Pheochromocytoma is a rare tumor of the adrenal gland. Given that this tumor is frequently symptomatic and harbors malignant potential, surgical resection via adrenalectomy remains the patient’s best chance for long-term survival and cure [1-3].
Minimally invasive adrenalectomy (SMI) has become more popular in recent years, and is currently recommended by consensus groups for several adrenal pathologies, when feasible and safe [2,3]. The Endocrine Society Clinical Practice Guidelines recommend SMI for small (<6 cm) and non-invasive tumors, in which there is a low risk of rupture and positive margin [4].
Proponents of SMI cite a shortened length of postoperative stay, reduced blood loss, and decreased morbidity relative to the open approach [5-8]. To date, most SMI data come from studies from single institutions and are limited by small sample size, or include a variety of adrenal pathologies [5,6,9-16].
Compared with other adrenal tumors, pheochromocytomas are more difficult to resect in a minimally invasive manner, since they are frequently larger at the time of diagnosis, and are highly vascularized tumors [13,17,18].
Despite the safety of SMI for presumed benign pheochromocytomas and other benign adrenal tumors, there are few data specifically analyzing outcomes in malignant pheochromocytomas. Currently, open adrenalectomy is recommended for patients with suspected malignant pheochromocytoma [4,19]. Given that only 100 to 200 cases of malignant pheochromocytomas are diagnosed annually in the United States [20], it remains unclear whether SMI is appropriate.
Pheochromocytoma is diagnosed with a combination of typical symptoms, biochemical tests, and imaging [1,4].
Reports have established large tumor size as a marker of malignant nature, although that is not widely accepted [13,21].
Aside from visualizing the presence of local invasion, or distant metastatic disease, on preoperative imaging, designating a pheochromocytoma as malignant before adrenalectomy remains difficult. Often, the diagnosis of malignancy is not determined until histopathological examination, but certainty diagnosis is still challenging [22]. Therefore, surgeons can perform SMI without suspecting malignant pheochromocytomas.
In this study, the National Cancer Database (NCDB) was used to analyze postoperative outcomes among patients undergoing adrenalectomy for malignant pheochromocytoma, stratified by surgical approach.
The primary outcome was overall survival. Secondary outcomes included: short-term postoperative outcomes, such as positive margin rate and length of hospital stay, among others. The authors hypothesized that SMI for malignant pheochromocytoma might be associated with improved short-term outcomes, but perhaps lower oncologic efficacy.
| Methods |
> Institutional guarantees
The Institutional Review Board at University Hospitals Cleveland Medical Center deemed this retrospective analysis of a de-identified public data set exempt from review.
> Data origin
The NCDB is a national database maintained jointly by the American College of Surgeons and the American Cancer Society. This database receives patient information from Commission on Cancer- accredited hospitals throughout the US, and contains de-identified information on approximately 70% of all new malignancies diagnosed in the US each year.
The accuracy of the data reported, statistical analyzes performed, and conclusions drawn are not monitored or verified by the American College of Surgeons , nor by the American Cancer Society . The NCDB Participant User File data dictionary contains definitions of variables used in the present study [23].
> Patient cohort
Adult patients diagnosed with pheochromocytoma who underwent adrenalectomy were identified between 2010 and 2016, using code 8700 of the International Classification for Diseases in Oncology (third edition). All pheochromocytomas included in the NCDB are categorized as invasive (NCDB behavior code 3). This study period was chosen because the surgical approach was not recorded in the NCDB before 2010.
> Exhibition
Patients undergoing adrenalectomy were stratified according to the initial surgical approach: open adrenalectomy (AS), or SMI. Both laparoscopic and robotic adrenalectomies were included.
> Results
The primary outcome was overall survival, which was defined as the number of months from the date of diagnosis to the date of death or the patient’s last follow-up. Disease-specific outcomes cannot be assessed using the NCDB. Data regarding recurrence or cause of death are not captured.
Secondary outcomes included: presence of positive resection margin (yes/no), conversion to open procedure (yes/no), length of stay (continuous), unplanned readmission to hospital within 30 days of surgery (yes /no), and postoperative mortality at 30/90 days (yes/no).
> Statistical analysis
Statistical comparisons between groups were made using the Wilcoxon rank sum test for continuous variables, and Pearson’s c2 or Fisher’s exact test for categorical variables, as appropriate. Demographic and clinical characteristics are described using median and range or interquartile range for continuous variables, and frequency and percentages for categorical variables.
