Parathyroid carcinoma: Is there a role for adjuvant radiation therapy?

Abstract

BACKGROUND

The authors proposed to determine risk factors associated with postoperative progression of parathyroid carcinoma within the neck (locoregional) and to assess the efficacy of postoperative adjuvant radiation therapy in preventing disease progression within the neck.

METHODS

A retrospective review of patients with pathologically confirmed parathyroid carcinoma who underwent surgical resection was performed. Risk factors identified on univariate analysis were applied in a proportional hazards analysis to identify significant independent predictors of locoregional disease progression and cause-specific survival after surgical resection. Fifty-seven patients were treated with surgery alone (no adjuvant radiation therapy [RT]) and were determined to have sufficient follow-up and pathologically confirmed features to be included in the current analysis. Four patients were treated with surgery and adjuvant RT. Four patients received RT to the neck and mediastinum for unresectable locoregional disease progression. Patients were followed for a median of 75.6 months (range, 8.4–358 months).

RESULTS

Twenty-five patients (44%) developed locoregional disease progression at a median of 27.1 months after surgery (range, 6.2–138.3 months). The univariate analysis revealed that surgical margin status and the institution at which the initial surgery was performed were predictive of locoregional progression-free survival. The institution at which the initial surgery was performed was found to be an independent predictor of cause-specific survival. Of the four patients treated with surgery and adjuvant RT, all were alive and without disease at the time of last follow-up. All four patients who received RT for locoregional disease progression after initial surgery achieved locoregional disease control.

CONCLUSIONS

Patients with parathyroid carcinoma are reported to have a significant risk of locoregional disease progression after surgery alone. The results of the current study demonstrated that the risk of postoperative disease progression can be predicted by surgical margin status and the institution at which the initial surgery is performed. Patients treated with surgery and postoperative RT may have a lower risk of locoregional disease progression and improved cause-specific survival. RT can be used to provide locoregional control of recurrent disease. Cancer 2003. © 2003 American Cancer Society.

Carcinoma of the parathyroid gland is a rare cause of hyperparathyroidism, accounting for < 1% of patients with hyperparathyroidism.1 The indolent and progressive natural history of parathyroid carcinoma-induced hyperparathyroidism frequently includes both skeletal and renal complications with eventual death.1, 2 Local cervical invasion, spread to cervical lymph nodes, and metastasis to sites such as the lung and bone are common.2

Treatment guidelines for parathyroid carcinoma have continued to evolve. In 1969, Holmes et al. reviewed the cases of 46 patients with parathyroid carcinoma and suggested that locally invading tumors could be controlled effectively by an initial radical surgery.3 Since that time, several reviewers have confirmed that initial en bloc surgical excision provides the only chance for cure.1, 4 Several studies have reported that neither adjuvant chemotherapy nor radiation therapy (RT) plays a role in improving outcome.2, 5–7

Postoperative progression of parathyroid carcinoma is often fatal. Disease progression rates of 30–67% have been reported.8 Although repeated surgical interventions have proven beneficial in palliative care,9 excision of progressive tumor is not consistently curative.10 In a recent review of 10 cases of parathyroid carcinoma treated at the Princess Margaret Hospital,11 it was suggested that local RT to the tumor bed may decrease the strong predilection for local progression of the disease.

In the current study, we report the exploration of two hypotheses. The first states that there are independent clinical, surgical, or pathologic predictors of postoperative disease progression of parathyroid carcinoma that can be determined through a retrospective review of cases seen within a single institution. These predictors can help to identify those patients at greatest risk for disease progression and a cancer-related death who, therefore, may benefit the most from effective adjuvant therapy. The second hypothesis is that adjuvant RT for patients with the aforementioned risk factor(s) can reduce the risk of disease progression and cancer-related death when compared with treatment with surgery alone.

MATERIALS AND METHODS

Prior to the gathering of data, a multispecialty panel comprised of the authors together identified potential risk factors for the postsurgical progression of parathyroid carcinoma that were to be assessed in the current study. Patient demographics, presenting characteristics, surgical treatment and presentation, and pathologic characteristics were included (Table 1). Selected endpoints were locoregional progression-free survival (LRPFS), cause-specific survival (CSS), and overall survival (OS). LRPFS was defined as the length of time after surgery that the patient was free from clinical and/or pathologic tumor progression anywhere superior to the clavicles and inferior to the base of the skull and the inferior border of the mandible.

Table 1. Potential Risk Factors Considered for Postsurgical Locoregional Progression of Parathyroid Carcinoma

MEN-1: multiple endocrine neoplasia-type 1.

