Primary hyperparathyroidism-related giant parathyroid adenoma (Review)

  • Authors:
    • Adina Ghemigian
    • Alexandra Ioana Trandafir
    • Eugenia Petrova
    • Mara Carsote
    • Ana Valea
    • Alexandru Filipescu
    • Ana-Maria Oproiu
    • Florica Sandru
  • View Affiliations

  • Published online on: November 26, 2021
  • Article Number: 88
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Primary hyperparathyroidism (PHPT), an endocrine condition caused by a parathyroid adenoma (PTA) in 80‑85% of the cases, has shifted in the modern era to a mildly symptomatic phenotype due to the prompt recognition of hypercalcemia and to a minimally invasive surgical approach which has a curative potential. Clinical complications of PHTH are either related to high calcium or parathyroid hormone [also parathormone (PTH)] or both, while the originating tumor typically is small, without local mass effects. A distinct entity is represented by giant PTA (GPTA) which is considered at a weight of more than 3 (3.5) grams. The present article is a review of the literature involving practical points of non‑syndromic PHPT‑related GPTA. Most authors agree that pre‑operatory calcium and PTH are higher in GPTA vs. non‑GPTA. However, the clinical presentation of PHPT may be less severe, probably due to local mass effects that bring the patient to an early medical evaluation. Age distribution, sex ratio, rate of successful pre‑operatory location do not differ from non‑giant PTA. Hypovitaminosis D is more frequent in PTA of higher dimensions. Post‑operative hypocalcemia, but not recurrent/persistent PHPT, is expected, even hungry bone disease. A higher rate of atypia is described although the tumor is mostly benign. Unusual presentations such as cystic transformation, initial diagnosis during pregnancy or auto‑infarction have been reported. The ectopic localization of PTA presented in almost 15% of all cases may also be found in GPTA. What are the exact cutoffs for defining GPTA is still an open issue.

1. Introduction

Primary hyperparathyroidism (PHPT), an endocrine condition caused by a parathyroid adenoma (PTA) (80-85%), hyperplasia or carcinoma, has shifted in the modern era to a mildly symptomatic phenotype due to the prompt recognition of hypercalcemia and to a minimally invasive surgical approach which has a curative potential (1,2). An overlap with a vitamin D deficiency-related secondary component is also common due to the global prevalence of hypovitaminosis D (1-3). The incidence of PHPT of 27 to 30 per 100,000 person-years increases with age and is 2 to 3 times higher in women (4,5). In addition, a potential association of increased incidence and obesity has been described, but this condition has also experienced an increased general prevalence worldwide in addition to other multiple complications, whether they are bone-related or not (6,7).

The clinical complications of PHTH are either related to high calcium levels (acute or chronic) or increased parathyroid hormone [also parathormone (PTH)] or both such as osteoporosis and associated low-trauma fractures, neuropsychiatric disorders, neuromuscular manifestations, gastrointestinal disturbances, nephrocalcinosis, and urolithiasis, eventually complicated with urinary infections and kidney failure (8). When it comes to the primary tumor itself, typically the lesion is small and there are no local mass effects unless a carcinoma is the underling diagnosis which is positive in less than 1% of all cases, and also some exceptional cases of very large/giant parathyroid adenoma (GPTA) have been described (9). GPTA is an extremely rare type generally defined as having a weight of at least 3.5 grams (g) or 3 g (depending on the study), and some authors consider this particular endocrine mass as a distinct entity (9). Large PTA is usually considered a tumor weighing between 1 and 3 g (9). PTA, regardless of the size, are identified based on anterior cervical ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT) as well as functional imagery such as 99Technetium-labelled sestamibi-single photon emission CT or scintigraphy (1,9). Regardless of the dimension, surgical removal of a PTA cures the disease with a considerable improvement of many of the associated complications (unless severe kidney disease is already established) (10).

