Primary hyperparathyroidism (pHPT) is the 3rd most common endocrine disease and the only curative treatment is surgery (1). By minimizing the risk of complications that may occur in primary hyperparathyroidism, the highest cure rate can be achieved in the first surgical intervention (2-5). However, even in experienced centers, secondary interventions are necessary in some patients due to persistent or recurrent disease (6,7). Parathyroidectomy can be performed with an operative success rate of over 95% in experienced centers (2,5,8). However, 1-10% recurrence and 2-22% persistent disease have been reported in primary hyperparathyroidism (2,7,9-14).
The recurrence of hypercalcemia and high PTH levels within 6 months after surgery is defined as persistent hyperparathyroidism, and the recurrence of hypercalcemia and high PTH levels 6 months after surgery is defined as recurrent hyperparathyroidism (2). Achievement of normocalcemia 6 months postoperatively is considered as cure (9). Persistent disease is usually related with parathyroid gland pathology that was present in the first operation but not removed. Recurrent disease is usually related with newly developing parathyroid gland pathology (6,7). Seventy percent of secondary operations are performed because of persistent disease (7). Therefore, persistent disease defines surgical failure.
Secondary surgical interventions may be required for persistent and recurrent disease in patients with pHPT. In secondary surgical interventions, the risk of complications may be higher and the cure rate may be lower compared to the first operation (15-17).
In this study, we aimed to evaluate the development of persistent disease and related factors in patients with sporadic pHPT in our clinic.
Materials and Methods
The data of 159 patients who underwent parathyroidectomy for primary hyperparathyroidism in the 2nd General Surgery Clinic of Şişli Hamidiye Etfal Training and Research Hospital between 2000 and 2010 were evaluated retrospectively. Among these patients, 3 patients with familial and hereditary hyperparathyroidism, 1 patient with parathyroid cancer, 23 patients who were followed up for less than 6 months postoperatively and then lost follow-up were excluded from the study. A total of 132 patients with more than six months of follow-up were included in the study.
Primary hyperparathyroidism was diagnosed biochemically in all patients. Ultrasonography and/or scintigraphy were performed as preoperative imaging modality. Preoperative biochemical values, preoperative imaging methods, surgical method, frozen and histopathologic examination results, postoperative Ca, PTH and Ca values at 6 months were evaluated.
All operations were performed under general anesthesia. Bilateral or unilateral cervical exploration was performed. Bilateral cervical exploration was performed through the standard Kocher's necklace incision. Unilateral cervical exploration was performed through two different skin incisions. Unilateral cervical exploration was performed with the standard Kocher's necklace incision through the midline or the anterior border of the sternocleidomastoid (SCM) muscle with a lateral approach. In the other approach, a 2-3 cm skin incision for focused surgery was made at the anterior border of the SCM muscle and the thyroid lobe was entered laterally. The enlarged parathyroid gland was removed and frozen examination was performed in the pathology clinic. Since rapid PTH was not measured, focused surgery was not performed and unilateral exploration was performed through this incision. In patients who underwent unilateral exploration, bilateral exploration was performed if no enlarged parathyroid gland or 2 enlarged parathyroid glands were found on the explored side.
The 132 patients included in the study were divided into 2 groups as patients who did not develop persistent hyperparathyroidism (Group 1) (124 patients) and patients who developed persistent hyperparathyroidism (Group 2) (8 patients). Age, preoperative PTH, preoperative Ca, postoperative PTH, postoperative Ca and follow-up time were compared between the 2 groups. The effect of age, gender, type of surgery, presence of ectopia, multiple gland disease, nodular thyroid disease and the relative risks of these factors on persistent hyperparathyroidism were evaluated.
Statistical Evaluation
Age, preoperative and postoperative calcium, PTH values, and follow-up periods of the groups were compared by Mann-Whitney U test. Comparisons in terms of gender, type of operation, presence of ectopia, multiple gland disease, and nodular thyroid disease were performed with Chi-square and Fisher's exact test. Relative risk was calculated for these characteristics. p<0.05 was considered significant.