Demographic data

Age

Gender

Race

Presurgical/presenting data

Presence of lump

Serum calcium levels

Bone disease

Nephrolithiasis

Gastrointestinal disturbances

Central nervous system alterations

Neuromuscular abnormalities

Cardiac manifestations (aortic/mitral valve calcifications)

Family history of cancer including association with MEN-1 or other familial syndrome

Health status

Surgical data

En bloc removal

Ipsilateral thyroid gland

Adjacent lymph nodes

Adherent strap muscles

Recurrent laryngeal nerve

Piecemeal tumor removal (or enucleative biopsy)

Pathologic data

Macroscopic appearance

Tumor size

Gray-brown/gray-white

Macroscopic evidence of fibrosis

Surgical margins

Histologic

Well differentiated vs. atypia

Immunologic markers

Genetic

Aneuploidy, euploidy

For cases to be included in the current analysis, the following criteria were required to be met. Patients were required to have received some portion of their initial or subsequent treatment for pathologically confirmed parathyroid carcinoma (either surgery, RT, or both) at the Mayo Clinic. Patients seen in consultation only or those seen for some other unrelated medical illness with no treatment intervention and/or no follow-up were not included. All obtainable pathologic specimens were reviewed to confirm the presence of established diagnostic characteristics. The diagnosis was confirmed by pathologic evaluation, including the following characteristics: 1) fibrous trabeculae, mitotic figures, or capsular and/or vascular invasion; 2) invasion of contiguous neck structures (thyroid gland, trachea, strap muscles, esophagus, etc.); or 3) regional and/or distant metastases. Patients were required to have a minimum of 6 months of follow-up.

LRPFS, CSS, and OS were estimated from the date of surgery using the Kaplan–Meier method.12 Risk factors used in the univariate analysis were applied in a proportional hazards analysis to identify significant independent predictors of locoregional disease progression.

After Institutional Review Board approval and with informed consent from the patient (if still alive), data regarding the patients in the current study were obtained through a comprehensive search of the medical records system at the study institution catalogued by diagnosis in central computer archives. The records of 70 patients who were diagnosed with parathyroid carcinoma and evaluated between December 1928 and October 1999 were identified and reviewed.

Suspicion for parathyroid carcinoma was based on one or more of the following clinical criteria on initial evaluation: hypercalcemia-related symptoms (including nephrocalcinosis), arthralgias, bone pain, muscle cramps, pruritus, a palpable neck mass, odynophagia, hoarseness, weight loss, and fatigue. Serum calcium levels and parathyroid hormone levels were obtained in the majority of cases. The diagnosis was confirmed pathologically.

Of the 70 patients identified, 57 who were treated with surgery and 4 who were treated with surgery and adjuvant RT fulfilled the inclusion criteria. Nine patients were excluded from the analysis because they did not receive treatment at the Mayo Clinic (six patients) or they were found to have an atypical parathyroid adenoma on pathologic review (three patients).

Surgical procedures were comprised of removal of the tumor with one to three parathyroid glands and lymph node dissection or radical en bloc removal of the primary tumor, adjacent organs and tissues, and lymph node dissection. Unfortunately, sufficient surgical reports allowing for the careful analysis of the adequacy of resection performed at institutions other than the Mayo Clinic were not available for all patients.

Patients receiving adjuvant RT were treated as outlined in Table 2.

Table 2. Characteristics, Treatments, and Outcomes of Four Patients Treated with Adjuvant Radiation Therapy

Case no.	Gender	Age at surgery (yrs)	Palpable neck nodule	Serum calcium (ref: 8.9–10.1 mg/dL)		Serum PTH (ref: 1.0–5.2 pmol/L)		Surgery/pathologic margins	Adjuvant RT	Status (follow-up, mos)a
				Preoperative	Post-RT	Preoperative	Post-RT
NED = No evidence of disease; RT: radiation therapy; PTH: parathyroid hormone; F: female; Gy: gray; fx: fractions or number of treatments; AP/PA: anteroposterior/posteroanterior; MV: megavolts; MeV ele: megaelectron volts. a Follow-up data were as of May 12, 2003. b This value is from an outside laboratory with an unknown reference range. c This patient received 3 days of radiation therapy and then underwent pancreatic surgery for a mass discovered on the radiation therapy planning CT scan. The patient then resumed the radiation therapy 23 days after the pancreatic surgery and completed another 30 treatments.
1	F	41	Unknown	17.5b	9.3	15	2.6	Outside institution: in tracheoesophageal groove, “adherent to surrounding tissues,” “had to-be dissected off the esophagus,” “did dissect out quite well”/surgical margins negative for tumor, although tumor within 2 mm in some sections	70 Gy/35 fx/49 days, AP/PA:Obliques, 6 and 10 MV photons	NED (67)
2	F	46	Yes	14.8	9.9	190	4.2	14-g tumor removed in toto without any capsular violation/margins negative for tumor	66 Gy/33 fx/63 days,c AP/PA:Obliques, 6 MV photons, 9 MeV ele	NED (53)
3	F	49	Yes	12.8	9.2	39	3.8	Right inferior gland removal/resection margins, thymus, multiple lymph nodes, and right neck tissue were all negative for tumor	70 Gy/35 fx/50 days, AP/PA:Obliques, 6 and 10 MV photons	NED (66)
4	F	57	Yes	12.8	Not avail- able	100	Not avail- able	Worrisome masses in both lobes of thyroid extending below the inferior poles, tumor surrounding right recurrent laryngeal nerve—nerve protected intact, total thyroidectomy, thymectomy/surgical margins negative for tumor	70 Gy/35 fx/50 days, Obliques, 6 MV photons	NED (54.5)