Logistic regression analysis was used to determine if there was an association between clinical/demographic characteristics and surgical approach (SMI vs SA). The Kaplan Meier method was used to estimate survival, and it was compared with the log-rank test.
The multivariable Cox proportional hazards regression model was used to analyze overall survival. The NCDB does not include survival data for patients diagnosed in 2016, so those patients were not included in the survival analyses. StataSE software, v16.0 (Stata Corp, LLC, College Station, TX) was used for statistical analyses. A P value < 0.05 was used to indicate statistical significance.
| Results |
> Demographic and clinical data
A total of 276 patients were included in this analysis: 140 (50.7%) underwent SA, and 136 (49.3%) underwent SMI. A greater proportion of white patients underwent SMI (77.9% vs 68.6%; P = 0.029) compared to SA. Otherwise, demographic characteristics were similar between groups.
Tumors were larger in patients undergoing SA, relative to SMI (8.2 vs 4.7 cm; P < 0.01). A greater proportion of tumors ≥ 6 cm underwent planned SA, compared with SMI (69.6% vs 25.1%; P < 0.01). There was no difference in laterality. Of the SMIs, 22 (16.2%) were performed robotically, and 114 (83.8%) were performed laparoscopically.
> Factors associated with minimally invasive adrenalectomy
Multivariable logistic regression was performed to determine whether any demographic or clinical factors were associated with SMI, compared to SA. There was a trend toward a higher likelihood of SMI among white patients compared with black/other races (odds ratio [OR] = 1.89; P = 0.065).
Other demographic factors were not associated with the surgical approach. Laterality was not associated with SMI, but increasing tumor size was associated with a decrease in the probability of performing SMI (≥ 6 cm vs < 6 cm: OR = 0.23; P < 0.001).
> Short-term postoperative results
Of the patients undergoing SMI, 16 (11.6%) required conversion to open surgery. There was an increase in conversion as tumor size increased (< 6 cm vs ≥ 6 cm: 9.2% vs 17.0%; P = 0.182): but it did not reach statistical significance.
The rates of positive margin, unplanned readmission, and 30/90-day mortality were similar between SMI and SA. There was no difference in margin positivity when laparoscopic and robotic adrenalectomies were compared (13.3% vs 15.8%; P = 0.723).
Similarly, there was no difference in positive margin rate based on starting approach, when stratified by tumor size (<6 or ≥6 cm). The median length of stay was twice as long after SA, relative to SMI (6 vs 3 days; P < 0.001).
A subgroup analysis of short-term outcomes was performed among patients with malignant pheochromocytoma ≥6 cm, based on surgical approach. The 90-day postoperative mortality rate was similar between SA and SMI (6.4% vs 8.3%; P = 0.324), as was the rate of positive margins (15.6% vs 7.9% ; P = 0.392), and unplanned readmissions (5.4% vs 4.3%; P = 0.774). Length of stay was longer after SA compared to SMI (6 vs 4 days; P = 0.002).
> Survival analysis
The overall survival of the patients was similar between the 2 surgical approaches ( P = 0.226). The 5-year survival rates were also similar between SA (74.3%) and SMI (79.1%). There was no significant difference in survival based on the surgical approach between tumors < 6 cm, or ≥ 6 cm.
Using multivariable risk regression, the surgical approach did not have an impact on overall survival (SMI vs SA: hazard ratio [HR] = 1.169; P = 0.667), when adjusted for age, sex, race, insurance type , type of healthcare institution, Charlson-Deyo comorbidity index, laterality, and tumor size. Increased tumor size was associated with worse survival (≥ 6 cm vs < 6 cm: ORR = 2.343; P = 0.024).
| Discussion |
Surgical resection of malignant pheochromocytoma is associated with a survival benefit compared with nonoperative management [24,25].
Due to the rarity of this disease, data on postoperative outcomes are scarce and often limited to single institution studies, or including non-malignant cases.
Using a national database, the authors demonstrate that short- and long-term outcomes after adrenalectomy for malignant pheochromocytoma are similar between open and minimally invasive approaches to adrenalectomy. These data are important because adrenalectomy is frequently the only therapeutic modality in patients with resectable malignant pheochromocytoma [1], and they suggest that SMI may be appropriate for selected patients.
SMI for pheochromocytoma was first described in 1992 [26]. Since then, numerous studies have analyzed short-term postoperative outcomes [5-8,16,27,28]. A critical aspect of adrenalectomy for malignant pheochromocytoma is complete resection, maintaining a complete tumor capsule (i.e., a margin-negative resection).
