A nationwide study on parathyroid carcinoma

Figures & data

Table 1. Clinical and laboratory characteristics of the study patients (n = 132).

	Parathyroid carcinoma	Atypical adenoma	Adenoma	p Value	Parathyroid carcinoma	Atypical adenoma	Adenoma	p Value
N (M/F)	32 (14/18)	28 (12/16)	72 (26/46)
Age at diagnosis	61 (17–83)	59 (31–84)	62 (15–83)	.057^a
Follow-up time	6.7 (2.0–13.9)	6.0 (0.3–10.7)	7.0 (2.3–10.1)	.19
	Preoperative values				Postoperative values
Ca-ion (mmol/l)	1.76 (1.61–1.97)	1.56 (1.50–1.70)	1.44 (1.38–1.51)	<.001	1.38 (1.23–1.48)	1.26 (1.20–1.39)	1.20 (1.16–1.26)	<.001^a n = 116
PTH (ng/l)	989 (461–1518)	355 (149–959)	160 (122–251)	<.001	11 (1–35)	8 (2–45)	19 (12–35)	<.001^a n = 123
Creatinine (μmol/l)	106 (76–147)	82 (68–146)	70 (62–86)	<.001	100 (80– 145)^b			.39^a
25 OH D (nmol/l), n = 82	37 (32–43)	46 (40–53)	50 (39–63)	.052
Alkaline phosphatase (IU/l), n = 81	119 (74–166)	83 (72–109)	79 (57–106)	.018
Phosphate (mmol/l), n = 66	0.8 (0.63–1.04)	0.68 (0.60–0.97)	0.76 (0.59–0.87)	.662
Renal manifestation	16 (50%)	13 (48%)	16 (22%)	.010
Renal failure	14	8	11
Kidney/urinary stones	2	5	5
Bone manifestation	15 (47%)	4 (15%)	27 (38%)	.002
Osteoporosis	11	2	22
Pathological fractures	3	2	11
Brown tumors	5	0	0
Both renal and bone manifestations	9 (28%)	2 (7%)	4 (6%)	.004
Hypercalcemic crisis or hypercalcemia treated in hospital	14 (44%)	6 (22%)	2 (3%)	<.001
Palpable neck mass	8 (25%)	1 (4%)	2 (3%)	.001
Benign parathyroid tumors previously or during the follow-up	12 (35%)	1 (4%)	0 (0%)	.002

Age and follow-up time (years) are presented as median and range.

All continuous variables are presented as medians and IQR.

^a For comparison of preoperative and postoperative levels in each subgroup.

^b One year after operation.p values <.05 are considered statistically significant (marked in bold).

Normal ranges: ca-ion 1.15–1.30 mmol/l, PTH 15–65 ng/l, creatinine 60–100^♂, 50–90 ^♀ μmol/l, 25 OH D > 50 nmol/l, alkaline phosphatase 35–105 IU/l., phosphate 0.71–1.53 ^♂, 0.76–1.41^♀ mmol/l.

Figure 1. Distribution of preoperative serum ionized calcium and parathyroid hormone concentrations in subgroups of parathyroid carcinoma (1), atypical adenoma (2) and benign adenoma (3).

Figure 2. Diagnostic (A–B) and typical (C–F) findings in parathyroid carcinoma. A: Infiltrative growth to adipose tissue, B: Vascular invasion, C: Diffuse growth pattern, and 100% chief cells, D: Nuclear atypia, E: Fibrous bands and hemosiderin, F: Necrosis.

Table 2. Histopathological findings in the different subgroups.