2. Aim

This article is a review of the literature regarding GPTA that causes PHPT focusing on different aspects including pre-operative biochemistry correlates, post-parathyroidectomy outcome, histological issues, unusual locations as ectopic/intra-thyroid, and particular clinical aspects such as diagnosis during pregnancy. The main research tool was the PubMed database. A number of 90 references are cited. We systematized in a table the papers published between 2010 and 2020 displaying HPTH-related GPTA. The level of evidence varied from case report or series to retrospective studies or meta-analyses. Cases with parathyroid carcinoma or hyperplasia or associated multiple endocrine neoplasia syndromes were not included.

3. Giant parathyroid adenoma: Concept around the size considerations

Spanheimer et al considered that a GPTA may represent a particular condition characterized by a larger lesion, a paradoxically less severe phenotype at presentation and a more severe evolution after surgical removal in terms of low calcium levels, not of persistent/recurrent hypercalcemia (9). This study included 300 patients that identified 15 GPTAs with a weight >3.5 g or ≥95th percentile (median GPTA weight of 5.65 g) vs. non-giant PTA group of 285 subjects (median PTA weight of 0.56 g) (9). Analyzing the clinical and laboratory features, the patients with a giant lesion had a statistically significant higher value of calcium (11.07 vs. 10.9 mg/dl) and PTH (227.6 vs. 136.7 pg/ml) before surgery and a lower percent of symptomatic PHPT (9). The pre-operative success rate of localization using different imaging techniques was similar between the two groups (9). The risk of post-operative symptomatic hypocalcemia was higher in GPTA (9). The groups were similar regarding age at diagnosis, sex ratio, location, and the rate of post-operative persistent/recurrent hyperparathyroidism (9).

4. Pre-operative biological correlates

Leong et al published a retrospective study between 2013 and 2018 of 555 patients (a mean PTA weight of 1.022 g) and found a strong positive correlation between preoperative PTH levels and parathyroid weight (r=0.602, P<0.001), a medium correlation between calcium before surgery and parathyroid gland (r=0.474, P<0.001). Thus, PTH appears to be a better predictor of PTA weight than calcemic levels (11). Another cohort of 378 cases presenting with PHPT found a statistically significant correlation of preoperative calcium, respective PTH values and adenoma dimensions and weight. A calcium level >11.5 mg/dl and PTH >165 pg/ml were found to predict a PTA of more than 2.18 cm and 2.7 g (12). A statistically significant correlation (P=0.0001) between adenoma weight with serum calcium, respective PTH (and not serum phosphate) was pointed out in a retrospective study of 69 cases with a mean age of 54 years (mean PTH of PTA of 770.971 pg/ml before surgical removal in association with mean total calcium of 11.47 mg/dl) (13). A study in 2019 of 519 candidates for parathyroidectomy considered ‘dwarf’ PTA the cases with a tumor weight of <3 g (N=100, median 2 g) vs. ‘giant’ PTA, tumors more than 3 g (N=56, median weight of 4.3 g) (14). ‘Dwarf’ when compared with GPTA had statistically significant lower values of calcium and PTH, but overall a weak correlation of biochemistry parameters to adenoma size was established (14). During 40 months of post-operative follow-up, none of the GPTA cases had recurrent disease; the fact that the tumor was large did not underline a malignancy (14). Grover et al published a study in 2020 of 79 patients with PHPT and PTA; 11.3% of them had a giant tumor (maximum diameter between 3.5 and 5.5 cm) without pre-operative correlations in biochemical elements and adenoma size (15). Another potential useful correlation was described in one study between neutrophil/lymphocyte ratio and PTA size (a study on 32 parathyroid tumors, mean age of 53 years, 75% of them were females) (16).