Findings
Of the 132 patients included in the study, 107 were female (81.1%) and 25 were male (18.9%) with a mean age of 54.8±12.8 years (20-96). Age, gender, preoperative and postoperative Ca and PTH values and follow-up periods of the patients in groups 1 and 2 are summarized in Table 1 and there was no significant difference between the groups in terms of these characteristics. Of the 131 patients with pathologic diagnosis, 114 (87%) were single adenomas, 6 (4.6%) were double adenomas, and 11 (8.4%) were hyperplasia.
Examination of Group 2 Cases: The characteristics of the patients in group 2 are summarized in Table 2. During this follow-up period, 7 of the persistent patients were treated with a 2nd operation. 1 patient remained persistent.
In 5 of the patients (cases 3,4,5,6,7,8), PTH values taken before excision in the first operation and at 10 and 20 minutes after excision could be evaluated postoperatively. There was no significant decrease in four patients, while 1 patient (case 7) had a decrease of more than 50% to normal values. If rapid PTH was checked in these patients, it could have contributed in 4 of them.
Case 4: Intraoperative rapid PTH measurement would have been helpful in this patient. However, since bilateral exploration was performed in this patient and a pathologic parathyroid gland was detected, the operation was terminated because the other 2 parathyroid glands seen were normal. To find the 4th gland, the carotid sheath was not opened. Postoperative hyperparathyroidism persisted and SPECT/CT examination revealed MIBI uptake compatible with adenoma in the medial neighborhood of the carotid sheath in the superior pole of the left thyroid lobe. Persistence could have been prevented in this patient if the carotid sheath had been opened in the same session and rapid PTH value could have been monitored.
Case 5: In this patient, lateral unilateral intervention was performed because USG and scintigraphy indicated a single gland. When the first scintigraphy was evaluated retrospectively, intraoperative rapid PTH or bilateral exploration could have been performed, taking into account the MIBI retention on the right, which was attributed to the thyroid nodule. According to the postoperative values of this patient, if rapid PTH had been checked perioperatively, the values could have been warning. However, it should be kept in mind that the rapid PTH value is limited in double adenoma.
The striking feature in cases 5 and 6 is the thyroid nodules. In case 5, the weak activity uptake on the right was attributed to a thyroid nodule, but the activity uptake on the right increased in the second scintigraphy performed after the first operation and this uptake was found to be due to the second parathyroid adenoma on the right postoperatively. In the sixth case, intense activity uptake on the left was due to postoperative follicular thyroid cancer. After its removal, activity uptake was detected on scintigraphy on the lower right. Substraction scintigraphy in both patients could have contributed to differentiate whether the activity uptake was due to a thyroid nodule or not. In addition, intraoperative rapid PTH measurement would have contributed if it could have been performed in patient 6.
Cases 3, 7, 8: In all 3 cases, parathyroidectomy was performed without rapid PTH measurement because both imaging methods pointed to the same gland (Figure 6,7). In patient 3, no additional exploration was performed because the thyroid nodule was evaluated as parathyroid on frozen examination. In patients 3 and 8, the pathologic gland could not be seen in this exploration because it was located in the thymus. In addition, even if rapid PTH was checked in patient 7, the exploration would have been terminated at this stage because the PTH value dropped to normal.
Statistical comparisons of the characteristics and risk assessments for peristan development of the groups are summarized in Table 3. There was no significant difference between the two groups in terms of gender. There was also no significant difference between the two groups in terms of the type of surgery performed and the presence of additional goiter. Although there was no statistical difference, the relative risk of persistence in the presence of goiter was 1.8. The rate of persistent hyperparathyroidism was significantly higher in the presence of ectopic gland (p=0.001). The relative risk of developing persistence was 11.81 times higher in the presence of an ectopic gland.
When single adenoma, hyperplasia and double adenoma were compared for multiple gland disease, the development of persistent disease was significantly higher in the presence of multiple glands (p=0.0001). In the relative risk assessment, the risk of persistence in double adenoma was 32.29 times higher than single adenoma. Since there were no persistent patients in the hyperplasia group, relative risk calculation could not be made because this column was 0 in the statistical evaluation.
