Breast Radiation Correlates with Side of Parathyroid Adenoma
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- Woll, M.L., Mazeh, H., Anderson, B.M. et al. World J Surg (2012) 36: 607. doi:10.1007/s00268-011-1394-y
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Prior head and neck irradiation is a known risk factor for hyperparathyroidism. It is not clear whether irradiation for breast cancer, which may expose the neck to radiation, is also a risk factor for hyperparathyroidism. The present study analyzes the association between the side of radiation to the chest following breast surgery and the side of subsequent parathyroid adenoma development.
We analyzed a prospective database of 1,428 consecutive patients who underwent parathyroidectomy at our institution between November 2000 and August 2010. Patients who had previously undergone breast surgery were identified. Patients with multigland disease were excluded. Patients with bilateral breast surgery were counted as having had two separate procedures; one on each side. Patients who had radiation therapy following breast surgery (RadRx) were compared to those who had breast surgery without radiation treatment (No RadRx).
A total of 146 breast procedures were performed in 121 patients. Forty procedures were in the RadRx group versus 106 cases in the No RadRx group. Patients with radiation therapy were older (68 ± 1.8 years versus 63 ± 1.2 years; P = 0.02) and had higher preoperative calcium levels (11.3 ± 0.1 mg/dl versus 10.9 ± 0.1 mg/dl; P = 0.001). However, there was no significant difference in either parathyroid hormone (PTH) level or gland weight. The latency period between breast irradiation and parathyroid surgery was 8 ± 0.9 years. Interestingly, the side of radiation therapy was associated with the side of the parathyroid adenoma in 76% of cases, compared to only 44% in those who had breast surgery without radiation exposure (P = 0.0004).
The present study demonstrates that, similar to prior head and neck radiation, prior breast irradiation correlates with the development of parathyroid disease. Specifically, there is a strong correlation between the side of the radiation therapy and the side of a subsequent parathyroid adenoma. Breast irradiation should therefore be considered a risk factor for the development of parathyroid adenomas.
In the middle of the twentieth century, several studies investigated the relationship between prior radiation therapy and the risk of tumor development. Duffy and Fitzgerald first established the connection in a paper concerning 27 patients with childhood thyroid cancer, 10 of whom had previously been exposed to radiation . The relationship between radiation and development of a parathyroid tumor was reported in 1975 when Rosen et al. published a case report about a woman with facial hirsutism who received radiation therapy and subsequently developed a parathyroid adenoma and hyperparathyroidism . In the late 1980 s and early 1990 s, studies reported a 2.9-fold increase in the incidence of hyperparathyroidism in patients who had previously received neck radiation therapy compared to those who had not [3, 4].
Radiation exposure, whether given at high or low doses, has been shown to increase the frequency of many tumors, including those of the skin, breast, salivary glands, thyroid, and parathyroid glands [5–9]. While once a relatively common treatment for conditions such as acne and tonsillar enlargement, head and neck irradiation was phased out as treatment option for benign disease in the middle of the twentieth century. It is now reserved primarily for treatment of malignant conditions such as Hodgkin’s lymphoma and neuroblastoma.
Irradiation for breast cancer is associated with numerous side effects, including fatigue, skin irritation, rib fractures, radiation pneumonitis, cardiac toxicity, and myelosupression [10–13]. Breast irradiation has also been associated with an increased risk of cancer of the skin, muscle, lung, and soft tissues [10, 12]. However, an association between breast irradiation and hyperparathyroidism has never been established.
The aim of the present study was to investigate the correlation between breast irradiation and parathyroid adenoma. We investigated whether the side of the breast irradiation correlated with the side of a subsequently developed parathyroid adenoma. The objective was to determine whether breast irradiation should be considered a risk factor for the development of a parathyroid adenoma.
A review of a prospective database (University of Wisconsin Parathyroid Surgery Database) was performed for all patients with hyperparathyroidism. Data on demographics, past surgical history, previous smoking history, location of parathyroid adenoma, and other histological and pathological features of the adenoma were collected prospectively. Laboratory studies, including serum calcium and parathyroid hormone levels were recorded prior to and after the operation, in addition to gland weight. All parathyroidectomies were performed by one or another of two endocrine surgeons in the Department of Surgery at the University of Wisconsin.