5. Relationship with vitamin D status

Vitamin D deficiency is a stimulus for parathyroid hyperplasia; the component of secondary hyperparathyroidism may be additional to a primary one and it may cause a supplementary increase in parathyroid tumor, regardless of the positive diagnosis of associated osteoporosis, menopausal status or body weight (17). Agarwal et al studied the influence of vitamin D levels and parathyroid tumor weight on 59 patients that were included in a retrospective case-control study based on the PTA weight as small <1 g (N=12 patients), large PTA of 1-3 g (N=34 subjects), GPTA of >3 g (N=13 patients) and based on the 25-hydroxyvitamin D level (deficient, insufficient, sufficient). PTH was higher in vitamin D deficient vs. sufficient subjects while 25-hydroxyvitamin D was lower in patients with larger vs. smaller tumors (18). A prospective study on 51 consecutive patients (mean age of 43 years) with PTA also grouped the PTA based on weight: small <1 g, large 1-3 g, GPTA >3 g and it showed a higher percentage of hypovitaminosis D in GPTA (19).

6. Histological issues

Authors have questioned whether GPTAs have a higher risk of malignancy (20). A retrospective analysis of 3,643 PTAs included 52 atypical PTA (N=34) and 18 malignant parathyroid carcinoma (PC) concluded that PCs have statistically significant higher dimensions (20). Another retrospective analysis of 353 PTA patients divided the lesions into small and large tumor weight (a cut-off of 2 g) and found a statistically significantly higher frequency of atypical lesions among the large tumors (21). Chandramohan et al published a retrospective analysis of 264 patients with PHPT, and 26 patients of these exhibited atypical ultrasound features associated with a larger lesion of the adenoma (22). In 2020, an exceptional case presenting with a GPTA mimicking PC was published. The histological report showed a tumor with dimensions 6.5x5x3 cm; weight of 90 g with preoperative hypercalcemia of 12.5 mg/dl and PTH of 2,747 pg/ml, noting that in the literature the largest weight was 145 g in a female with a GPTA (23,24).

Another unexpected situation is the process of apoplexy in GPTA (25). Garrahy et al reported a case of a 45-year-old female with acute airway compromise due to PTA apoplexy with a mass effect (hypercalcemia of 13.3 mg/dl, and PTH of 367 pg/ml) due to a PTA of 10.7x5.2x4.2 cm (25).

Cystic GPTA associated or not with PHPH have been reported, and liquid accumulation is expected to increase the tumor size (26-28). The parathyroid cysts, functional or non-functional, represent less than 1% of all neck cysts of different etiologies (26-28). Here a few studies are presented. Pontikides et al published 9 cases of cystic parathyroid lesions (female/male ratio of 7/2), of nonfunctioning type (6/9) and with HPTH (3/9) (27). Ghasemi-Rad et al published a retrospective study of 109 cystic (26/109, mean age 43.3 years) and solid (83/109, mean age 48.6 years) adenomas associated with a serum calcium level statistically significant higher in the solid PTA group (11.18 vs. 11.95 mg/dl) while size was higher in the cystic group (28). Hu et al published a retrospective study of 907 patients. The cystic PTAs (37/907) when compared with the solid PTAs (870/907) showed higher PTH, calcium values, and increased risk of hypercalcemic crisis (29). Papavramidis et al published a meta-analysis of cases with 359 cystic PTAs of mean age 49.24 years (females/males: 65/35%), either asymptomatic or running as HPTH, of mean 4.81 cm (ranging from 0.5 to 15 cm) (30).

7. Ectopic PTA of large dimensions

Ectopic PTA tissue is not uncommon, with an incidence of approximately 16% of all cases according to one study from 2019, and some of them are GPTA without a clear incidence (31). The most common sites are the mediastinum, thymus and thyroid (31). A previously mentioned case that was published in 2011, introduces a female with giant mediastinal PTA measuring 7x5x4 cm and weighing 145 g (PTH of 642 pg/ml and calcium of 13.2 mg/dl) (24). Intra-thyroid PTA of large dimensions have been reported (32,33). For instance, Yalcin et al published such a case of a 76-year-old female with preoperative biochemistry revealing hypercalcemia (12 mg/dl) with high levels of parathyroid hormone (512 pg/ml), and a lesion of 2.4x1.9x1.6 cm (33). Vilallonga et al reported a giant inthra-thyroidal parathyroid adenoma of 3 cm maximum diameter, weighing 70 g in a 19-year-old patient with hypercalcemia (14.2 mg/dl) and elevated PTH (1207 pg/ml) (34). Silaghi et al reported an intra-thyroid PTA of 4 cm, complicated with brown tumors (35). Another case with high dimensions at ultrasound was that of a 82-year-old male who presented with classical PHPT symptoms, increased calcium levels and high PTH of 210.4 pg/ml, with a thyroid ultrasound revealing a giant intra-thyroidal nodule (a PTA) of 6.9x5.2x4.8 cm (36).

