Ultrasound combined with biochemical parameters can be used to differentiate parathyroid carcinoma from benign tumors in patients with primary hyperparathyroidism

Abstract

BACKGROUND:

Primary hyperparathyroidism (PHPT) results from excessive secretion of parathyroid hormone from parathyroid tumors. Differentiating parathyroid tumors can be challenging before operation.

OBJECTIVES:

To differentiate parathyroid carcinoma from benign tumors in patients with PHPT by the application of ultrasound and biochemical parameters.

METHODS:

This study is a retrospective study. The study enrolled 17 patients with parathyroid carcinoma (PC) and 57 patients with parathyroid adenoma (PA), confirmed by postoperative pathology, between September 2010 and July 2017. This study retrospectively compared the ultrasonic features of the tumors included echotexture, maximum lesion diameter, shape, margin, blood flow inside the mass, intralesional calcifications, cysts in the mass, and biochemical parameters included serum calcium, phosphorus, parathyroid hormone (PTH), alkaline phosphatase (ALP) levels, gender distribution and age of patients between patients with PC and those with PA.

RESULTS:

In the US images, the two groups showed significant differences in heterogeneity, the appearance of a taller-than-wide shape, irregular or lobulated margins, and intralesional calcifications (p < #x003C;< #x200A;0.05). However, no significant difference was found in echogenicity, maximum lesion diameter, blood flow, and cystic components of the mass (p > #x003E;> #x200A;0.05). The mean PTH levels were significantly different between the two groups (p < #x003C;< #x200A;0.05). The PC and PA patients did not differ significantly in terms of mean serum calcium, mean serum phosphorus, and mean ALP levels (p > #x003E;> #x200A;0.05). There were significant differences to distinguish PC from PA in calcifications in mass or/and taller-than-wide shape combine with PTH > #x003E;> #x200A;1000 pg/mL (p < #x003C;< #x200A;0.05). Significant difference existed in the age between the two groups (p < #x003C;< #x200A;0.001). No significant difference existed in the gender distribution between the two groups (p > #x003E;> #x200A;0.05).

CONCLUSION:

Ultrasound features especially intralesional calcifications and taller-than-wide shape combine with an extremely high serum PTH (>1000 pg/mL) are helpful in differentiating between benign and parathyroid tumors in patients with PHPT.

Keywords

Adenoma biochemical findings parathyroid carcinoma primary hyperparathyroidism ultrasonography

1 Introduction

PHPT is one of the most common endocrine diseases worldwide. The excessive secretion of PTH leads to primary hyperparathyroidism (PHPT). Both a single lesion and multiple tumors in the parathyroid glands can lead to PHPT [1]. Parathyroid tumors include carcinoma, adenoma, or hyperplasia. Approximately 80–95% of PHPT is caused by parathyroid adenomas (PA), and 0.1–5% is caused by parathyroid carcinomas (PCs) [2 –6]. The curative treatment for parathyroid tumor is surgical resection. The parathyroid cancer needs radical resection with surrounding tissue, while in case of parathyroid adenoma a local parathyroidectomy is sufficient. However, local recurrent rate of PC is very high, and PC can be transferred far away. It is crucial to recognize PC before surgery. But differentiating between PC and PA presurgically is difficult, due to the similarities of the clinical and imaging features, particularly for lesions that are noninvasive or metastatic [7 –10].

99mTc-sestamibi (MIBI), SPECT/CT, and 18F-fluorcholine PET/CT are usually used for the preoperative localization of parathyroid lesions in patients with PHPT, especially for ectopic parathyroid lesions [11, 12]. Fine needle aspiration cytology (FNAC) could be used to identify PC and PA, but FNAC is not recommended for diagnose PC preoperative, because FNAC could cause rupture, seeding of the tumor, and the progression of parathyroid disease [13, 14]. US could be used to locate and diagnose parathyroid lesion of the neck. US has the advantages of being economic and convenient, and does not require radiation exposure [5 , 15–16]. Some studies also showed contrast-enhanced ultrasonography (CEUS) could use for localization and diagnosis of pathologic parathyroid glands due to their typical microvascularization [17 –20]. However, ultrasonography features of parathyroid tumor, especially in malignant tumor, and the biochemical findings have not investigated. Therefore, this study aimed to identify the preoperative ultrasound features and main biochemical findings that could help to differentiate PAs from PCs.

