2018 年 65 巻 2 号 p. 245-252
Primary hyperparathyroidism is the most common hormonal manifestation associated with multiple endocrine neoplasia 1 (MEN1). It is generally caused by parathyroid hyperplasia, and parathyroid carcinoma is rare. Here, we report a case of MEN1 with parathyroid carcinoma in two parathyroid glands causing primary hyperparathyroidism. A 40-year-old man with primary hyperparathyroidism due to MEN1 underwent a total parathyroidectomy. His corrected calcium and intact PTH (i-PTH) serum levels were 10.8 mg/dL and 203 pg/mL, respectively. Although three glands were successfully removed, the left upper parathyroid gland could not be detected. Since the right lower parathyroid lesion had invaded into the thyroid, right lobectomy was performed. A portion of the left lower parathyroid tissue was transplanted into his forearm. The histological findings of the left lower and the right upper parathyroid glands were consistent with hyperplasia while that of the right lower parathyroid gland was parathyroid carcinoma. Since the post-surgical i-PTH levels remained high, the intrathyroidal lesion of the left lobe, which was initally diagnosed as an adenomatous nodule, was suspected to contain parathyroid tumor. A fine needle aspiration of the tumor revealed a high concentration of i-PTH. One week after the first surgery, a left thyroid lobectomy was performed. The pathological diagnosis of the tumor was parathyroid carcinoma. After the surgery, calcium and i-PTH levels were normal. Although it is rare, parathyroid carcinoma should be considered as a cause of hyperparathyroidism in MEN1 patients. Since it is difficult to diagnose parathyroid carcinoma before surgery, intraoperative findings are important for the appropriate treatment.
PRIMARY HYPERPARATHYROIDISM (PHPT) occurs in more than 90% of the multiple endocrine neoplasia 1 (MEN1) patients during their life time [1]. Pathological diagnosis of the removed parathyroid tissue is generally either parathyroid adenoma (PA) or hyperplasia (PH). Parathyroid carcinoma (PC) is a rare malignancy that is found in less than 5% of PHPT patients [2]. PC occurs only in 2% of MEN1 patients that have received surgery for PHPT [3] in contrast to the 15% of PC found in hyperparathyroidism-jaw tumor syndrome patients [4]. Here, we report a case of MEN1 with PC causing primary hyperparathyroidism.
A 40-year-old man was referred for follow up of MEN1. His mother was diagnosed as PHPT due to MEN1, 3 years before by his previous doctor but she had not yet been treated. She also had non-functioning pancreatic tumor, lung cartinoid and was suspected as having prolactinoma as her serum PRL level elavated and pituitary gland swelled. At that time, the previous doctor examined his serum calcium (Ca) and intact-PTH (i-PTH) level and detected hypercalcemia and elevation of i-PTH. He had no other family history that suggests MEN1. PHPT due to MEN1 was suspected but his previous doctor did not detect an enlarged parathyroid. Our laboratory tests revealed hypercalcemia due to elevated i-PTH (Table 1). A 12 mm cystic pituitary tumor (Fig. 1) and a 21 mm pancreatic tumor were found (Fig. 2). The levels of pituitary hormones were all within normal range (Table 1). The level of gastrin was slightly high due to hypercalcemia (Table 1). The level of insulin was normal (Table 1). Since the patient did not have any symptoms, he did not desire to be treated at that time, and no further examination was performed. After that, he was followed for PHPT, with a non-functioning pituitary tumor and pancreatic tumor as components of MEN1. Genetic testing was not performed. Five years later, he had the first urinary stone attack and a scapula fracture. He was examined in preparation for treatment. A 99m-Technetium Methoxy-Isobutyl-Isonitrile scintigram showed 4 uptakes in the neck (Fig. 3). A neck ultrasonography revealed two well-defined lobulated masses (1 cm and 2.5 cm) behind the right thyroid, (Fig. 4a). On the left side, two oval masses (1 cm and 8 mm) were found behind the thyroid, (Fig. 4b, 4c). A solid and cystic mass (2.5 cm) in the left thyroid lobe was considered as an adenomatous nodule (Fig. 4d). Serum Ca and i-PTH levels were 11.0 mg/dL and 522 pg/mL, respectively. The T-score of bone density in