8. Risk of post-operative hypocalcemia

Most authors agree that after removal of a GPTA, the risk of developing low PTH-related hypocalcemia is higher than seen in patients with smaller tumors (37,38). Hungry bone syndrome may be expected especially if pre-operative PTH is highly increased (37,38). A cases series of 3 GPTAs exhibited severe hypocalcemia after surgery: a 57-year old male with PTH of 1,780 pg/ml, calcium of 14.14 mg/dl, ultrasound features of the PTA of 5x3x2 cm, a weight of 30.6 g; a 60-year old female, with calcium of 16.17 mg/dl, PTH of 863 pg/ml, tumor dimension 5.5x4x3 cm, a weight of 35.2 g, and also a 33-year old subject with calcium of 12.58 mg/dl, PTH of 1,174 pg/ml, and 30 g weight for the PTA (39).

Another exceptional condition is hypocalcemia following an auto-infarction of a previously known or unknown PTA (40). For instance, a reported case from 2018 revealed such a situation involving a GPTA auto-infarction resulting in hungry bone syndrome (40). This case was a 71-year-old man known with atrial fibrillation, treated with rivaroxaban, who was found with severe hypercalcemia of 14.6 mg/dl and elevated PTH of 2,555 pg/ml; ultrasound size of PTA was 4.1x3.6x3.1 cm (40). Therefore, a parathyroidectomy was planned, rivaroxaban was halted 5 days prior to surgery, but the patient developed hypocalcemia before surgery due to spontaneous infarct of the tumor (40). Whether the use of an anticoagulant is a trigger for self-infarction as seen in adrenal glands, it is difficult to establish due to the limited published data (40). Novodvorsky et al reported a series of two cases with auto-infarction: a 51-year-old subject with hypercalcemia of 12.44 mg/dl, PTH of 253.66 pg/ml, PTA at ultrasound of 3.3x1.9x 2.3 cm and a 54-year-old patient admitted for severe hypercalcemia of 18.32 mg/dl in addition to increased PTH of 486.58 pg/ml associated with a PTA of 4.4 cm at MRI (41). The two cases with auto-infarction were managed differently, the first case underwent surgery and the second case was conservatively approached (41).

Table I introduces the review of the literature of cases/studies identified between 2010 and 2020 available via PubMed in the field of HPTH-related GPTA.

Table I

A review of published articlesa between 2010 and 2020 involving giant PTA complicated with PHPH.

Table I

A review of published articlesa between 2010 and 2020 involving giant PTA complicated with PHPH.