2 Materials and methods

2.1 Patients

Between September 1, 2010, and July 31, 2017, consecutive patients who had undergone parathyroid resection for tumors were retrospectively reviewed. The inclusion criteria were as followed: (1) primary hyperparathyroidism, (2) the diagnoses were confirmed by pathology, (3) US performed and biochemical test performed before operation. The exclusion criteria were as followed: (1) secondary hyperthyroidism, (2) invasions or metastasis, (3) incomplete clinical-pathological data or ultrasonic imaging data. Ultimately, 17 patients with parathyroid carcinoma and 57 patients with parathyroid adenoma were enrolled. The hyperplasia was excluded, because all lesions in hyperplasia in this study were secondary to hyperparathyroidism. One patient with PC had 2 lesions.

Written informed consent was obtained from all patients, and the approval from the Institutional Ethics Committee of the hospital for this study was waivered.

2.2 US

All of the patients were subjected to preoperative US examinations. The scanner was equipped with a 5–12 MHz linear transducer (Philips IU22, Bothell, WA, USA or Aplio500, TOSHIBA, Tokyo, Japan).The patients were placed in a supine position with a shoulder pad pillow and with the anterior neck fully exposed. The thyroid gland was marked, and the scanning areas focused on the posterior trachea and the carotid artery. The subclavicular region and center of the mandible were also included. The general condition was chose for scanning the thyroid and parathyroid. For deep lesions, the frequencies of the probe were appropriately reduced, the depth and focus were also adapted appropriately. In addition to adjusting the depth and focus, the local magnification function also used to show more details of the smaller lesions (<1 cm). Color Doppler sonography was performed (scale 2.0–5.0 cm/s) to observe vascularization of the lesions. The scans were performed by 7 radiologists with 2–20 years of experience.

The US images were retrospectively reviewed in consensus by 2 radiologists with 5 and 18 years of experience in thyroid imaging. The imaging features were analyzed, with a focus on the following factors: echogenicity (hyper-, iso- or hypo- intense, relative to the sternocleidomastoid muscle [21]), echotexture of the solid portion of the mass (homogeneous or heterogeneous), maximum lesion diameter, shape (taller-than-wide or wider-than-tall [21]), margin (smooth, irregular, or lobulated), blood flow inside the mass (rich or poor), and presence of calcifications and cysts in the mass. According to Adler’s method, the vascularity was subjectively determined to be absent (grade 0), minimal (grade 1), moderate (grade 2), or marked (grade 3). In general, 1 or 2 areas of blood flow (usually < #x003C;< #x200A;1 mm in diameter) were considered minimal flow. If a main vessel was seen in the area or several small vessels were visualized, then blood flow was judged to be moderate. When 4 or more vessels were visualized, the tissue was classified as having marked vascularity [22]. In this study, rich blood flow was identification as 2 or 3 grade, while poor was 0 or 1grade.

2.3 Biochemical findings

The serum calcium level, serum phosphorus level, serum parathyroid hormone (PTH), alkaline phosphatase (ALP) level were measured preoperatively.

2.4 Statistical analysis

The US features were analyzed by chi-square or Fisher’s exact tests, and were shown as the number of individuals and percentages. The differences between the groups in terms of biochemical parameters, age, gender distribution, and maximum lesion diameters were analyzed with t-tests, and shown as the mean±standard deviation. P < #x003C;< #x200A;0.05 was considered statistically significant. Multivariate logistic regression analysis of US features was conducted to identify the independent risk factors of PC. The analyses were executed using SPSS20.0 software (SPSS Inc., IBM Corp. Armonk, NY, USA). Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of the US features for PC and PA were calculated, respectively.