		Parathyroid carcinoma (n = 32)	Atypical adenoma (n = 28)	Adenoma (n = 72)	p Value
Proliferation	Mitotic activity Strong mitotic activity (>1/10 cells)	8 (25%) 2	3 (9%) 1	1 (1%) 0	.001
	Pathological mitoses	2 (6%)	1 (5%)	0	.086
	Nuclear atypia	14 (44%)	5 (18%)	8 (11%)	.003
Dominant cell type	Chief 100% ≥50%	22 (69%) 28 (88%)	19 (68%) 23 (82%)	30 (41%) 58 (78%)	.003 .39
	Clear cytoplasmic ≥50%	1 (3%)	0	4 (5%)	.951
	Oncosytic ≥50%	3 (9%)	5 (16%)	14 (20%)	.079
Growth pattern	Diffuse 0% ≥50% 100%	4 (13%) 24 (75%) 20 (63%)	11 (39%) 17 (61%) 11 (39%)	45 (63%) 25 (34%) 12 (17%)	<.001
	Follicular 0% ≥50%	28 (88%) 2 (6%)	17 (61%) 8 (29%)	29 (40%) 22 (30%)	.007
	Cystic ≥50%	1 (3%)	2 (7%)	6 (8%)	.844
	Islet-cell ≥50%	8 (25%)	6 (19%)	28 (38%)	.301
Necrosis		3 (9%)	0	0	.024
Fibrous septae		28 (88%)	25 (93%)	2 (3%)	<.001
Hemosiderin deposits		18 (56%)	17 (61%)	1 (1%)	<.001
Cysts		10 (31%)	14 (44%)	17 (53%)	.037

p Values <.05 are considered statistically significant (marked in bold).

Figure 3. Parafibromin stain in parathyroid carcinomas (A negative and B positive). Digital images of Ki-67 staining in Tissue Micro Array in a parathyroid adenoma with a low PI (C) and in an aggressive parathyroid carcinoma with high PI (D). The corresponding pseudocolor image of Immunoratio-program respectively with low PI (E) and high PI (F).

Table 3. Parafibromin and Ki-67 proliferation indices and germ-line CDC73 mutation status in the different subgroups.

	Parathyroid carcinoma (n = 32)	Atypical adenoma (n = 27)	Adenoma (n = 71)	p Value
PARAFIBROMIN STAIN
Positive	7 (22%)	9 (33%)	54 (76%)	<.001^a, .34^b
Weak positive	21 (66%)	17 (63%)	17 (24%)
Negative	4 (13%)	1 (4%)	0 (0%)
GERM-LINE CDC73 GENE MUTATION POSITIVE
Parafibromin positive	0% (4/7)	0% (4/9)
Parafibromin weak positive	0% (12/21)	10% (10/17)
Parafibromin negative	50% (2/4)	0% (1/1)
KI-67 INDICES^c
Ki-67 (TMA)	2.7% (0.4–15.6)	2.0% (0.3–7.5)	0.9% (0.2–4.7)	<.001^a, .23^b
Ki-67 (original specimen)	5.0% (1–40)	2.0% (1–10)		0.17^b

Immunohistochemical results were obtained from the tissue micro array.

CDC73 gene mutation analysis was available for 18/32 (56%) and 16/28 (57%) of the patients with PC and APA, respectively. Percentages of CDC73 mutation positive patients are presented with proportions of patients who underwent mutation analyses in brackets.

The tissue sample of one APA patient with CDC73 gene analysis was not sufficient for TMA technique. The patient is excluded from this table.

^a for comparison of three subgroups, for PC vs. PA, and for APA vs. PA.

^b for comparison of PC vs. APA.

^c Median and range.

p Values < .05 are considered statistically significant (marked in bold).

Figure 4. Survival analysis in parathyroid carcinoma, atypical adenoma and parathyroid adenoma. 5-year and 10-year survivals are 90.6 and 71.9% for PC, 83.9 and 73.4% for APA, and 91.7 and 82.5% for PA (p = NS).

Figure 5. Incidence of parathyroid carcinoma in Finland (per 10,000,000/year).

Table 4. Recurrences, treatments and survival in the different subgroups.