Study: First author, year of publicationAge (years)/sex of the subjectsType of study/number of patientsDimensions of the parathyroid adenoma (cm)Weight of PTA (g)Type of lesion (pathological report)Serum calcium (mg/dl)Blood PTH (pg/ml)(Refs.)
Hong et al, 201052/MCase report/18x5.6x4.687Cystic PTA13.28 (N: 8.2-10)93 (N: 16-87)(53)
Tahim et al, 201053/MCase report/13.5x2.0x1.59.25Giant PTA20.8 (N: 8.48-10.6)3,957 (N: 12-75)(54)
Jayant et al, 201145/FCase report/15.0x4.0x3.035Giant PTA14.21,543(55)
O'Neal et al, 2011Mean age 58/F:M=3.5:1Retrospective analysis/353Mean max diameter 1.24<2 gPTAMean 11.3Mean 145(21)
 Mean age 56/F:M=1:1 Mean max diameter 2.52≥2 gParathyroid carcinomas (n=3)Mean 12.0Mean 297 
Asghar et al, 201255/FCase report/111x7.0x6.0-Giant cystic PTA22 (N: 8.6-10.2)1,182 (N: 16-87)(56)
Agarwal et al, 201241/F 18/M; Mean age 36.3 (24-78)Retrospective case-control study/59-Mean 3.543PTAMean 13.6 (N: 8.5-10.2)Mean 683 (N: 9-55)(18)
Mazeh et al, 201279/FCase report/13.5x1.0x0.43.1Cystic PTA13.5 (N: 8.5-10.2)325 (N: 15-65)(57)
Pontikides et al, 201252/FCase series/93.4x3.8x3.5-Cystic PTA-58(27)
 35/F 3.4x2.9x2.3   - 
 48/F 2.6x1.8x3.0   28 
 49/F 6.0x3.1x2.5   32 
 31/F 4.5x3.5x5.0   - 
 22/F 1.2x2.5x3.1   41 
 82/M 5.6x4.0x4.2   1,064 
 51/M 3.3x2.5   881 
 43/F 4.0x3.6x2.1   171 
Khan et al, 201258/FCase report/13.5x4.5x3.2-Cystic PTA23.3 (N: 8.6-10.6)1,364 (N: 10-65)(58)
Zaman et al, 201254/FCase report/1--Giant cystic PTA17.41,182(59)
Vilallonga et al, 201219/FCase report/1Maximum diameter 3.070Giant intrathyroidal PTA14.2 (N: 8.8-10.2)1,207 (N: 7-82)(34)
Kamani et al, 2013F (n=52) M (n=17)Prospective study/69-Mean 8.6 (1.5-31.5)PTAMean 11.74Mean 770(13)
Suzuki et al, 201367/FCase report/11.68x1.62x2.00-Cystic PTA11.68270(60)
Spanheimer et al, 2013Mean age 59.7 yearsRetrospective- study/3000.56 (0.05-3.2)Non-giant PTAMean 10.9Mean 136.7(9)
 Mean age 59.3 years  5.65 (3.5-29.93)(n=285) Giant PTA (n=15)Mean 11.7Mean 227.6 
Sisodiya et al, 201352/FCase report/13.9x2.0x1.7-Giant PTA17598(61)
Singh et al, 2013Mean ageProspectiveMean diameterMeanweightSmall <1 gMean values-(19)
 49.7study/511.60.504Large 1-3 g11.32  
 42.5 2.11.902Giant >3 g12.6  
 45.3 3.69.134parathyroid12.32  
Dutta et al, 201324/FCase report/10.6x1.0-Intrathyroidal parathyroid cyst12.1 (N: 8.6-10.8)1,283 (N: 7-65)(62)
Kim et al, 201367/MCase report/1Maximum diameter 5.4-Cystic PTA10.3113(63)
Haldar et al, 201461/FCase report/16.5x3.0x1.512Giant PTA12.8 (N: 8.4-10.2)179 (N: 11.31-87.69)(64)
Salido et al, 201447/MCase report/1--Giant PTA9.88140.5(65)
Neagoe et al, 201457/MCase report/35.0x3.0x2.030.6Giant PTA14.141,780(39)
 60/F 5.5x4.0x3.035.2 16.17863 
 33/F  30.0 12.58 (N: 9-11)1,174 (N: 15-68) 
Kawashima et al, 201467/FCase report/11.2x1.1x5.4-Cystic PTA14 (N: 8.5-10.2)239 (N: 15-65)(66)
Yalcin et al, 201476/FCase report/12.4x1.9x1.6-Intrathyroidal parathyroid cyst12 (N: 8.8-10.2)512 (N: 13-92)(33)
Zeren et al, 201553Retrospective study/32Maximum diameter 2.9-Parathyroid adenoma Parathyroid carcinoma11.7663(16)
Garas et al, 201553/FCase report/17.0x3.7x2.727Giant PTA15.9 (N: 8.4-10.5)4,038 (N: 10-65)(67)
Sumana et al, 201546/FCase report/16.0x4.0x3.021Cystic PTA16.9 (N: 8.5-10.2)880.1 (N: 12-88)(68)
Colsa-Gutiérrez et al, 201576/FCase report-25Cystic PTA--(69)
Dogan et al, 201569/FCase report/12.8x1.5-Intrathyroidal PTA13.7 (N: 8.2-10.9)507 (N: 15-88)(70)
Taghavi Kojidi et al, 201670/MCase report/1-75PTA14.4 (N: 8.4-10.2)930 (N: 10-65)(71)
