Parathyroid carcinoma in more than 1,000 patients: A population-level analysis

Parathyroid carcinoma in more than 1,000 patients: A population-level analysis Claire Sadler, BA,a Kenneth W. Gow, MD,b Elizabeth A. Beierle, MD,c John J. Doski, MD,d Monica Langer, MD,e Jed G. Nuchtern, MD,f,g Sanjeev A. Vasudevan, MD,f,g and Melanie Goldfarb, MD, MS,h Los Angeles and Santa Monica, CA, Seattle, WA, Birmingham, AL, San Antonio and Houston, TX, and Portland, ME

Background. Parathyroid carcinoma (PC) is a rare malignancy with a moderate prognosis. The staging system, prognostic indicators, and optimal surgical management are still under debate. This large cohort explores prognostic factors for PC. Methods. 1,022 cases of PC in the 1998–2011 National Cancer Data Base that underwent surgery were examined for predictors of lower overall survival (OS) and relative risk (RR) of death at 5 years. Results. The 5-year OS was 81.1% in 528 patients with $60 months of follow-up. The overall cohort was mainly non-Hispanic (96.5%), white (77.4%), and insured (94.3%), with a median age of 57 years. Mean OS was lower and RR of death greater in older (P < .001), black (P = .007) patients with a secondary malignancy (P = .015) and $2 comorbidities (P = .005), whose surgical specimen had positive surgical margins (P = .026) or positive lymph nodes (P < .001). Multivariate cox regression demonstrated that positive lymph nodes (hazard ratio [HR], 6.47; 95% CI, 1.81–23.11) and older age (HR, 2.35; 95% CI, 1.25–4.43) were associated with lower OS. Conclusion. PC is a rare malignancy with a 5-year OS of 81.1%. Positive lymph nodes and older age predict lower OS and an increased risk of death. (Surgery 2014;156:1622-30.) From the Department of Surgery,a University of Southern California Keck School of Medicine, Los Angeles, CA; Division of General and Thoracic Surgery,b Seattle Children’s Hospital, Seattle, WA; Department of Surgery, Division of Pediatric Surgery,c University of Alabama at Birmingham, Children’s of Alabama, Birmingham, AL; Department of Surgery,d Methodist Children’s Hospital of South Texas, University of Texas Health Science Center- San Antonio, San Antonio, TX; Department of Surgery,e Maine Children’s Cancer Program, Tufts University, Portland, ME; and Michael E. DeBakey Department of Surgery,f Baylor College of Medicine, and Department of Surgery,g Texas Children’s Hospital, Houston, TX; and Department of Surgery,h John Wayne Cancer Institute at Providence St. John’s Health Center, Santa Monica, CA

PARATHYROID CARCINOMA (PC) is a rare disease that affects 1.25–5.73 per 10,000,000 persons per year and comprises 1–2% of patients with primary hyperparathyroidism.1,2 Almost all patients present with functional tumors as well as signs and symptoms of severe hypercalcemia.1 The diagnosis of PC is most often made intraoperatively with None of the authors have any conflicts of interest statement nor any financial disclosures to report. Presented at the 35th American Association of Endocrine Surgeons Annual Meeting, Boston, Massachusetts, April 2014. Accepted for publication August 21, 2014. Reprint requests: Melanie Goldfarb, MD, MS, FACS, Assistant Professor of Surgery, Endocrine Surgery, John Wayne Cancer Institute at Providence St. John’s Health Center, Santa Monica, CA 90404. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.08.069

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identification of a firm, gray, large mass that is adherent to the surrounding tissues, or is misdiagnosed as a parathyroid adenoma at the initial operMalignancy may be suspected ation.3,4 preoperatively when both parathyroid hormone and calcium levels are significantly elevated. The natural course of the disease is generally slow and progressive, with the eventual development of local recurrence and distant metastases. Most patients die from severe hypercalcemia or unrelated conditions.5 The 5-year overall survival (OS) rates range from 80 to 90%, although recurrent disease occurs in upwards of 50% of patients.4-6 Current surgical recommendation is en bloc resection of the tumor with removal of the ipsilateral hemithyroid and any other involved tissues, but the benefits of the addition of an ipsilateral prophylactic central compartment lymph node (LN) dissection or other more radical surgery