In the evaluation of the follow-up, recurrence was detected in 2 patients. Recurrence was detected in 1 of the patients at the 42nd month. Since the patient could not be reached for the last follow-up, he could not be examined for recurrence. The Ca level of the second patient was within normal limits until the 17th month follow-up, but increased to 11 mg/dl and PTH level to 90 pg/ml at the 18th month follow-up. This patient did not accept localization studies for the etiology of recurrence and second operation if necessary. Unilateral exploration was performed in 1 patient who remained persistent in the first operation and in one patient who developed recurrence, and bilateral exploration was performed in the other patient who developed recurrence. The overall cure rate in this study was 97.73% (1 persistent, 2 recurrences).
In the postoperative period, transient vocal cord paralysis developed in 1 patient, permanent hypoparathyroidism in 2 patients, wound infection in 1 patient, and wound hematoma in 2 patients (unilateral cases).
Discussion
In our series, gender, type of surgery, presence of ectopic gland, multiple gland disease, and additional goiter disease were evaluated in terms of persistent disease. The presence of ectopic gland and double adenoma were significantly higher in patients with persistent disease. Relative risk assessment showed that the risk of persistence was 11.8 times higher in the presence of ectopic localization and 32.3 times higher in the presence of double adenoma compared to single adenoma. Although there was no statistically significant difference in terms of gender, type of surgery and additional nodular thyroid disease, the presence of nodular thyroid disease was higher in patients who developed persistence. Accordingly, the risk of persistence was 1.8 times higher in the presence of additional nodular disease.
When we review the literature, the most common causes of persistent and recurrent disease are ectopic localization, parathyroid glands and multiple gland disease (6,7,12,14,16,18). Although all these causes are important factors in the development of persistence, surgical experience in the first operation is the most important factor that may affect the possibility of persistent disease (19,20). In a study evaluating population-based predictive factors of persistent hyperparathyroidism, patient age above 70 years was determined as a predictive factor and a high-volume center (over 100 cases per year) was determined as a preventive predictive factor against the development of persistent disease. The presence of negative or suspicious scintigraphy has been reported to be associated with a low success rate (20).
The traditional surgical treatment of primary hyperparathyroidism is bilateral exploration and an operative success rate of over 95% has been reported in experienced centers (2,5,8,9). Since 85-95% of pHPTs are due to a single adenoma and with the development in preoperative imaging methods and increased use of intraoperative PTH measurement, focused surgical interventions have replaced bilateral exploration as the standard approach in many specific centers around the world (8,21). Comparable results have been reported with unilateral and focused surgery compared with bilateral exploration (9,22). In various studies, it has been reported that unilateral and focused surgery resulted in a reduction in postoperative morbidity, operative time, hospital stay and better cosmetic results due to smaller incision and less dissection (8,9,22).
Although most of the data on limited surgical interventions are of short duration, the number of studies comparing with bilateral exploration is increasing (16). The most important criticism of limited exploration is that it is more likely to leave an enlarged gland on the non-explored side or region. Lee and Norton (23) evaluated the rate of single adenoma and multiple gland disease in 2166 patients in 21 studies with bilateral exploration and 2095 patients in 31 studies with focused unilateral exploration between 1995 and 2001.
The rates of single adenoma and multiple gland disease were 79.7%, 92.5%, 19.3% and 5.3%, respectively, and this difference was found to be significant. (24) prospectively evaluated the proportion of enlarged glands that could be left behind by performing limited exploration with preoperative scintigraphy, USG and intraoperative PTH guidance, followed by standard bilateral exploration. They found that 20% of enlarged glands were left when focused surgery was performed when USG and MIBI were compatible. Appropriate intraoperative PTH lowering can only reduce this rate to 16%. Accordingly, the authors reported that operative failure or recurrence may develop at a higher rate than the early reported results.
On the other hand, it was reported that there was no difference in terms of persistent and 5-year recurrent disease in patients who underwent bilateral exploration and minimally invasive intervention due to single gland disease (25). However, cure rate was found to be significantly higher in focused surgery in 2 large series (4,26). In the study of Irvin et al. (4), multiple gland disease in the focused surgery group was 7% lower than in the bilateral exploration group and this difference was statistically significant. The recurrence rate was 4% in the bilateral group with a mean follow-up of 11.3 years and 3% in the focused surgery group with a mean follow-up of 4.2 years. Although the recurrence rate was not different, the follow-up period was shorter in the focused surgery group (4). In a prospective randomized study comparing patients who underwent unilateral and bilateral exploration, the overall operative success rate was 97% and no significant difference was found between the groups in terms of early cure (22).