Rutledge et al, 201621/FCase report/18.0x5.5x3.058.8Giant intrathyroidal PTA15.84 (N: 8.81-10.42)1,305 (N: 15-65)(38)
Pecheva et al, 201672/FCase report/13.9x3.7x1.919Giant PTA12.1-(72)
Krishnamurthy et al, 201650/MCase report/16.0x4.0-Giant PTA11.2669(73)
Taguchi et al, 201685/FCase report/13.6x2.5x211.3Cystic PTA10.4 (N: 8.1-10.5)1,348 (N:10.3-65.9)(74)
Sahsamanis et al, 201742/FCase report/13.3x2.0x1.45.39Giant PTA10.4 (N: 8.1-10.5)151(75)
Araujo Castro et al, 201740/FCase report/16.4x1.6x2.010.8Giant PTA12.8825 (N: 14-72)(76)
Garrahy et al, 201745/FCase report/15.2x4.2x10.7-Giant PTA13.2367 (N: 15-65) (N: 8.81-10.42)(25)
El-Housseini et al, 201787/FCase report/33.5x3.0x2.0-Cystic PTA13.84305(77)
 31/F 3.5x2.0x1.0  10.76259 
 34/F 5.0x4.5x4.0  11.041,410 
Papavramidis et al, 2018Female (n=228) Male (n=123); Mean age 49 Meta-analysis/359Mean diameter 4.81-Cystic PTA--(30)
Ebrahimpur et al, 201867/FCase report/13.3x3.4-‘Huge’ ectopic PTA13 (N: 8.4-10.2)291 (N: 10-65)(78)
Mantzoros et al, 201873/FCase report/15.0x2.5x2.530Giant PTA14.51629(37)
Verzijl et al, 201871/MCase report/14.1x3.6x3.1-Giant PTA14.6 (N: 8.8-10.48)2,555 (N: 13.2-71.66)(40)
Hu et al, 2018M:F=1:2.9; Mean age 52.8Retrospective study/907Mean diameter 2.1-Solid PTA (n=870)Mean 11.56Mean 408(29)
 M:F=1:1.3; Mean age 54.6 Mean diameter 4.05 Cystic PTA (n=37)Mean 12.52Mean 620 
Anagnostis et al, 201870/FCase report/1Maximum diameter 6.5-Cystic PTA10.8 (N: 8.4-10.4)187 (N: 10-53)(79)
Novodvorsky et al, 201951/MCase report/23.3x1.9x2.3-PTA12.44253.66(41)
 54/F Maximum diameter 4.4- 18.32 (N: 8.8-10.4)486.58 (N: 15-65) 
Çayir et al, 201952/FCase report/1Maximum diameter 8.0-‘Doughnut shaped’ PTA12.37 (N: 8.8-10.6)356.5 (N: 12-88)(80)
Al-Hassan et al, 201952/FCase report/14.0x2.5x1.57.7Giant PTA12.48503(81)
Mirza and Wei, 201931/FCase report/15.0x4.0x3.037Giant PTA14.1622(43)
Wang and Yuan, 201954/FCase report/15x3.2-Giant PTA13.88 (N:8.48-11.68)592.66 (N:6.5-36.8)(82)
Abdel-Aziz et al, 2019Mean age 69Cohort study/519-Mean 0.2Dwarf adenomasMean 11.36Mean 110(14)
 (24-89)  Mean 4.3(<3 g)Mean 12Mean 241 
 Mean age 65   Giant adenomas   
 (25-89)   (>3 g)   
Miller, et al, 201953/MCase report/18.0x3.0x3.030.9Giant PTA11.2179(83)
Chen et al, 201982/FCase report/16.9x5.2x4.8-Intrathyroidal PTA-210.4 (N: 12-68)(36)
Nastos et al, 202154/FCase report/1Maximum diameter 6.58.3Giant PTA12.1 (N:8.1-10.4)277 (N:15-65)(84)
Grover et al, 2020Range from 13-52 yearsProspective study/79 Out of these n=9 (11.3%) had giant PTAMaximum diameter ranged from 1.5 to 5.5-PTARange from 9 to 12.38Range from 225 to 2,444(15)
Leong et al, 2020Mean age 63.3 (17-93)Retrospective study/555-Mean 1.022PTAMean 10.86Mean 168(11)
Gücek Haciyanli et al, 2020Mean age 55.7 (40-71)Retrospective study/537Mean longest diameter 2.87 (ranges: 1-5.5)Mean 14.9 (4-38)PTAMean 15.9-(85)
Evola et al, 202052/FCase report/16.5x5.0x3.090Giant PTA12.5 (N: 8.4-10.2)2,747 (N: 19-65)(23)
Werner et al, 202056/FCase report/15.5x3.1x3.3-Cystic PTA13.52 (N: 8.8-10.6)190 (N: 6.7-38.8)(86)
Monsour et al, 202069/FCase report/13.5x2.1x2.0-Cystic PTA20.4731.8(87)
Güneş et al, 202069/MCase report/15.8x3.2-Cystic PTA--(88)
Papanikolaou et al, 202043/FCase report/13.7x2.5x4.0-Intrathyroidal PTA12.97 (N: 8.4-10.2)457.2 (N: 15-65)(32)
Krishnaraju et al, 202164/FCase report/1Maximum diameter 3.5-Cystic PTA12.8547(89)
Abdulsalam et al, 202163/FCase report/17.0x5.0x4.0145Giant PTA13.2642 (N: 8-97)(90)