Surgery Volume 156, Number 6 are widely debated.1,5-9 Use of adjuvant therapy is also controversial owing to the lack of large cohort studies or prospective analyses.5,10 Moreover, it is difficult to counsel patients on their prognosis owing to the lack of accepted prognostic indicators. A large analysis that could explore the prognostic significance of previously suggested risk factors, such as age, gender, race, extent of disease, and type of surgical excision, as well as any possible benefit from adjuvant therapy, could more definitively establish treatment guidelines.1,5-7,11 Therefore, the purpose of the present study was to examine the prognostic significance of demographic, tumor, and treatment variables in a large cohort of surgically treated patients with PC. METHODS Data source. The National Cancer Data Base (NCDB) is a joint project of the American College of Surgeons Commission on Cancer and the American Cancer Society. The NCDB contains data elements on patient demographics, insurance status, tumor characteristics, first course of treatment, and zip code–level socioeconomic factors for >1,500 Commission on Cancer–accredited hospitals. A recent analysis showed that 50–80% of all cancers in the United States are included in this database, which varies by disease site, and is significantly higher than the Surveillance, Epidemiology, and End Results (SEER) registry, which in 2014 captured only 28% of the incident cancer population.12 Data reporting to NCDB is highly standardized and similar to other federal cancer registry data systems.13 Released datasets only contain survival data up to 5 years before the dataset release date to provide the most accurate information. The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator. Because all patient information is de-identified, this study was determined by our institutional review board to be exempt from approval. Study cohort and measures. All cases of PC (NCDB site code C75.0; n = 1,098) diagnosed between 1998 and 2011 were examined. Patients that were diagnosed at autopsy (n = 6), had carcinoma in situ (n = 1), no histologic confirmation of carcinoma (n = 29), or did not undergo surgery (n = 40) were excluded. The 1,022 patients who met the criteria for analysis were included in the present study. Their demographics of patients that were excluded did not differ significantly from those included in the analysis.

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Variables were coded in accordance with the Facility Oncology Data Registry Standards and the SEER*Rx coding systems.14,15 Age was divided into ‘‘younger’’ (#57 years) and ‘‘older’’ (>57 years) after the median age was calculated for the entire cohort. Patient race was categorized by the NCDB as white, black, Asian/Pacific Islanders, or Native American and ethnicity as Hispanic or nonHispanic. Insurance status was classified as ‘‘uninsured’’ or ‘‘any insurance,’’ area-based measures of socioeconomic status by the median income in patients’ zip code of residence and by percent of population in the region without a high school degree, and geographic population size based on US census data (metro, urban, or rural). Distance from the treating facility was divided into 2 categories based on a top 7.5% cutoff (63 miles). Secondary malignancies (SMN) are malignant tumors and were defined by those tumors whose sequence number was $2. Tumor size was categorized as #3 or >3 cm; LN status as positive, negative, or unknown; margin status as positive or negative; and distant metastases as yes/no. Unknown distant metastases patients were assumed to not have metastases for survival analyses.16 Operative procedure was coded according to the ‘‘all other sites’’ section of the SEER Program Code Manual: Local excision, total removal of parathyroid gland, radical ‘‘en bloc’’ resection with total or partial removal of other organs, or debulking, and both radiotherapy and chemotherapy as yes/no. Results were also compared with Schulte’s modified risk classification system (Table I) that, unlike the classic TNM staging system, defines high- and low-risk patients based on the extension and spread of the primary tumor rather than tumor size.11,17 Patients were categorized into high- and low-risk groups when data were available for such categorization.11,17 High risk in the current study was defined as having positive LNs, distant metastases, lymph or vascular invasion; however, information on vascular or tissue invasion is not available for patients with survival data. Statistical analysis. Descriptive frequencies or mean values are given for all variables in the dataset. Nominal categorical variables were compared using 2-sided Fisher exact test and continuous variables were analyzed using the Mann–Whitney U test. The primary outcome of interest was OS. Predictors of lower OS were calculated first with Kaplan–Meier survival analysis and the log-rank test followed by cox proportional hazards modeling with forward regression to identify independent factors associated with risk of death (hazard ratio [HR]). All variables that were