In another study evaluating the 5-year follow-up of the patients in this study, the recurrence rate was found to be 5% in unilateral exploration and 3% in bilateral exploration and no significant difference was found between the groups (2). The authors reported that unilateral exploration provides equal long-term results with bilateral exploration and is a valid option in the surgical treatment of pHPT.
Although unilateral exploration is more likely to leave an enlarged parathyroid gland, the significance of this is currently unknown (23,24). In many studies, no correlation was found between parathyroid gland size and histology and PTH secretion (27-29). Enlarged glands may not hypersecretion. Therefore, gland size and histology may not be reliable indicators in detecting hypersecreting glands. These findings strongly support the idea that leaving a normal secreting parathyroid gland of varying size in situ with unilateral or focused surgery will not increase the long-term recurrence rate (8).
In a large study evaluating the predictive factors of recurrent disease, it was determined that bilateral exploration or minimally invasive parathyroidectomy was not an independent factor for recurrence (30). In our study, the mean follow-up period was 29 months and there was no significant difference between bilateral and unilateral exploration in terms of persistence and recurrence. Although our follow-up period was shorter than other studies, our data support that unilateral exploration does not increase the development of early persistence and recurrence.
Preoperative failure to detect multiple gland disease and inability to remove all pathologic glands in the operation is one of the most common causes of persistent disease. In our study, multiple gland disease had the highest relative risk rate and the rate of 57% among persistent patients is similar to the rates of 37-62% in persistent and recurrent hyperparathyroidism series (6,7,12,14,18). The risk of persistent disease is high especially when the pathologic gland cannot be visualized on USG and/or scintigraphy (14,20). The most important reason for this is that the ability of imaging methods to detect multiple gland disease is limited compared to single gland disease.
In our study, while USG did not detect the 2nd adenoma together in any patient with 4 adenomas, it is noteworthy that only 1 patient had weak activity uptake in the 2nd lesion on scintigraphy when evaluated retrospectively.
In the other case, the weak activity uptake on the opposite side of the follicular thyroid cancer with intense activity was not pathologically evaluated. The sensitivity of sestamibi scintigraphy in detecting single adenoma, double adenoma and hyperplasia preoperatively is 88%, 30% and 44%, respectively (31). Civelek et al. (11) reported that the combination of this method with SPECT increased the sensitivity values to 96%, 83% and 45%, respectively.
Hacıyanlı et al. (32) determined the suitability of sestamibi scintigraphy and USG alone and in combination in double adenomas as 30%, 40% and 60%, respectively. Even if these methods are combined, a significant portion of multiple gland disease cannot be detected by preoperative imaging methods. In addition, solid thyroid nodules and thyroid cancers, as in our 6th case in the persistent group, may cause false positive results and affect the success of surgery (33).
Although the combination of preoperative scintigraphy and USG increases sensitivity compared to single examination, the presence of thyroid nodules decreases sensitivity. (34) determined the sensitivity of sestamibi scintigraphy, high resolution USG and their combination as 96%, 100% and 100%, respectively, in the absence of thyroid nodules. In the presence of nodules in the thyroid gland, these rates decreased to 81%, 84% and 79%, respectively. In addition, when substraction scintigraphy performed by combining sestamibi with an agent such as Tc-pertechnetate or I-123, which visualizes the thyroid gland, is performed together with SPECT, false positivity related to thyroid nodules can be reduced (35).
Lorberboym et al. (35) reported that in parathyroid pathologies associated with multinodular goiter, the sensitivity of substraction scintigraphy with standard Tcpertechnetate and sestamibi increased from 68% to 95% with SPECT. Some patients with multiple gland disease may be incorrectly evaluated as sporadic hyperparathyroidism because of negative family history and asymmetric hyperplasia in the first operation (19).
Another important reason for persistent disease development due to inadequate initial surgery is ectopic localization. The most common localization is within the thymus, but rarely ectopic adenomas can be found in the mediastinum, intrathyroidal and carotid sheath. In addition to ectopic localization, the presence of double parathyroid adenoma, which is observed with a rate of 2-15%, should also be considered (36,37).