his forearm was decreased to –4.8 at that time. There was no change in the size and in the hormone levels of either the pituitary or pancreatic tumor. He initially refused surgery, but with time he was unable to bear the pain from the recurrent urinary stone attack, and he agreed to the surgery. A total parathyroidectomy was performed. Since the right lower parathyroid had invaded into the thyroid, a right lobectomy was also done. Tissue (133 mg) from the left lower parathyroid was transplanted into his left forearm. The pathological findings of the left lower and right upper parathyroid glands were consistent with hyperplasia (Fig. 5a, b). Capsular and vascular invasion were observed in the right lower parathyroid gland, and it was diagnosed as PC (Fig. 6a–c). The left upper parathyroid gland was not included in the resected specimen because the mass found there before surgery was fat. After surgery, the i-PTH level remained elevated (i-PTH concentration of 598 pg/mL). To confirm the intrathyroidal tumor in the left lobe as originating from parathyroid tissue, a needle aspiration was performed. The i-PTH concentration of the aspirate was over 150,000 pg/mL. One week after the first surgery, a left thyroid lobectomy was performed. Histologically, PTH-positive neoplastic cells had invaded penetrating the capsule and into blood vessels (Fig. 7a–d). Coagulative necrosis was present. The tumor was pathologically diagnosed as PC. The left lower and right upper parathyroid glands were positive for parafibromin (Fig. 8a). On the other hand, parafibromin was negative in PC of the right lower gland and in the intrathyroid parathyroid tumors (Fig. 8b). After the surgery, the calcium and i-PTH levels decreased (serum Ca concentration of 8.3 mg/dL and i-PTH concentration of 13 pg/mL). The patient is doing well without additional treatment, 1 year and 4 months after the last surgery.
| Normal range | ||
|---|---|---|
| Alb | 4.0 g/dL | 3.8–5.1 |
| Ca | 10.8 mg/dL | 8.5–9.9 |
| P | 3.0 mg/dL | 2.5–4.3 |
| ALP | 689 U/L | 115–359 |
| Cr | 0.77 mg/dL | 0.69–1.06 |
| i-PTH | 203 pg/mL | 16–65 |
| PRL | 11.7 ng/mL | 0–15 |
| IGF-1 | 215 ng/mL | 95–266 |
| LH | 7.1 mIU/mL | 1.7–11.2 |
| FSH | 6.4 mIU/mL | 2.1–18.6 |
| ACTH | 17.3 pg/mL | 7.2–63.3 |
| TSH | 0.252 mIU/mL | 0.38–4.3 |
| Insulin | 10.8 mIU/mL | 1.4–13 |
| Gastrin | 270 pg/mL | –200 |
| Urinary Ca | 0.21 g/day | 0.1–0.3 |
| Urinary Cr | 0.97 g/day | 1–2 |
| Urinary MN | 0.09 mg/mg/CRE | |
| Urinary NMN | 0.20 mg/mg/CRE |
Abbreviations Alb, Albumin; Ca, Calcium; P, Phosphorus; ALP, Alkaline phosphatase; Cr, Creatinine; i-PTH, intact-PTH; IGF-1, insulin-like growth factor-l; MN, metanephrine; NMN, Normetanephrine
Brain MRI (T1-weighted image)
Pituitary tumor (arrow)
Abdominal CT
Pancreatic tumor (arrow)
99m-Technetium Methoxy-Isobutyl-Isonitrile scintigram
The 99m-Technetium Methoxy-Isobutyl-Isonitrile scintigram show uptakes near the upper pole of the bilateral thyroid, an uptake near the lower pole left lobe, and another uptake in the isthmus of the thyroid.
Neck ultrasonography
a) Right upper parathyroid (arrow) and right lower parathyroid glands (arrow head).
b) Left upper parathyroid gland (arrow).
c) Left lower parathyroid gland (arrow).
Left: B-mode scan
Right: B-mode scan with color doppler
d) Solid and cystic mass in the left thyroid lobe that was considered as an adenomatous nodule.
Histological findings of the left lower and right upper parathyroid glands
a) Hematoxylin & Eosin staining
Chief cells and oxyphilic cells show solid or tubular proliferation. No capsular or vascular invasion was observed.
b) Hematoxylin & Eosin staining
Chief cells and oxyphilic cells show nodular and diffuse proliferation without any capsular or vascular invasion.
Histological findings of the right lower parathyroid gland
a) Hematoxylin & Eosin stain
Atypical tumor cells show solid and alveolar growth. Mitoses was rare. Necrosis was abscent.
b) Hematoxylin & Eosin stain
The tumor cells invaded through the capsule (arrows).
c) elastica van Gieson staining
The tumor cells caused venous invasion (arrow).
Histological findings of an intrathyroidal tumor in the left thyroid lobe
a) Hematoxylin & Eosin staining
Monotonous solid proliferation of tumor cells was observed. Mitoses was were rare.