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Table I. Schulte modified staging system Risk

Definition

Low

Capsular invasion combined with invasion of surrounding soft tissue Vascular invasion and/or lymph node metastases and/or invasion of vital organs and/or distant metastases

High

significant on Kaplan-Meier analysis were included and adjusted for in the cox proportional model. Unadjusted relative risks (RR) of death at 5 years were also estimated for all variables. Statistical analyses were not performed when cell counts were <5 for a given variable. Pearson’s R test was used to determine if variables were highly correlated before entering into a multivariate model, and a cutoff of >0.9 for colinearity was used. The variable with the most complete data and clinical relevance was chosen to remain in the model. All tests were 2-sided; P < .05 was considered significant. Missing value analysis was performed and listwise deletion was determined to be sufficient for analysis of most variables; tumor size and LN status retained an ‘‘unknown’’ category to account for the larger numbers of missing variables in these categories. Where data were incomplete, the exact number of patients included in analysis has been provided. Only entries with complete data were included in multivariate cox analyses. All analyses were conducted using SPSS software, Version 21.0 (SPSS Inc, Chicago, IL). RESULTS Between 1998 and 2011, 1,022 patients underwent a surgery for PC. Most patients were non-Hispanic (96.5%), white (77.4%), and insured (94.3%) with an equal gender distribution (Table II). Median age was 57 years (range, 10–89; 4 patients <21 years of age) and for 12.5% of patients, PC was a subsequent neoplasm (SMN). Most tumors were <3 cm, had negative LNs, and no known distant metastases. The most common operative procedure was a single (91.9%), local surgical excision (57.7%) that occurred within 30 days of diagnosis (90.3%) and was not followed by radiation therapy. However, the majority of patients (73.2%) who had >1 operative procedure had their definitive operation >30 days after diagnosis. The 5-year OS was 81.1% in 528 patients with $5 years of follow-up (median follow-up, 77.2 months). Mean OS was lower and RR of death at 5 years significantly greater in patients that were black, >57 years of age, had $2 comorbidities, and whose tumor was a SMN (Table III). Additionally,

positive surgical margins, positive LNs, and poorly differentiated histology all conferred a worse OS. Similarly, because in the current study LN positivity was a surrogate for Schulte’s high-risk classification owing to missing data for lymph and vascular invasion (which accounts for the discrepancy in the number of patients listed as ‘‘high risk’’ in Table II compared with the number of high-risk patients included in the survival analyses), Schulte’s highrisk patients had a worse OS and a higher RR of death at 5 years compared with low-risk patients. Although operative procedure was not associated with OS, patients who only had a local excision were more likely to have positive margins when compared with those who had total or en bloc resection (27.3% vs 16.7%; P < .001). Multivariate cox regression demonstrated that only age and positive LNs were associated with an increased risk of death (P = .001) after controlling for race, second malignancy, comorbidities, type of surgery, definitive surgery >30 days from diagnosis, positive margins, and radiation (XRT) therapy (Table IV). Patients with unknown LN status had similar survival characteristics to those with negative LNs when adjusted for the aforementioned significant variables (Fig 1, A) as well as for patients classified as low risk by Schulte’s risk classification (Fig 1, B). In a subgroup analysis of patients with PC as their only malignancy, the same factors (older age, black race, >2 comorbidities, positive LNs, and positive margins) demonstrated an increased risk of death at 5 years and a lower OS (P < .05 for all). The 5-year OS for this cohort was 82.6% compared with 76.2% (P = .127) for patients in which PC was a SMN or the first of multiple cancers (P = .025). Multivariate regression in this cohort also demonstrated that positive LNs (HR, 7.80; 95% CI, 2.07–29.37; P = .002) and older age (HR, 2.27; 95% CI, 1.13–4.56; P = .021) were important predictors of death. Having $2 comorbidities trended toward significance in the multivariate model as well (HR, 2.83; 95% CI, 0.98–8.11; P = .053). DISCUSSION PC is a rare malignancy, but an important cause of death for some patients with primary hyperparathyroidism. Current staging systems and prognostic factors are derived from small, institutional series and a select number of early national database analyses.2,4,11,17 The present study comprises the largest aggregation of PC patients to date and shows an association between positive LNs, older age, and lower OS. Black race and time and multiple comorbidities may lower OS as well.