Outcomes of treatment were obtained through either scheduled follow-up appointments; telephone contact with the patient, family, and/or primary care physician; and/or death certificate.

RESULTS

The clinical characteristics of the 61 patients included in the current study are shown in Table 3. Patients were followed for a median of 75.6 months (range, 8.4–358 months). Thirty-one patients were alive at the time of last follow-up.

Table 3. Baseline Characteristics of 61 Surgical Patients

Presenting characteristics	Overall (no., (%))
Gender
Female	35 (57%)
Male	26 (43%)
Mean age at surgery (yrs)	53.4
Median age at surgery (yrs)	52.3
Symptoms
Asymptomatic	2
Fatigue	15
Muscle cramps	4
Arthralgias/bone pain	22
Tooth pain	2
Epigastric discomfort/nausea	6
Hoarseness	1
Odynophagia	2
Symptomatic neck mass	2
Nephrocalcinosis/nephrolithiasis	17
Hematuria	1
Polyuria	3
Polydipsia	4
Constipation	5
Weight loss	4
Signs
Osteoporosis	3
Palpable cervical mass	17
Serum calcium (mg/dL)
Range	10.6–20.0
Mean	14.4
Median	13.8

A total of 57 patients with parathyroid carcinoma seen at the study institution had undergone surgical resection. Thirty-six of these patients underwent surgery at the Mayo Clinic, whereas the remaining 21 patients underwent resection at another institution. It is interesting to note that 4 of the 36 patients who underwent their initial surgery for parathyroid carcinoma at the Mayo Clinic had previously undergone surgery at another institution to remove what was determined to be a parathyroid adenoma. Locoregional disease progression was reported to have developed in 13 of the patients who underwent surgery at the Mayo Clinic (36%) at a median of 26.5 months and was reported in 12 of the patients who underwent surgery at another institution (57%) at a median of 30.3 months. Thus, a total of 25 patients (44%) developed locoregional disease progression at a median of 27.1 months after surgery (range, 6.2–138.3 months). The 5-year LRPFS was 56.6% (95% confidence interval [95% CI], 43–70%) (Fig. 1).

Figure 1. Locoregional progression-free survival in 57 patients with parathyroid carcinoma who were treated with surgery. 95% CI: 95% confidence interval.

On univariate analysis of the collected data, six risk factors were determined to have sufficient data and the potential to be significant independent predictors of locoregional disease progression. These factors were age of the patient; the pathologic factors of surgical margin status, tumor size, and tumor weight; the presence of vascular invasion; and the institution at which the initial resection was performed (Table 4). The univariate analysis revealed that surgical margin status (P = 0.03) was a predictor of locoregional disease progression (Fig. 2). There was a correlation noted between the institution at which the initial resection was performed and locoregional disease progression (P = 0.06) (Fig. 3). The institution at which the surgery was performed also was found to be a significant independent predictor of CSS (P = 0.03) (Fig. 4).

Table 4. Prognostic Risk Factors Used for Univariate Analysis of LRPFS

Risk factors (no. of patients)	LRPFS		P value
	Median (mos)	5-year (%)
LRPFS: locoregional progression-free survival; NR: median not reached at time of analysis.
Patient age (yrs)			0.59
< 54 (29)	NR	57.5
≥ 54 (28)	95	56.6
Site of initial treatment			0.06
Mayo Clinic (36)	NR	67.1
Other institution (21)	35.1	36.5
Tumor size (cm)			0.32
≤ 2.8 (23)	NR	66.2
> 2.8 (22)	138.3	54.4
Unknown (12)	33.4	38.1
Tumor weight (mg)			0.35
≤ 3895 (17)	NR	68.8
> 3895 (17)	138.3	51.8
Unknown (23)	66.9	50.1
Surgical margins			0.03
Negative (11)	NR	80.0
Close (≤ 5 mm) (7)	95	83.3
Positive/residual (6)	35.1	0
Unknown (33)	66.9	54.4
Vascular invasion			0.89
Present (5)	43.4	25.0
Not present (19)	NR	59.0
Unknown (33)	95	59.5

Figure 2. Surgical margin status as a predictor of locoregional progression-free survival in 57 patients with parathyroid carcinoma who were treated with surgery.