Inset: Immunohistochemical findings for parathyroid hormone.
The tumor cells were positive for parathyroid hormone.
b) Hematoxylin & Eosin staining
Necrosis was present (arrow).
c) Hematoxylin & Eosin staining
The tumor cells invaded through the capsule (arrow).
d) Hematoxylin & Eosin staining
The tumor cells caused venous invasion (arrow).
Immunohistochemical findings for parafibromin
a) Parafibromin was positive in the parathyroid hyperplasia
b) Parafibromin was negative in the parathyroid carcinoma
PHPT of MEN1 is mostly caused by parathyroid hyperplasia, and PC is quite rare as the causasive lesion with a prevalence reported as 0.28 to 2% [3, 5, 6]. There were 14 cases of MEN1-associated PC previously reported (Table 2) [5-16]. Very high levels of serum Ca and i-PTH, a palpable neck mass, and severe bone disease such as osteitis fibrosa cystica are the specific clinical features of PC [17]. In 10 of the reported cases, serum Ca levels exceeded 12 mg/dL. In the present case, the serum Ca was over 12 mg/dL only at one of the analyses. The parathyroid gland was palpable in 2 of the reported cases [6, 14]. In our case, the right upper and lower parathyroid glands together and the left intrathyroidal parathyroid were palpable. Hypercalcemic crisis occurred in 1 case [9]. In our case, the bone density was very low. In most of the cases, data on the bone density are not available. Imaging findings, such as invasion or metastasis, are a specific feature of PC. Ultrasonographic findings, such as irregular margins, heterogeneity, and a depth-width ratio ≥1 of the parathyroid gland, suggest malignancy [18]. In our case, though the depth-width ratio of the right lower parathyroid gland was near 1, heterogeneity and irregular margin were not observed. PC was not expected by ultrasonography. The clinical characteristics of PC occur sporadically and might be a clue to suspect PC in MEN1. It is still difficult to diagnose PC prior to surgery, because of no specific clinical or genetic features for PC associated with MEN1. Only in two cases, PC was suspected prior to surgery. with one case having a high Ca concentration [11] and the other case detected by an aspiration biopsy [12]. Generally, needle puncture of a parathyroid gland for the purpose of diagnosis is not recommended because of the risk of dissemination. In four other cases, including the present case, PC were diagnosed by the intraoperative findings, such as invasive growth or firm consistency of the mass [5, 6, 13]. In our case, the left upper parathyroid gland was ectopically situated in the thyroid. This anatomical variation made it more difficult to diagnose PC prior to surgery and similar to a case reported by Lee et al. [15]. Tamiya et al. reported the positive correlation between i-PTH and total calculated volume of parathyroid glands [19]. The predictive formula for volume (mm3) they have proposed was 15 × i-PTH (pg/mL) –1,000 and reported as it was useful for distinguishing swollen parathyroid gland and a thyroid nodule. Using this formula, the intrathyroidal tumor might be recognized as parathyroid gland before the surgery. In our case, the determination of i-PTH level of the aspirate from the tumor was useful, but it should be carried out as final procedure for undiagnosed tumor in order to avoid spread of tumor cells.