3 Results

3.1 Clinical findings

Most patients presented with asymptomatic hypercalcemia and were treated for cervical masses, while 5 patients with PAs were treated for dizziness, nausea, backache, or renal pain. Bone pain, knee pain, limb pain, or numbness was found in 9 patients with PA and 3 patients with PC (Table 1).

Table 1
Clinical features of 17 patients with parathyroid carcinoma and 57 patients with parathyroid adenoma

Symptoms PC PA

Abdominal pain/constipation 1 0

Renal pain/backache 0 3

Limbs, joint, bone pain/numbness 3 9

Dizziness, nausea 0 2

Serum calcium or PTH increased/cervical masses 10 40

Chronic pharyngitis 2 0

Loss of appetite, emaciation and fatigue 1 0

Symptoms	PC	PA
Abdominal pain/constipation	1	0
Renal pain/backache	0	3
Limbs, joint, bone pain/numbness	3	9
Dizziness, nausea	0	2
Serum calcium or PTH increased/cervical masses	10	40
Chronic pharyngitis	2	0
Loss of appetite, emaciation and fatigue	1	0

The 17 PC patients included 6 males and 11 females with a mean age of 53 years (27–82 years) and the 57 PA patients included 25 males and 32 females with a mean age of 47 years (20–69 years). The mean age of PC patients is older than PA patients (53.2±14.9 versus 47.2±12.5 years, p < #x003C;< #x200A;0.001). There are no significant differences between the patients with PC and PA regarding gender distribution (p = 0.429). The analysis of the US features revealed that heterogeneity, presence of a taller-than-wide shape, irregular or lobulated margin, calcifications in the lesions were significantly different between groups and were more frequently observed in patients with PC than in patients with PA (Table 2, Fig. 1A, B). There were no significant differences between patients with PC and those with PA in terms of hypo/isoechogenicity, maximum lesion diameter (2.32±1.24 versus 2.43±1.31 cm, p = 1.00), blood flow, and cysts inside the parathyroid mass (Fig. 2A, B). 11 patients with PC and 48 of 57 patients with PA had rich blood flow (grade 2 or grade 3) inside the masses.

Table 2

Comparison of the ultrasonographic features, the gender and age of the patients with parathyroid carcinomas and adenomas

		PC(n = 17)	PA(n = 57)	p value
Echotexture	Homogeneous	5	49	p < #x003C;< #x200A;0.001
	Heterogenenous	13	8
Shape	Wider-than-tall	10	51	p = 0.003
	Taller-than-wide	8	6
Margins	Smooth	2	45	p < #x003C;< #x200A;0.001
	Irregular/lobulated	16	12
Echogenicity	Hyper-	3	48	p = 0.441
	Hypo-/iso-	15	9
Blood flow in the masses	Rich	11	51	p = 0.05
	Few	7	6
Calcifications in a mass		12	2	p < #x003C;< #x200A;0.001
Cyst change in a mass		3	6	p = 0.441
Mean maximum diameter (cm)		2.32±1.24	2.43±1.31	p = 1.00
Gender	Male	6	25	p = 0.429
	Female	11	32
Age		53.2±14.9	47.2±12.5	p < #x003C;< #x200A;0.001

*Values are presented as mean±SD.

Fig. 1

Parathyroid adenoma in a 37-year-old woman. Grayscale (a) and color Doppler (b) ultrasonographic images show a hypoechogenicity mass with a wider-than-tall shape, homogeneous echotexture and rich blood flow signals in the mass.