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Table II. (continued)

Table II. Patient, tumor, and treatment characteristics Characteristics

Characteristics n (%)

Demographics Age (y) 1,022 Mean (SD) 56.9 (14.0) Median 57.0 Sex Male 505 (49.4) Female 517 (50.6) Race White 791 (77.4) Black 168 (16.4) Asian/Pacific Islander 30 (2.9) Native American 2 (0.2) Hispanic 33 (3.5) Insurance status Insured 920 (94.3) Uninsured 56 (5.7) Population size Metro 825 (85.4) Urban 128 (13.3) Rural 13 (1.3) Education (% with no high school degree) >29 162 (16.8) 20–28.9 228 (23.7) 14–19.9 245 (25.4) <14 328 (34.1) Distance to treating facility (miles) <63 472 (92.5) $63 38 (7.5) Income ($) <30,000 131 (13.6) 30,000–34,999 168 (17.4) 35,000–45,999 275 (28.6) 46,000 389 (40.4) $2 Comorbidities (Charlson/Deyo score) No 675 (96.0) Yes 28 (4.0) Tumor characteristics Tumor size (cm) 0–2 228 (22.3) 2.1–4 302 (29.5) >4 93 (9.1) <3 365 (35.7) $3 258 (25.2) Unknown 399 (39.0) Lymph nodes N0 298 (29.2) N1 23 (2.3) NX 701 (68.6) Distant metastases M0 567 (55.5) M1 9 (0.9) MX 446 (43.6) Grade Well/moderately differentiated 145 (14.2) (continued)

Poorly/undifferentiated Unknown Tumor sequence First malignancy Secondary malignancy Schulte risk stage Low risk High risk Unknown Treatment Parathyroid surgery Local excision Total removal Radical ‘‘en bloc’’ Debulking Lymph node removal No Yes Radiation therapy No Yes Chemotherapy No Yes Unknown Margins Negative Positive Unknown Definitive surgery Within 1 week of diagnosis No Yes Within 30 days of diagnosis No Yes >1 Surgical procedure No Yes

n (%) 8 (0.8) 869 (85) 894 (87.5) 128 (12.5) 175 (17.1) 76 (7.4) 771 (75.3)

567 350 53 12

(57.7) (35.6) (5.4) (1.2)

539 (64.6) 295 (35.4) 880 (87.4) 127 (12.6) 982 (96.1) 3 (0.3) 37 (3.6) 601 (58.8) 183 (17.9) 128 (24.2)

106 (14.8) 612 (85.2) 68 (9.7) 630 (90.3) 639 (91.9) 56 (8.1)

These findings support, to the best ability of this dataset, the risk classification system proposed by Schulte that places all patients with positive LNs, distant metastases, and vascular or tissue invasion into a high-risk category.17 Such a simplified system is useful to clinicians when discussing postoperative findings with patients and planning their frequency and type of follow-up. Because it is a pathologic staging system, it does not have the ability to guide surgeons on the aggressiveness of surgery. However, because positive LNs do seem to have a significant impact on OS, this study would suggest that removal and possible unilateral central compartment LN dissection in patients that have clinically suspicious