| Author | Year | Sex | Age | PCT/PIT | Ca (mg/dL) |
i-PTH (pg/mL) |
Genetic testing | Pathological diagnosis | Metastasis/Recurrence |
|---|---|---|---|---|---|---|---|---|---|
| Wu et al. [7] | 1992 | M | 52 | –/+ | 16.2 | 154.3 | PC×1 | Local recurrence Chest Wall | |
| Sato et al. [8] | 2000 | F | 51 | –/– | 10.7 | N/A | 842delC in exon 4 | PC×1, PA×3 | No |
| Dionisi et al. [9] | 2002 | M | 35 | +/– | 15.7 | 707.0 | PC×1 | Mediastinum | |
| Agha et al. [10] | 2007 | F | 65 | +/+ | 15.6 | 342.7 | PC×1, N×2 | Mediastinum | |
| Agha et al. [10] | 2007 | M | 32 | +/– | 14.8 | 254.5 | PC×1, N×1 | No | |
| Shih et al. [11] | 2009 | F | 53 | +/+ | 13.4 | 1,354 | c.1406_13dup8 | PC×1 | No |
| Kalavalapalli et al. [12] | 2010 | F | 44 | +/+ | 10.6 | 79.1 | PA×4 | Lungs | |
| del Pozo et al. [13] | 2011 | M | 50 | +/– | 12.4 | 204.0 | W183C in exon 3 | PC×1, N/A×2 | No |
| Juodele et al. [14] | 2011 | F | 39 | +/– | 13.4 | 311.8 | c.129insA-codon43 in exon 2 | PC×2 | Thyroid |
| Lee et al. [15] | 2014 | F | 59 | –/+ | 12.7 | 248.2 | PC×1 | No | |
| Ospina et al. [5] | 2014 | M | 62 | +/– | 12.2 | 127.3 | PC×1, PA×3, N/A×1 | No | |
| Christakis et al. [6] | 2016 | M | 54 | +/– | 10.5 | 42 | c.703G > A(p.E235K) | PC×1, PH×3 | No |
| Christakis et al. [6] | 2016 | M | 55 | +/+ | 13.8 | 673.1 | c.1378C > T(p.R460X) | PC×1, PH×3 | No |
| Cique et al. [6] | 2017 | F | 48 | +/– | 11.0 | 190 | IVS2-3G > C, c.497A > T, c > 499G > T |
PC×1, PA×1, PH×2 | No |
| Present case | 2017 | M | 45 | +/+ | 10.8 | 203 | PC×2, PH×2 | No |
Abbreviations PCT, Pancreatic tumor; PIT, Pituitary tumor; Ca, Calcium; i-PTH, intact-parathyroid hormone; PC, Parathyroid Carcinoma; PA, Parathyroid Adenoma; N, Normal parathyroid gland; N/A, Not Available; PH, Parathyroid Hyperplasia
The histopathological diagnosis of PC is made based on the distinctive histological features, such as the presence of a trabecular pattern, frequent mitoses, thick fibrous bands, and either capsular or vascular invasion similar to that proposed by Schantz and Castleman [20]. Recently, parafibromin, a protein encoded by the HRPT2. Its expression level is decreased or absent in PC in contrast to PA and PH in which HRPT2 expression is retained [21]. In our case, parafibromin expression was decreased in PC and not in PH, and this finding was consistent with the previous study. The conclusive factor is either capsular or vascular invasion. This is also applied to the diagnosis of MEN1-associated PC. In 8 cases [5, 6, 8, 10, 12, 14, 16], including our case, disease was present in multiple glands. PC occurred in two glands only in the cases of Kavalapalli et al. and in the present case [14]. PC occurring in multiple glands in MEN1 seems to be very uncommon. Diagnosis of PC is often difficult until the conclusive factor is not recognized. Indeed, in one case, the histopathological diagnosis was parathyroid adenoma but later the patient developed lung metastasis [12].
The mechanism of carcinogenesis in parathyroid tissues of MEN1 patients is unknown but recent study about expression of micro RNA in parathyroid tissues of MEN1 suggested that miR-1301 and miR-664 in these patients involved both formation of hyperparathyroidism and suppression of parathyroid carcinogenesis by targeting RB1 and CDC73/HRPT2 [22]. Therefore dysregulation of these microRNA or de novo mutation of the target genes in parathyroid tissues of MEN1 patients can be involved in carcinogenesis. Further studies may reveal new tumor markers or methods evaluate the risk of carcinogenesis in MEN1 patients in future.
It is difficult but important to become aware of PC in MEN1 patients prior to surgery in order to avoid incomplete resection.
Although MEN1-associated PC is very rare, it should be evaluated as one of the differential diagnostic candidates in cases of MEN1-associated PHPT. Since presurgical diagnosis is challenging, surgeons must take care to examine the surgical findings to treat patients appropriately.
Ca, Calcium; CDC73, Cell Division Cycle 73 gene; CT, Computed tomography; HRPT2, Hyperparathyroidism 2 gene; i-PTH, intact-PTH; MEN1, Multiple endocrine neoplasia 1; MRI, Magnetic resonance imaging; PA, Parathyroid adenoma; PC, Parathyroid cancer; PCT, Pancreatic tumor; PH, Parathyroid hyperplasia; PHPT, Primary hyperparathyroidism; PIT, Pituitary tumor; RB1, Retinoblastoma 1 gene
Not applicable.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
The authors declare no conflict of interest associated with this manuscript.
YO participated in the surgery and drafted the manuscript, KH and MT participated in the surgery, KH and EN performed the surgery, OI diagnosed the patient clinically, YN made the pathological diagnosis, and TO made the final approval of the manuscript.
We wish to thank Mr. Y. Hasegawa of the Department of Surgical Pathology for his excellent technical assistance in immunohistochemistry.