Fig. 2

Parathyroid carcinoma in a 49-year-old woman. Grayscale (a) and color Doppler (b) ultrasonographic images show a hypoechogenicity mass with a taller-than-wide shape, heterogeneous echotexture, intralesional calcifications (arrow), and rich blood flow signals in the mass.

3.2 US features

The diagnostic value of US for the differentiation between PC and PA were as follows: sensitivity 73.3%, specificity 91.7%, PPV 68.8%, NPV 93.2%, accuracy 88%.

3.3 Biochemical parameters

The mean serum PTH level was significantly different between the two groups (1693 versus 668 pg/mL, p = 0.002). In the PA group, the majority of patients had serum PTH < #x003C;< #x200A;1000 pg/mL (PC 36.4%, PA 82.9%). The mean serum calcium (2.94 versus 2.99 mmol/L, p = 0.729), phosphorus (1.13 versus 0.8 mmol/L, p = 0.069) and ALP levels (211 versus 338 U/L, p = 0.181) were not useful for distinguishing PC from PA (Table 3).

Table 3
Comparison of the main hematological examination of the patients with parathyroid carcinomas and adenomas

PC(n = 17) PA(n = 57) p value

PTH level (12–88 pg/mL) 1693±1099 668±632 p = 0.002

Serum calcium (2.10–2.60 mmol/L) 2.94±0.45 2.99±0.41 p = 0.729

Serum phosphorus (0.97–1.62 mmol/L) 1.13±0.69 0.80±0.24 p = 0.069

ALP level (0–110 U/L) 211±235 338±564 p = 0.181

	PC(n = 17)	PA(n = 57)	p value
PTH level (12–88 pg/mL)	1693±1099	668±632	p = 0.002
Serum calcium (2.10–2.60 mmol/L)	2.94±0.45	2.99±0.41	p = 0.729
Serum phosphorus (0.97–1.62 mmol/L)	1.13±0.69	0.80±0.24	p = 0.069
ALP level (0–110 U/L)	211±235	338±564	p = 0.181

*Values are presented as mean±SD.

3.4 US feature and biochemical findings

The multiple logistic regression analysis of US features showed that the taller-than-wide shape and calcifications in the lesions were found to be favorable factors to differentiate PC from PA. Calcifications in mass together with the PTH > #x003E;> #x200A;1000 pg/mL was significantly different between the two groups (p < #x003C;< #x200A;0.001), with a sensitivity 71.4% (5/7), specificity 100%. The taller-than-wide shape together with the PTH > #x003E;> #x200A;1000 pg/mL was significantly different to identify PC and PA (p = 0.01), with the sensitivity 66.7% (4/6), specificity 75% (3/4). There were also significantly different to identify patient with PC and patient with PA in presence of calcifications in mass and taller-than-wide shape combined with PTH > #x003E;> #x200A;1000 pg/mL (p = 0.003), with the sensitivity 100%, specificity 100% (Table 4).

Table 4
Comparison of the US features combined with biochemical parameters in the patients with parathyroid carcinomas and adenomas

PC PA p value

PTH>1000, intralesional calcifications 7 (38.9%) 1 (1.8%) p< #x003C;< #x200A;0.001

PTH>1000, Taller-than-wide 6 (33.3%) 4 (1.8%) p = 0.01

PTH>1000, Taller-than-wide, intralesional calcifications 4 (22.2%) 0 p = 0.003

	PC	PA	p value
PTH>1000, intralesional calcifications	7 (38.9%)	1 (1.8%)	p< #x003C;< #x200A;0.001
PTH>1000, Taller-than-wide	6 (33.3%)	4 (1.8%)	p = 0.01
PTH>1000, Taller-than-wide, intralesional calcifications	4 (22.2%)	0	p = 0.003