	Parathyroid carcinoma (n = 32)	Atypical adenoma (n = 28)	Adenoma (n = 72)	p Value
Persistent diseases	3	2	0
Recurrences	6 (21%)	1	1
Median time to recurrence (months, range)	24 (4–60)	23	18
Total number of operations for PHPT (mean and range)	2 (1–5)	1 (1–4)	1 (1–3)	<.001
≥2 operations	47%	22%	6%
Metastasis during follow-up time	5 (neck lymph nodes, lungs, bone)	0	0
TREATMENTS
Calcium decreasing medication*	22 (69%)	5 (19%)	4 (6%)	<.001
Radiation therapy	7 (22%)	0	0	<.001
Chemotherapy	4 (13%)	0	0	<.001
COMPLICATIONS (TOTAL)
Laryngeal nerve palsy	11 (34%)	3 (11%)	3 (4%)	<.001
Transient unilateral	4	0	1
Persistent unilateral	7	2	2
Persistent bilateral	0	1	0
Hypoparathyroidism	18 (56%)	5 (18%)	1 (1%)	<.001
Temporary, prolonged	11 (34%)	4 (15%)	1 (1%)
Persistent	7 (22%)	1 (4%)	0
SURVIVAL
Deaths during follow-up	8	6	8	.79
Disease-related deaths	4 (13%)	0	0
Overall 5-year survival	91%	84%	92%	NS
Overall 10-year survival	72%	73%	83%	NS

*Pre- and postoperatively.

p Values <.05 are considered statistically significant (marked in bold).

Table 5. Clinical, biochemical and histological findings in patients with recurrent vs cured parathyroid carcinoma (PC).

	PC with recurrence (n = 6)	PC cured in the primary operation, no recurrences (n = 23)	P - value
Age (median)	61 (45 - 68)	65 (17 – 84)	.89
Male	3 50%	11 48 %	1.00
Ca-ion, mmol/l	1.86 (1.61 – 2.42)	1.72 (1.55 – 1.97)	.20
PTH, ng/l	1030 (358- 2120)	904 (68 – 2220)	.41
Creatinine, μmol/l	119 (68-163)	106 (58 – 430)	.30
Alcaline phosphatase, IU/l	134 (119-256)	70 (24 – 651)	.27
Palpable tumour	2 33 %	6 26 %	1.00
Hypercalcaemic crisis	3 50 %	10 43 %	1.00
Renal manifestation	5 83 %	9 39 %	.08
Bone manifestation	3 50%	10 43 %	.64
Tumor size (cm)*	3.0 (0.5 – 3.5)	2.9 (1 – 5)	.46
Metastasis*
Local	2 (trachea, muscle)	1 (thyroid)	.09
Lymph nodes	2 (cervical)	0	.03
Primary surgery
Local resection*	3^# 50 %	13^# 57 %	1.00
En bloc or radical
resection*	3 50 %	10 43 %
Invasion
Capsular	5 83 %	16 70 %	.64
Vascular	6 100 %	17 74 %	.29
Perineural	2 33 %	1 4 %	.10
Proliferation
Mitotic activity:	3 50 %	5 22 %	.045
> 1/10	2 33 %	0
Pathological mitoses	2 33 %	0	.02
Nuclear atypia	5 83 %	5 22 %	.02
strong	0	2
Dominant cell type
Chief cell 100 %	4 67 %	16 72 %	1.00
≥ 50 %	6 100 %	19 87 %	1.00
Clear cytoplasmic ≥50 %	0	2 9 %	1.00
Oncocytic ≥50 %	1 17 %	3 9 %	.19
Growth pattern
Diffuse 100 %	5 83 %	13 57 %	.65
Follicular ≥50 %	0	2 9 %	1.00
Cystic ≥50 %	0	1 4 %	1.00
Islet-like ≥50 %	1 17 %	6 21 %	.51
100% chief cells and 100 % diffuse	4 67 %	9 41 %	.37
Necrosis	3 50 %	0	.006
Fibrous septae	5 83 %	20 87 %	1.00
Hemosiderin deposits	2 33 %	14 61 %	.36
Cysts	1 17%	7 30 %	.71
Immunohistochemical markers in TMA
Parafibromin median	0.5	1.0	.01
0 / 1 / 2^∘	2 / 4 / 0	0 / 17 / 6
Ki-67 mean/median	8.2 / 7.9	3.1 / 2.3	.11

All continuous variables are presented as medians and range.

* at primary operation,

# 1 patient with radical second operation.

∘ in parafibromin staining: 0 = negative staining, 1= decreased staining, and 2 = normal staining for parafibromin.

Normal ranges: Ca-ion 1.15-1.30 mmol/l, PTH 15-65 ng/l, creatinine 60-100^♂ , 50-90 ^♀ μmol/l, alkaline phosphatase 35-105 IU/l.

P-values <.05 are considered statistically significant (marked in bold).