Figure 3. Surgical institution as a predictor of locoregional progression-free survival in 57 patients with parathyroid carcinoma who were treated with surgery.

Figure 4. Surgical institution as a predictor of cause-specific survival in 57 patients with parathyroid carcinoma who were treated with surgery.

The median CSS and OS for patients treated with surgery alone were 204.7 months and 142.2 months, respectively. The 5-year CSS and OS were 82% (95% CI, 71–93%) and 76.9% (95% CI, 66–88%), respectively (Fig. 5).

Figure 5. Cause-specific survival and overall survival in 57 patients with parathyroid carcinoma who were treated with surgery. 95% CI: 95% confidence interval

Four patients seen at the Mayo Clinic were treated with both surgery and adjuvant RT. The characteristics of these patients are shown in Table 2. Three patients had their initial resection performed at the Mayo Clinic. Two had invasive tumors (through the capsule into soft tissues). All four tumors were greater than the median size and weight. Consultation with a radiation oncologist was sought because of concerns regarding residual subclinical/microscopic disease. It is interesting to note that all 4 patients were alive and without detectable disease at 53 months, 54.5 months, 66 months, and 67 months (median, 60 months) of follow-up.

Four patients who received high-dose RT to the neck and mediastinum for unresectable locoregional disease progression achieved locoregional control for 24 months, 26 months, 40 months, and 218 months, respectively.

Three patients received low-dose palliative RT for bone metastases or locoregional disease progression.

DISCUSSION

The standard of care for patients with localized parathyroid carcinoma is complete resection of the primary lesion at the time of the initial surgery. Many patients fail to receive such treatment, however, and experience subsequent tumor progression. In the current study, the 5-year rate of locoregional disease progression in postoperative patients not treated with adjuvant therapy was 44.4%. It has been speculated that optimal treatment may have been prevented by the rarity of this condition as well as late intraoperative recognition.13 The results of the current study suggest that LRPFS and CSS may be more likely to be higher at institutions that have experience in the surgical removal of parathyroid tumors. Alternatively, the current study was conducted as a retrospective review that may inherently have unknown or undetected selection or referral biases that may account for the differences in outcome when analyzed by the institution at which the initial surgical resection was performed. For example, patients with disease progression may be more likely to be referred to an institution such as the Mayo Clinic than patients without disease progression.

Surgical or pathologic predictors of locoregional disease progression traditionally have aided in deciding whether to include adjuvant therapy. The potential predictors analyzed in the current study included the age of the patient and the pathologic factors of surgical margin status, tumor size and weight, and vascular invasion, with only pathologic surgical margin status demonstrating significance. Actuarial analysis from the National Cancer Data Base Report indicated that no particular correlation was observed between tumor size and survival.13 The results of the current study indicate that patients who have undergone subtotal resection of a localized tumor have a significant risk of locoregional disease progression and therefore may benefit from effective initial adjuvant treatment.

Previous studies have reported limited success in the use of RT to decrease hormone production and control tumor growth.2, 5–7 In contrast, the experience of the Princess Margaret Hospital demonstrated no evidence of locoregional disease progression in 6 patients receiving postoperative adjuvant RT for a time period ranging from 12–156 months (mean, 62.3 months).11 Our experience with 4 patients who received postoperative adjuvant RT who were without evidence of disease at 53–67 months of follow-up (median, 60 months) provides further preliminary support that parathyroid carcinoma may be a radiosensitive tumor and that RT may prevent locoregional disease progression. The surgical margin status for these 4 patients was negative in 3 patients and close (≤ 2 mm) in 1 patient. Three patients underwent surgery at the Mayo Clinic and one patient had undergone surgery at another institution. Therefore, based on our surgery-alone series, we would have anticipated one or two patients would develop locoregional disease progression.

However, the average time between surgery and the development of locoregional disease progression has been reported previously1 and also was demonstrated by the current study data to be approximately 3 years. Previous reports of 5-year survival rates for patients with parathyroid carcinoma vary from 40–86%.1, 8, 14, 15 The recent National Cancer Data Base Report on 134 cases reported that the overall relative survival rates at 5 years and 10 years were 85.5% and 49.1%, respectively.13 Therefore, longer follow-up is necessary for those patients in the current study who were treated with adjuvant RT.

Because of the rarity of parathyroid carcinoma, we believe that a prospective, controlled, randomized trial to test the efficacy of adjuvant therapy will not be possible. Along with the experience reported from Princess Margaret Hospital, the current retrospective review indicates the potential benefit of RT as an adjuvant to surgery. Continued follow-up will define the role of RT further in locoregional tumor control and CSS in patients with parathyroid carcinoma.