[i] aThe studies appear (lines) in the order of the publication year. PTA, parathyroid adenoma; PTH, parathyroid hormone; F, female; M, male; g, grams; cm, centimeter; N, normal values; n, no. of cases.

9. Future considerations

Several topics are still an open issue since, to date, only a limited amount of published data are available. We mention three such categories.

Diagnosis of GPTA during pregnancy

PHTP is exceptionally diagnosed during pregnancy starting most probably from the detection of high calcium values which might be completely asymptomatic (42,43). The newborn may experience convulsions after birth due to calcium metabolism anomalies (42). Some single case reports introduce such situations such as a 29-year-old pregnant female with double PTAs causing PHTP (a calcium level of 11.3 mg/dl, and a PTH of 678 pg/ml) or a diagnosis of HPTP during the first trimester of pregnancy in a female with a serum calcium of 14.1 mg/dl due to high PTH of 622 pg/ml underling a GPTA of 5x4x3 cm with a weight of 37 g (42,43).

Syndromic PHTP-related parathyroid tumors

PHTP is associated with a multitude of other non-parathyroid endocrine/neuroendocrine and non-endocrine tumors such as type IIA multiple endocrine neoplasia; but in cases with specific gene background as RET mutations, the parathyroid tumors actually underline a hyperplasia, not an adenoma (44-48). Since the relationship with genetic makeup and the presence of other tumors influence the timing of PHTP diagnosis and its frequency among a particular syndrome such as other less described neoplasia associations are still incompletely understood (for instance, meningioma and PTA), we consider this heterogeneous chapter a completely different topic and thus we did not discuss it here (47,48).