From March 2001 to August 2010, 1,428 patients with hyperparathyroidism underwent parathyroidectomy at the University of Wisconsin. Included in this database were 121 patients who had previously undergone breast surgery (146 procedures). Adenoma patients with positive preoperative localization by Tc-99 m sestamibi and/or neck ultrasound routinely underwent minimally invasive parathyroidectomy. Cure was confirmed by an intraopertaive parathyroid hormone (PTH) level drop greater than 50% below pre-excision levels. If preoperative imaging studies were negative, no adenoma was identified on initial exploration, or PTH levels did not drop sufficiently, bilateral exploration of the neck was performed.
Detailed data were retrospectively collected on the 121 breast cancer survivors and included age at the time of the breast procedure, etiology for surgery, extent of surgery, side of surgery, and whether the patient had been treated with adjuvant radiotherapy. Patients who underwent bilateral breast surgery were counted as having had two separate operations, one on each side (thus the total of 146 procedures). Patients with no history of breast surgery, patients with bilateral multigland parathyroid disease, and patients in whom the side of the tumor could not be determined were excluded.
The patients were then divided into two groups: a RadRx group, i.e., those also treated with breast radiation and a No RadRx group, i.e., patients who underwent breast surgery but did not receive subsequent radiation. The two groups were compared for multiple variables, including demographics, laboratory studies, gland weight, and latency period between the breast and parathyroid surgeries.
The side and location of the parathyroid adenoma in each case was recorded as right versus left and upper versus lower and compared to the side of the breast procedure in both groups. To identify differences between the RadRx and the No RadRx groups, univariate analysis with Chi-square and t-test were used. Statistical calculations were completed with the statistical software SPSS version 11.5 (SPSS, Inc., Chicago, IL), and a P value < 0.05 was considered to represent statistical significance for all comparisons.
All patients in both groups were women. Patients in the RadRx group were significantly older (68 ± 1.8 years versus 63 ± 1.2 years; P = 0.02). The RadRx group also had a higher mean preoperative calcium level (11.3 ± 0.1 versus 10.9 ± 0.1 mg/dl; P = 0.001), however, there was no significant difference in PTH level (131 ± 13 mg/dl versus 116 ± 6 mg/dl; P = 0.25) or gland weight (581 ± 107 mg versus 567 ± 61 mg; P = 0.90).
Breast procedure type in both groups
RadRx (n = 40)
No RadRx (n = 106)
Gland location in both groups
RadRx (n = 40)
No RadRx (n = 106)
Ipsilateral to breast surgery
Contralateral to breast surgery
All patients in both breast surgery groups were identified as having parathyroid hypercellularity on final pathology, and none were diagnosed with parathyroid carcinoma. At a mean follow-up of 15 months and a median of 11 months (range: 6–61 months), only 3 (2%) patients of the entire cohort developed recurrent hyperparathyroidism. All three patients were in the No RadRx group (P = 0.22).
If breast irradiation had no impact on the development of parathyroid adenoma, then the expected rate of having a parathyroid adenoma on the same side as the radiation would be 50%, as demonstrated in our entire cohort. The primary finding in the present study is that breast surgery followed by radiation therapy was associated with significantly higher rates of ipsilateral parathyroid adenomas (76% versus 44%; P = 0.0004).
The understanding that radiation increases the risk for tumor development evolved over the second half of the twentieth century. It is not incidental that the thyroid and parathyroid gland tumors are associated with neck irradiation. In 1950, Duffy and Fitzgerald first established the association in a report concerning 27 patients with childhood thyroid cancer, 10 of whom had previously been exposed to radiation . The relationship between radiation and a parathyroid tumor was first reported as a case report in 1975 , and subsequently in larger series that reported a 2.9-fold increase in the incidence of hyperparathyroidism in patients who had previously received neck radiation therapy compared to those who had not [3, 4].
Radiation therapy following breast surgery is often “complementary” to surgical removal of the tumor. There are several indications for breast, chest, and axillary irradiation following surgery for breast cancer, and it is used with increasing frequency as an adjuvant treatment. While the techniques and modalities used in this field are constantly changing, the fact remains that any type of radiation therapy poses downstream risks to the patient. While radiation therapy for breast cancer is generally very well-tolerated, it does pose the risk for multiple acute and chronic side effects [10–13], including an increased risk for cancer within the irradiated tissue. In breast cancer patients, this risk has been estimated at approximately 1%, and becomes detectable after at least 5 years of follow-up .