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Table III. Survival characteristics Characteristic (n) Demographics Gender Male (304) Female (339) Age (y) #57 (348) >57 (295) Race White (500) Black (102) Asian/Pacific Islander (17) Hispanic No (567) Yes (20) Insured No (27) Yes (580) Population size Metro (527) Urban (73) Rural (9) Education (no HS diploma) $29% (95) 20–28.9% (152) 14–19.9% (148) <14% (214) Distance to treating facility (miles) <63 $63 Income ($) <30,000 (83) 30,000–34,999 (101) 35,000–45,999 (171) $46,000 (254) Comorbidities 0–1 (312) $2 (12) Tumor characteristics Tumor size (cm) <3 (204) $3 (156) Unknown (283) Grade Well/moderately differentiated (94) Poor (6) Lymph node status N0 (169) N1 (18) NX (456) Tumor sequence First primary (571) Second malignancy (72)

Mean survival (mo)

P value (log rank)

5-year mortality, RR (95% CI)

.548 131.50 131.41

P value .376

1.00 0.82 (0.53–1.27) <.001

148.60 108.09

<.001 1.00 3.54 (2.20–5.70)

.007 133.31 107.53 134.69

1.00 1.95 (1.13–3.33) 1.13 (.31–4.15)

.021 .741

.255 132.99 111.68

1.00 2.07 (0.70–6.11)

.191

1.34 (0.43–4.24)

.538

1.61 (0.77–3.37)* 0.62 (0.29–1.36)* 0.69 (0.08–5.81)*

.244 .293 .999

1.47 1.03 1.23 0.64

.200 .897 .427 .097

.768 97.09 133.16 .624 130.99 134.92 120.49 .044 120.89 125.27 124.06 142.58

(0.82–2.64)* (0.62–1.72)* (0.74–1.24)* (0.39–1.05)*

.787 131.47 131.89

0.76 (0.31–1.88)

.673

1.57 1.40 0.88 0.69

.142 .228 .705 .135

.090 112.11 127.22 128.19 139.75

(0.87–2.83)* (0.80–2.46)* (0.53–1.47)* (0.44–1.11)*

.005 97.61 68.86

135.29 129.69 128.23

2.63 (0.74–9.39)

.128

0.726 (0.38–1.36) 1.59 (1.03–2.48)*

.337 .043

4.27 (0.78–23.27)

.106

7.27 (2.50–21.07) 0.83 (0.52–1.32)

<.001 .466

.286 .792y

.142 123.84 85.72 <.001 138.15 66.16 132.20 .015 134.33 109.81

2.05 (1.14–3.69)

.025 (continued)

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Table III. (continued) Characteristic (n) Schulte risk stage Low risk (68) High risk (23) Treatment characteristics Parathyroid surgery Local excision (347) Total removal (235) En bloc resection (34) Lymph nodes removed Yes (187) No (412) Radiation therapy No (569) Yes (65) Margins Negative (385) Positive (101) Time from diagnosis to definitive surgery #1 week (288) >1 week (52) #30 days (294) >30 days (26) >1 Surgical procedure No (298) Yes (22)

Mean survival (mo)

P value (log rank)

5-year mortality, RR (95% CI)

P value

15.67 (4.12–59.69)

<.001

0.93 (0.59–1.46)* 0.92 (0.57–1.47)* 1.93 (0.82–4.55)*

.818 .726 .131

1.26 (0.78–2.03)

.384

2.08 (1.13–3.81)

.021

1.81 (1.01–3.23)

.043

<.001 93.87 65.75 .061 133.00 134.92 101.53 .917 129.72 132.25 .065 133.64 114.66 .026 138.56 116.88 119.92 104.84 95.75 106.37

.036

.314 1.07 (.96–1.19)

.084

.540 0.49 (0.11–2.23)

.198 96.12 104.98

0.57 (0.13–2.58)

.746

*RR calculated compared with all others values within given variable. yLog-rank value excluding tumor: ‘‘unknown.’’ RR, Relative risk.