In our 4 persistent patients with double adenomas, the second adenoma was located in the carotid sheath in one and in the thymus in the other. The total ectopic rate among our persistent patients was 57%. Although the ability of USG to detect ectopically located glands is limited, sestamibi scintigraphy can detect parathyroid pathologies in ectopic localization (38).
The application of sestamibi scintigraphy with SPECT increases the sensitivity in ectopically located glands, double adenomas and small adenomas (39,40). While the sensitivity of hybrid imaging obtained by combining SPECT with computed tomography (SPECT/CT) remains unchanged, the specificity of anatomical localization with SPECT/CT has been reported to increase from 48% to 96% (40).
Goiter was detected in 5 of 8 persistent cases in our series. In the first scintigraphy of 2 patients with concurrent thyroid nodules, the weak activity on the contralateral side was attributed to the thyroid nodule detected on USG. The second lesion with weak activity in case 5 was found to be due to the second adenoma. In this case, the second lesion was evaluated as false negative on the first scintigraphy because of the thyroid nodule.
In case 6, the left lesion with high activity on the first scintigraphy was found to be a false positive due to thyroid follicular cancer. In addition, when the first scintigraphy was carefully examined retrospectively, it was not considered as pathologic uptake because there was a weak activity uptake in the lower right. Considering the literature, SPECT in combination with subtraction scintigraphy could have been helpful in the preoperative period in these patients with significant thyroid involvement, especially in localizations with pathological activity uptake.
In 4 patients with scintigraphy and USG compatible adenomas, 2 of whom had single adenomas and the other 2 had double adenomas, additional imaging was not considered because additional imaging was not generally considered in the literature. Bilateral exploration was already performed in 2 patients with negative scintigraphy.
In parathyroid surgery, intraoperative rapid PTH measurement is recommended to decrease the persistence rate and increase the cure rate, especially in focused or unilateral surgery (9,41,42). However, other studies have reported that intraoperative rapid PTH measurement does not increase the cure rate in appropriately selected patients (43,44). The need for intraoperative rapid PTH measurement depends on the type of surgery and the results of preoperative localization studies (19).
If preoperative scintigraphy and USG are compatible for a single gland, it can be performed with 98% success. Since intraoperative rapid PTH measurement will not contribute significantly to the outcome, focused surgery can be performed without intraoperative rapid PTH measurement. If one test is positive, focused surgery can be performed with intraoperative rapid PTH measurement. If two tests are discordant, bilateral exploration or focused surgery with intraoperative rapid PTH measurement can be performed as an alternative (19,45).
One of the most important points of focused surgery is that multiple gland disease is missed due to preoperative imaging methods. Although intraoperative rapid PTH measurement does not provide the same contribution in all patients, it increases the success rate when combined with preoperative imaging methods. When MIBI shows a single gland, the success rate increases from 83% to 92%. When USG shows a single gland, the success rate increases from 71% to 86% with intraoperative rapid PTH measurement.
Although the overall suitability of intraoperative rapid PTH measurement was 80% in this study, it was 87% in single gland disease and 58% in multiple gland disease (46).It has been reported that intraoperative rapid PTH measurement can detect multiple gland disease in 87% of patients with multiple gland disease in whom MIBI showed a single focus.In this study, it was also reported that intraoperative rapid PTH measurement changed the operative treatment in 17% of all patients and increased the operative success to 97% (47).
However, intraoperative rapid PTH measurement in patients undergoing focused surgery may cause the rate of multiple gland disease to be lower than the existing rate.Intraoperative rapid PTH measurement showed a decrease of less than 50% in 43-45% of patients with double adenomas after removal of the first gland and the other gland could be demonstrated (32,48).
(32) found that the appropriateness of the combination of MIBI, USG and intraoperative rapid PTH measurement was 80% in detecting double gland disease.In another study, intraoperative rapid PTH measurement was able to detect multiple gland disease in 83% of patients and the combination of 3 tests in 89% of patients (49). In addition, in these two studies, the false negative rate of intraoperative rapid PTH measurement in double adenomas was high and reported to be 55-57% (32,48). The false positive rate may be related to the difference in the size of adenomas.
