Ki-67 counts [5% should be subject to closer follow-up due to an increased risk of malignancy [16]. In our case, there was evidence of capsular and vascular invasion, with extraparathyroid metastatic lymph node spread. Immunohistochemical staining revealed a Ki-67 score higher than the cut-off value, showing an increased neoplastic growth fraction and suggesting aggressive behaviour of the lesion. The high NORA values, recorded by standardized AgNOR analysis, also indicated an elevated proliferation rate, thus strongly reinforcing the Ki-67 data. Indeed, the literature suggests that AgNOR analysis may be helpful in distinguishing PC from adenoma [15, 24, 25]. Tuccari et al. [6] showed that NORA values assist in distinguishing hyperplastic, adenomatous and cancerous parathyroid lesions because the corresponding mean ± SE NORA values were 2.895 ± 0.171, 3.638 ± 0.125 and 4.701 ± 0.179 lm2, respectively. Furthermore, all the highest values pertained to metastatic PC [6]. The 4.972 lm2 NORA value in our patient agrees with these previous data [6]. Our report on a single case of PC provides
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further evidence that prognostic parameters such as Ki-67 and AgNORs may aid the pathological assessment of parathyroid tumors which are clearly not benign. In particular, the value of AgNOR quantity in predicting the biological behavior of parathyroid lesions is strengthened by the combination with other cell growth markers like Ki-67. In conclusion, the present case provides evidence that parathyroid malignancy cannot be a priori excluded on the basis of normocalcemic hyperparathyroidism, emphasizing the variability in clinical presentation of PC. Moreover, Ki67 expression and AgNOR analysis confirm their additional value for the pathologist in complementing the routine histological evaluation of a parathyroid mass. Conflict of interest None of the authors had any personal or financial conflicts of interest.
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