4 Discussion

For examination of parathyroid glands, conventional sonography is the cheapest and fastest preoperative investigation, while Scintigraphy is much more expensive and time consuming [17]. The diagnostic sensitivity of US was superior to that of 99mTc-MIBI and SPECT/CT in pathologic parathyroid glands [12]. PHPT is a result of autonomous production of PTH from 1 or more abnormal parathyroid glands caused by parathyroid tumor. The characteristics of PHPT are hypercalcemia with an increased/inappropriately high (nonsuppressed) PTH level [8–11 , 23–26]. Some studies have shown that patients’ age did not differ significantly between patients with PA and those with PC [27], some studies shown that patients with PC were on average one decade younger than those with PA, and PC has an equal gender distribution with PA [28]. In this study, The PC patients were older than PA patients, perhaps the older age of the patient is useful to recognize PC. The gender distribution in present results was the same as in the literature. PA usually shows mild PHPT, whereas PC be associated with severe PHPT. The majority (90%) of parathyroid cancer tumors are hormonally functional and hypersecrete PTH [6, 29]. In this study, patients with PCs had similar clinical symptoms to those with PAs. The mean calcium, phosphorus, ALP levels were not useful to differentiate PC and PA. However, patients with PC had higher preoperative PTH levels than patients with PA, and the majority of patients with PA had serum PTH < #x003C;< #x200A;1000 pg/mL.

Based on the results of the main biochemical features, the US features were more valuable to differentiate PC from PA. Several previous studies have compared the US features of PC to those of PA and have emphasized the value of preoperative US examinations in patients with PHPT [9–13 , 27–31]. Antoine et al reported that lesion size was not significantly different between patients with PC and those with PA [32]. This study showed that the maximum lesion diameter of PC were 0.9 up to 6.0 cm, mean maximum lesion diameter of PC was 2.32±1.24 cm, while the maximum lesion diameter of PA were 0.5 up to 6.7 cm, maximum lesion diameter of PA was 2.43±1.31 cm. There were no significant differences between patients with PC and those with PA in terms of maximum lesion diameter. Studies reported that parathyroid masses with heterogeneous echotexture, irregular margin, Depth/Width >1, presence of calcification could be PC [3, 11]. Consistent with the studies, the US characteristics of heterogeneous echotexture, taller-than-wide shape, irregular or lobulated margin, and calcifications in the masses were more frequently observed in patients with PC than in patients with PA. Nevertheless, both PCs and PAs showed few intra-nodular cysts. The lesions in both groups showed hypoechogenicity or isoechogenicity compared to the sternocleidomastoid muscle. The multiple logistic regression analysis of US features showed that the taller-than-wide shape and calcifications in the lesions were more favorable to distinguish the two groups. In addition, intralesional calcifications (sensitivity 71.4%, specificity100%) and taller-than-wide shape combine with the PTH > #x003E;> #x200A;1000 pg/mL (sensitivity 100%, specificity100%) were useful to distinguish PC from PA (p < #x003C;< #x200A;0.05).

There were several limitations in this study. First, the results were based on a retrospective review at a single institution. Second, the sample size of each group was small. Third, the peak systolic velocity (PSV) and retention index (RI) were not evaluated in all included patients, due to incomplete imaging data, as some of the radiologists did not use pulsed wave US to measure the PSV and RI of the mass. Forth, contrast-enhanced ultrasonography was not used to evaluate the vascularization and qualitatively diagnose. This research will be continued.

5 Conclusion

Ultrasonography is a key tool for identifying benign or malignant parathyroid tumors in patients with PHPT. Relying only on the PTH level in an individual patient does not allow a clear diagnosis. However, US features especially intralesional calcifications and taller-than-wide shape combined with an extremely high PTH levels, are helpful in differentiating between benign and malignant parathyroid tumors in patients with PHPT.

Ethical approval

This manuscript has not been published or presented elsewhere in part or in its entirety and is not under consideration by another journal.

Conflict of interest

All authors declare that they have no conflict of interest.

Footnotes

Acknowledgments

This work has been supported by Medical Utrasonics, the First Affiliated Hospital, Sun Yat-sen University.

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