Table IV. Cox proportional survival model Characteristic Age > 57 y N1 (positive lymph nodes) NX (unknown lymph nodes)

Hazard ratio (95% CI; n = 216)

P value

2.35 (1.25–4.43) 6.47 (1.81–23.11)

.008 .004

1.23 (0.63–2.42)

.541

nodes provides important prognostic information and should be performed. However, given that patients with unknown LN status had a similar survival compared with patients with negative LNs, the authors cannot make a conclusion regarding the utility of a prophylactic node dissection, which would require a prospective, randomized study. This further demonstrates the burden on surgeons to recognize potentially malignant characteristics during parathyroid surgery. Further study of tumor markers such as parafibromin or mutations such as HRPT2/CD73 found in jaw-tumor syndrome, may aid in preoperative diagnosis, prognosis, and more strategic surgical planning.8,18,19

The demographics and OS of the present cohort are similar to previously reported series.4 Adjunctive radiotherapy, however, is not supported by the results of the current study. In fact, patients who received XRT had a lower 5-year OS, although this may be a reflection of patients with more aggressive disease being referred for radiotherapy.5 Additionally, the NCDB only captures information about treatment of the primary tumor, and not recurrence, where radiotherapy could play an important role. Interestingly, this is the first time a possible association between secondary malignancy and OS has been demonstrated, although this finding did not retain significance after adjusting for other significant variables. Moreover, the same variables retained significance in a multivariate model when patients with only parathyroid cancer were examined. Without data on disease-specific survival, it is unclear whether the increased mortality was related more to the primary malignancy or to the parathyroid cancer itself. Preoperative diagnosis of PC is difficult, increasing the occurrence of positive resection margins or piecemeal tumor excision, which are

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Figure. (A) Cumulative survival for lymph node status. (B) Cumulative survival for Schulte’s modified risk stage.

known to increase local recurrence and can impact survival for many malignancies. Surgeons must rely on the recognition of tumor characteristics such as a firm, large mass with possible invasion of surrounding tissues. However, in this study, neither large tumor size nor positive resection margins were important predictors of OS after controlling for other variables. Tumor size was reported as unknown for 39% of the sample, which may be indicative of more than one piece-meal or partial excisions, and conferred an increased risk of death at 5 years on univariate analysis. Moreover, because the NCDB reports data based on the final status of the tumor, the incidence of negative resection margins may be higher in the present study, thus masking a potential association with initially positive margins. Additionally, time to definitive surgery trended toward significance in the hazard model of OS and may be a surrogate for positive resection margins at the initial operation. This may simply reflect the difficulty of a definitive preoperative diagnosis or a surgeon’s inability to recognize that they might be dealing with a cancer intraoperatively. However, undergoing >1 operative procedure did not impact OS nor did distance from the treating facility. Therefore, this may imply that a second ‘‘clean-up’’ operation shortly after an incomplete primary operation, possibly owing to lack of a preoperative diagnosis, may mitigate any potential deleterious effect of an incomplete first operation. This study represents the largest series to date of patients treated for PC. However, the study has inherent limitations. Foremost is the lack of data on disease recurrence and disease-specific survival, which may cause significant morbidity owing to both local symptoms and those of hypercalcemia. Many patients lack information on tumor grade, and documentation of vascular or tissue invasion (which

is not mandated to be reported) was not present for any patients with survival data. The presence of distant metastases was not included in the multivariate model owing to lack of adequate patient numbers for calculated cells in the statistical analysis. Variables that have been implicated to impact prognosis in other series, such as preoperative calcium and parathyroid hormone levels, were also not collected by the NCDB.3 Additionally, postoperative outcomes specific to these procedures, such as recurrent laryngeal nerve injury, were not captured in any database and may be an important consideration in recommending the optimal operative procedure. Although the NCDB captures information from more than half of the cancers diagnosed in the United States, our dataset demonstrates a very high proportion of insured patients. Last, this study’s attempt to validate Schulte’s modified risk classification system in a large dataset is also imperfect owing to the lack of pathologic detail described.11,17 It is unlikely that any single institution will compile a large enough number of parathyroid cancer patients for a robust statistical analysis and, although cancer registries such as the NCDB are crucial, this study underscores the need for a multi-institutional, prospective database to better understand this rare disease. In conclusion, this study supports the use of Schulte’s classification system for risk categorization of PCs. Older age and positive LNs were important prognostic indicators for an increased risk of death at 5 years and a worse OS. These results have important implications for surgical planning as well as patient counseling.