Detailed information about the radiation received by women in our cohort is lacking, as the majority of women were treated at outside institutions. Treatment typically encompasses the whole breast or chest wall via tangential beams to a dose of approximately 50 Gray, with or without coverage of the regional lymphatics (axillary, supraclavicular, internal mammary) to a dose of approximately 50 Gray, as dictated by the cancer’s stage and other features. Irradiation of the lumpectomy cavity or mastectomy scar is often boosted to approximately 60 Gray, via fields that would not include parathyroid tissue. In the modern era, computed tomography (CT)-based treatment planning is used to customize radiation therapy field design on the basis of each patient’s unique anatomy. Generally, however, to provide adequate coverage of the residual breast tissue or chest wall, tangential radiation fields extend superiorly to just below the clavicular head. If irradiation of the supraclavicular lymph nodes is required, then a small additional anterior/posterior field is designed to cover this area, with a common superior border near the C5–C6 vertebral interspace. Therefore, depending on a patient’s anatomy and the extent of radiation coverage prescribed, radiation dose to the ipsilateral parathyroid glands could be as high as 45–50 Gray if the glands are encompassed within the radiation fields, or much lower if they are outside the fields. Contralateral parathyroid glands would be expected to receive a lower dose, considering their increased distance from the radiation field borders.
To our knowledge, the association between prior breast irradiation and the development of a parathyroid adenoma has never been established. The results of the present study indicate that a clear majority of patients developed a parathyroid adenoma on the same side where they received breast radiation therapy, suggesting that there is indeed some causality.
In the present study, the latency period in the RadRx group was 8 ± 0.9 years. Previous studies have identified a much longer latency period between neck irradiation and the development of hyperparathyroidism. A study conducted by Stephen et al. in 2004 documented the latency period between head and neck irradiation and the development of hyperparathyroidism to be between 18 and 65 years, with an average of 52 years . Similar studies have described the latency period to be between 35 and 49 years [16–18].
The reason for the shorter latency period identified in our study is not clear, but it is probably related to the higher dose of radiation administered in the treatment of breast cancer. In the past it has been suggested that the high dose of radiation given as adjuvant therapy for breast cancer is associated with a shorter latency period of subsequent malignancies . The association of higher dose radiation to a shorter latency period was also established by Obedian et al. . Thus, the reason for the substantial decrease in the latency period in this study could be due to the much higher doses of radiation usually used in breast cancer treatment as compared to the much lower doses used in nonmalignant conditions, such as acne and tonsillar disease.
In the present study, there were no parathyroid carcinomas identified on final pathology. As opposed to thyroid malignancy, parathyroid cancer is extremely rare, and thus the odds of finding one in such a relatively small cohort is low. Furthermore, the sequence between parathyroid adenoma and carcinoma is ill defined. It is not established that patients with untreated parathyroid adenomas progress to develop carcinomas, and therefore it is not unreasonable that no parathyroid carcinomas occurred in this study.
This is a retrospective observational study, and as such it has several inherent disadvantages. The cohort of patients was identified from all patients that underwent parathyroidectomy at our institution over nine years. This poses a selection bias. No patients in this cohort have undergone thyroid resection, and therefore no conclusions can be drawn regarding a possible association between breast irradiation and benign or malignant thyroid tumors. Our control group (patients with breast surgery and no radiation therapy) is heterogeneous, and the majority of the patients in this group did not have breast cancer. Such bias is inevitable. Furthermore, we lack data regarding the radiation dosing, regimen, and fields for each patient, as the majority of the patients were treated at outside institutions.
Current technology enables radiation therapy to be delivered in a much more targeted manner, and therefore radiation dosing and exposure to other body areas can be minimized. Larger, perhaps multi-institutional, studies are needed to further establish the association between breast irradiation and parathyroid adenomas, but even national databases will unlikely be able to report other data needed, such as the side of the breast surgery, radiation, and the parathyroid adenoma. Despite the noted disadvantages of our study, the results reveal a statistically significant association between the side of breast irradiation and the side of a subsequent parathyroid adenoma.
In summary, the present study demonstrates that, similar to prior head and neck radiation, prior breast irradiation correlates with the later development of parathyroid disease. Importantly, the side of radiation therapy is related to the side on which the parathyroid adenoma later develops. The latency period between radiation treatment and treatment of hyperparathyroidism in this cohort is significantly shorter than previous studies at only eight years. Breast irradiation should therefore be considered a risk factor for the development of parathyroid adenomas. Because many breast cancer patients are now long-term survivors, vigilance regarding the diagnosis of hyperparathyroidism is needed as part of their long-term follow-up.