Sitges-Serra et al. (50) obtained false positive results in 2/3 of patients with double adenomas after removal of the first of the double adenomas. This occurred when the first adenoma was larger than the second.In the other study, the size of the first adenoma removed was statistically significant in predicting false positivity (48).
(24) found multiple gland disease in 22% of patients in whom preoperative imaging methods showed a single gland when routine bilateral exploration was performed. Intraoperative rapid PTH measurement was able to predict multiple gland disease in only 22% of these patients.In our study, PTH values obtained before excision in the first operation and at 10 and 20 minutes after excision could be evaluated postoperatively in 5 of the persistent patients. Four patients had no significant decrease and 1 patient had a decrease of more than 50% and normal values. If rapid PTH monitoring had been performed in these patients, it would have contributed in 4 of them.
In parathyroid surgery, frozen examination is used to differentiate parathyroid tissue from other tissues (45). Westra et al. (51) determined the suitability of frozen examination as 99.2% in determining parathyroid tissue in a series of 1579 cases. They reported that it is a reliable method for determining tissue type in parathyroid operations.However, despite low false-positive rates on frozen section, misdiagnoses may occur (52).
Parathyroid tissue may be difficult to distinguish from fat, lymph node and thyroid tissue on frozen sections. Especially in adenomatous nodules rich in principal cells, since the principal cell type is smaller than the other 2 types of parathyroid cells, their lesions may be confused with lymphoid tissue on frozen sections.
Since nodules of the parathyroid gland rich in oxyphil cells resemble hurthle (oncocytic) cell lesions of the thyroid gland, if normal parathyroid or thyroid tissue is not seen around the nodule in frozen sections, the thyroid or parathyroid origin of the tissue may not be distinguished or may lead to diagnostic confusion. However, the nature of the tissue can be determined by immunohistochemical study with parathormone, TTF1 or thyroglobulin antibodies after paraffin tracing (53,54).
In our study, lymph node in 1 patient and follicular adenoma in 1 patient were reported as parathyroid on frozen examination. In one patient, parathyroid and thyroid could not be differentiated. Except for these cases, parathyroid differentiation could be made in all our patients operated in this period.
Reexploration is difficult in persistent and recurrent patients. The risk of hypoparathyroidism and recurrent laryngeal nerve injury is high because of the loss of tissue plans related to the first operation and the developing scar tissue (8). In patients who are biochemically proven to have persistent and recurrent laryngeal nerve injury and for whom surgery is decided, the findings of the first operation should be evaluated in the preoperative period, vocal cord examination should be performed and pathologic focus should be investigated with preoperative imaging methods in order to plan the operation (8).
Initial imaging methods should be noninvasive and inexpensive. Expensive and/or invasive tests should be reserved for cases that these tests cannot localize (38). The most commonly used tests are scintigraphy and USG. The sensitivity of scintigraphy increases significantly when combined with SPECT (35). In the literature, the sensitivity of SPECT in secondary cases varies between 50-90%.
The sensitivity of USG is reported to be 57-72% (6,55). The ability of USG to detect lesions in deep cervical tissue and mediastinum is limited (19). Computed tomography and magnetic resonance imaging can also be used before secondary interventions and may contribute to the detection of ectopic and mediastinal lesions that USG cannot visualize. The sensitivity of these methods has been reported in a wide range between 29-88% (6,9,55). The combination of these methods with functional scintigraphic images significantly increases localization rates (1,40). Selective venous sampling can be performed in patients who cannot obtain results with noninvasive methods (55). The overall appropriateness of USG and scintigraphy before reoperation is reported to be over 85% (19).
In our cases, the mediastinal adenoma was detected by SPECT, and the second adenoma localized in the carotid root was detected by SPECT/CT. In one case with double adenoma, the lesion was confirmed by MRI. Otherwise, USG and scintigraphy were sufficient. In conclusion, the lesion was localized preoperatively with noninvasive examinations in all patients. Persistent disease was successfully treated in all patients who accepted treatment.
In conclusion, despite successful surgical treatment of primary hyperparathyroidism, persistent disease may develop at an acceptable rate. Multiple gland disease, especially double adenoma and ectopic location are the most important risk factors for persistent disease. With careful preoperative evaluation of patients with persistent disease and imaging methods, a satisfactory cure rate can be achieved in secondary operations.