REFERENCES 1. Givi B, Shah JP. Parathyroid carcinoma. Clin Oncol (R Coll Radiol) 2010;22:498-507.

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2. Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 2007;109:1736-41. 3. Schaapveld M, Jorna FH, Aben KK, Haak HR, Plukker JT, Links TP. Incidence and prognosis of parathyroid gland carcinoma: a population-based study in The Netherlands estimating the preoperative diagnosis. Am J Surg 2011; 202:590-7. 4. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985-1995: a National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1999;86:538-44. 5. Busaidy NL, Jimenez C, Habra MA, et al. Parathyroid carcinoma: a 22-year experience. Head Neck 2004;26:716-26. 6. Sandelin K, Auer G, Bondeson L, Grimelius L, Farnebo LO. Prognostic factors in parathyroid cancer: a review of 95 cases. World J Surg 1992;16:724-31. 7. Koea JB, Shaw JH. Parathyroid cancer: biology and management. Surg Oncol 1999;8:155-65. 8. Sharretts JM, Kebebew E, Simonds WF. Parathyroid cancer. Semin Oncol 2010;37:580-90. 9. Holmes EC, Morton DL, Ketcham AS. Parathyroid carcinoma: a collective review. Ann Surg 1969;169:631-40. 10. Mohebati A, Shaha A, Shah J. Parathyroid carcinoma: challenges in diagnosis and treatment. Hematol Oncol Clin North Am 2012;26:1221-38. 11. Talat N, Schulte KM. Clinical presentation, staging and long-term evolution of parathyroid cancer. Ann Surg Oncol 2010;17:2156-74. 12. Lerro CC, Robbins AS, Phillips JL, Stewart AK. Comparison of cases captured in the National Cancer Data Base with those in population-based central cancer registries. Ann Surg Oncol 2013;20:1759-65. 13. Raval MV, Bilimoria KY, Stewart AK, Bentrem DJ, Ko CY. Using the NCDB for cancer care improvement: an introduction to available quality assessment tools. J Surg Oncol 2009; 99:488-90. 14. Facility oncology registry data standards; 2013. Available from: http://www.facs.org/cancer/ncdb/cocmanuals.html. 15. SEER coding and staging manuals; 2013. Available from: http://seer.cancer.gov/tools/codingmanuals/. 16. Allen ME, Semrad A, Yang AD, Martinez SR. Parathyroid carcinoma survival: improvements in the era of intact parathyroid hormone monitoring? Rare Tumors 2013;5:e12. 17. Schulte KM, Gill AJ, Barczynski M, et al. Classification of parathyroid cancer. Ann Surg Oncol 2012;19:2620-8. 18. Okamoto T, Iihara M, Obara T, Tsukada T. Parathyroid carcinoma: etiology, diagnosis, and treatment. World J Surg 2009;33:2343-54. 19. Cetani F, Banti C, Pardi E, et al. CDC73 mutational status and loss of parafibromin in the outcome of parathyroid cancer. Endocr Connect 2013;2:186-95.

DISCUSSION Dr Irving B. Rosen (Toronto, Canada): A thousand cases is a lot of cases, so I am going to ask you just 2 questions. In your reading or research, do you feel that the incidence of this disease is increasing? Would you cite malignancy to a patient, either prevention or detention, as an indication for parathyroidectomy?