Parathyroid incidentaloma

The detection of a parathyroid tumor, even very large (especially it is posterior cervical or ectopic), may be incidental, and the assessment of the biochemistry and endocrine panel may become irrelevant, meaning that PHPT is not confirmed (49,50). The diagnosis of PHPT is based exclusively on biological data, a synchronous increase in both calcium and PTH, at least two assays; thus imaging findings, even impressive like in cases of large/giant PTA, do not impact the diagnosis of PHPT itself (1,49,50). Surgical removal of a non-functioning PTA depends mostly on the size and local compressive effects (1,49,50). However, when it comes to a GPTA respecting an incidentaloma scenario, the tumor may be non-functional, but in most cases the clinical identification comes first because of the neoplasia size, thus the accidental imaging detection as part of traditional endocrine incidentaloma definition is not applicable (49). Incidentalomas at the level of the parathyroid gland, regardless of the size, are still a controversy issue in relationship to a clear definition, standards or protocol of management and follow-up, contrary to the massive amount of medical information we have up to this moment about adrenal and pituitary incidentaloma, regardless of whether they are cystic or solid or mixed, of small or large dimensions (49,50). We report here two cases of giant non-functioning PTA. Mossinelli et al described a case of a 46-year-old male with a giant retro-tracheal non-functioning PTA (measuring 5.5x4x2.5 cm and weighing 42 g; normal calcium levels of 9.2 mg/dl and PTH of 70.03 pg/ml) (51). Zhang et al described a 56-year-old male with a compressive giant non-functional parathyroid cyst of 9x6 cm associated with a serum calcium value of 9 mg/dl, and a PTH level of 37.98 pg/ml (52).

Table I introduces the review of the literature of cases/studies identified between 2010 and 2020 available via PubMed in the field of HPTH-related GPTA (11,13-16,18,19,21,23,25,27,29,30,32-34,36-41,43,53-90).

10. Conclusions

A GPTA represents a fascinating particular entity that is associated, in most cases, with PHPT with higher calcium/PTH values at detection, but less complications of PHPT vs. non-giant PTA, probably due to the local mass effects that bring the patient to an early medical evaluation. Post-operative hypocalcemia, but not necessarily recurrent/persistent PHPT, is expected, and even hungry bone disease. A higher rate of atypia is described although the tumor is mostly benign. Unusual presentations such as cystic transformation or diagnosis during pregnancy have been reported. An ectopic PTA localization of almost 15% of cases may also be found. The cut-off for defining a GPTA is still an open issue; but, the values used so far, include a weight of >3-3.5 g.


Not applicable.


Funding: No funding was received.

Availability of data and materials

All information is documented by relevant references.

Authors' contributions

AG drafted the manuscript and critically revised the final form. AIT drafted the manuscript in light of the literature studies. EP researched the literature data. MC drafted the manuscript in light of the literature studies. AV researched the literature. AF is the corresponding author and helped the manuscript drafting in light of the literature studies. AMO researched the literature in connection with all cases of giant parathyroid adenoma and wrote the article according to the requirements of the journal. FS drafted the manuscript, revised the English language of the article and researched the literature with the selection of all the data necessary for the writing of the article. All authors read and approved the final manuscript for publication.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



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Ghemigian A, Trandafir AI, Petrova E, Carsote M, Valea A, Filipescu A, Oproiu A and Sandru F: Primary hyperparathyroidism-related giant parathyroid adenoma (Review). Exp Ther Med 23: 88, 2022
Ghemigian, A., Trandafir, A.I., Petrova, E., Carsote, M., Valea, A., Filipescu, A. ... Sandru, F. (2022). Primary hyperparathyroidism-related giant parathyroid adenoma (Review). Experimental and Therapeutic Medicine, 23, 88.
Ghemigian, A., Trandafir, A. I., Petrova, E., Carsote, M., Valea, A., Filipescu, A., Oproiu, A., Sandru, F."Primary hyperparathyroidism-related giant parathyroid adenoma (Review)". Experimental and Therapeutic Medicine 23.1 (2022): 88.
Ghemigian, A., Trandafir, A. I., Petrova, E., Carsote, M., Valea, A., Filipescu, A., Oproiu, A., Sandru, F."Primary hyperparathyroidism-related giant parathyroid adenoma (Review)". Experimental and Therapeutic Medicine 23, no. 1 (2022): 88.