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Dr Claire Sadler (Los Angeles, CA): I do not recall reading that there is an increase in incidence. As for preoperative consultation, I think it is always important to cite the risk of malignancy, but it is really difficult to make that determination preoperatively. The only thing that has been suggested as a risk factor is very high levels of parathyroid hormone and calcium, which may increase the suspicion, but the diagnosis of cancer is not something you can really determine until either in the operating room or afterward. Dr Ashok R. Shaha (New York, NY): It is interesting, because yesterday we heard another paper about parathyroid carcinoma from the Wisconsin group. They had a 23-year experience; they had 405 cases. You had an 11-year experience and you have 1,022 patients, a huge disparity of numbers. I know the collection bias, but I just want to bring up that when we look at these data, we need to be very critical and careful how we analyze them. Because yesterday they analyzed their data, the day is over, and now we listened to another group with different conclusions. Yesterday, the conclusion was made, and if I am correct, that lymph node metastases did not have a major impact on the disease-specific survival in parathyroid carcinoma---405 cases, we would have taken that message home. Today we take another message home that there is an impact on survival. So I just want to be critical. Maybe you can make a comment as to why this disparity occurs and how we should be very analytical, and what take home messages can be made based on huge registries from where there may be some quality control issues. Two points I want to bring up. You talk about positive margins. I think we need to be very critical and careful when the pathologist reports positive margins. One margin is always the strap muscle in the air. It is going to be positive in large tumors. That has very little impact on the outcome unless we have left gross tumor behind or the surgery was not satisfactory. The last comment I want to make is, you mentioned about the role of radiation therapy. I think we need to be very careful when we make that statement because 50% of these patients recur. And they recur because the tumor was aggressive or they belonged to a high-risk group. We do not have any prospective data. We went through this with thyroid cancer, the same philosophy. I think before we say that the radiation is not going to have a major impact, we need to have good data. Without that, I think people will not use radiation in high-risk patients.

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Dr Claire Sadler: Your points are well taken. We know there are limitations in large databases. I think when you compare the results our study with the study that was reported on yesterday, we found that positive lymph nodes significantly impacted survival and the other group did not. We are not trying to make any statements regarding the utility of a prophylactic node dissection. I think it is important, however, that if there are suspicious nodes present in the operating room and you are suspecting parathyroid carcinoma, for prognostic purposes, it might be worthwhile to remove those suspicious nodes. Dr Nancy Perrier (Houston, TX): A comment and 2 questions. The comment is the importance of what Dr Shaha was saying about the database and how we look at these. The new 8th edition of the AJCC guidelines are underway. Currently, there is no staging for parathyroid carcinoma. So I would like to ask your opinion on how you think staging for parathyroid carcinoma could look like as we evolve and begin to write that. You eloquently showed a cutoff age of 57. Do you really think that that is the right age cutoff and we would put that in the guidelines? What made you get to that age? I think that is important for us to know and learn. Atypical parathyroid neoplasms are frequently diagnosed. Whether or not those are really benign atypical lesions or low grade carcinomas is not always clear. I am assuming that those were not in the database because they were not absolutely classified as cancers. If those were included, how do you think those would change your results? Dr Claire Sadler: To answer your first question about what AJCC staging might look like, Schulte and Talat proposed both the simplified risk

Surgery December 2014

classification system that was used in the current study as well as a 4-stage system. I think this simplified risk classification, which takes into account the histopathologic features of the tumor, nodal disease, and distant metastases, and has now been validated in both our large study as well as in their own prospective series, might be appropriate for staging. But because there are so few patients with parathyroid carcinoma, we do not have enough data to know for sure. For age, we calculated the median age of our patient cohort, which was 57, and used that as our cutoff. We also looked at age as a continuous variable as well as in 10-year increments. The results were the same. So we just split it dichotomously to make it the most simple and clinically useful. But I am sure that if you looked at a different dataset, you might have come up with a slightly different age cutoff. Dr Nancy Perrier: If atypia were included, it could be a low-grade, early parathyroid carcinoma? Can you at least acknowledge that you could be missing a huge segment of those low grades that are not included? Dr Ivan Paunovic (Belgrade, Serbia): In your conclusion, you said en bloc resection with possible central node clearance. Did you mean unilateral or bilateral central node clearance? Dr Claire Sadler: Unilateral. Dr Herb Chen (Madison, WI): Although our 2 papers disagree on the impact of lymph nodes, I think the commonality between the 2 studies is that lymph node metastases are a pretty uncommon event, 2% in your database, 3% in ours. I think that the take home message should be that the vast majority of patients do not need lymph node dissection because they are uncommonly involved.