At this point, the Endocrine Society Clinical Practice Guidelines recommend that tumors ≥ 6 cm, or those with evidence of local invasion, undergo SA, to reduce the risk of tumor rupture, and decrease the rate of incomplete resections [4]. . However, small studies have evaluated the safety of SMI in pheochromocytoma ≥ 6 cm [13,29,30].
In the present study, no association was identified between the initial surgical approach and resection margin positivity, even among larger tumors. SMI appears to be a reasonable option for patients with a malignant pheochromocytoma <6 cm.
Of note, the sample size of patients undergoing SMI for malignant pheochromocytoma ≥6 cm was limited in the present analysis. Additional research is needed to determine whether minimally invasive resections are appropriate for larger malignant pheochromocytomas.
The length of stay after SA was twice that of SMI in this analysis (6 vs 3 days), which is similar to previous reports [27,31]. Interestingly, a study on SMI at 2 academic medical centers showed that almost 50% of SMIs were performed in outpatients, including some patients with pheochromocytomas ( n = 14; 6.9% of the study population) [16 ].
Among inpatients with SMI, the median length of stay was approximately 1 day, which is 2 days less compared to the present study. This discrepancy is probably multifactorial.
In the present analysis, approximately 11% of patients who underwent complete SMI (that is, did not require conversion) had a length of stay ≥ 10 days. That may be a marker of postoperative complications and likely impacted the median length of stay.
Additionally, the reported length of stay in the previously mentioned studies included multiple adrenal pathologies and not only pheochromocytomas. Perioperative care of patients with pheochromocytoma may include management of challenging hemodynamic changes [32], which may require the patient to remain in the hospital for several days.
The present analysis also demonstrated that patients with malignant pheochromocytoma who underwent adrenalectomy had a 5-year overall survival of 76%, regardless of the surgical approach.
To the best of the authors’ knowledge, this finding is novel. As stated previously, preoperative classification of pheochromocytoma as malignant is challenging [22]. Therefore, pheochromocytomas presumed to be benign that were resected by SMI may be malignant in the final pathology report.
The data from this study are reassuring in that overall survival between SA and SMI is similar when controlling for tumor size, laterality, and other clinicodemographic variables. In contrast, increased tumor size was associated with poor survival. Taken together, those data suggest that SMI may be an acceptable approach for small malignant pheochromocytomas (<6 cm), but more attention should be paid to planned SA for larger tumors.
Finally, a trend toward a lower likelihood of SMI in non-white patients was identified, when controlling for other demographic and clinical characteristics. Within the limitations of the NCDB, there were no identifiable variables that could explain this difference. A recent analysis of the national database demonstrated that among 1141 adrenalectomies for different pathological conditions, 23% were minority (i.e., non-white race), similar to the present study [33].
Minority patients are more likely to be treated by a low-volume surgeon, and are more likely to experience postoperative complications [33]. There was no difference in surgical approach based on race in the previously mentioned report; however, 87.5% of all adrenalectomies were minimally invasive [33].
Other reports have also shown that minority races were more likely to receive care from low-volume surgeons [34], and less likely to undergo adrenalectomy for adrenocortical carcinoma [35], or metastasectomy for adrenal metastases. [36].
These studies appear to support a common theme: racial disparities exist in the surgical treatment of adrenal pathologies. Future efforts should aim to ensure that all patients with adrenal pathology have access to high-quality care.
Despite using a large sample size, the present study has numerous limitations. Perhaps most importantly, the NCDB does not include clinical or pathologic staging data (TNM stage) for patients with malignant pheochromocytoma. Similarly, the authors did not have access to cross-sectional images, so important preoperative data (e.g., local invasion, lymphadenectomy) could not be included in the analyses.
Tumor size was used as a surrogate for disease burden. All pheochromocytomas captured in the NCDB are considered malignant; however, the data set does not capture histopathological features, other than invasiveness, that are associated with malignancy [22]. As such, it is possible that nonmalignant cases were included in the analysis. However, the authors consider that this closely mimics clinical reality.
Preoperative confirmation of malignant pheochromocytoma in patients without local invasion or metastatic disease (similar to the present cohort) is challenging. Care was taken to exclude patients with documented metastatic disease, in order to set this analysis squarely in the setting of patients with localized disease undergoing surgery.
The authors believe these data are reassuring in that even if a pheochromocytoma was resected with SMI and determined to be malignant on pathologic examination, the postoperative outcomes were similar to those of planned SA.
Data on recurrence are not recorded, so analysis of long-term outcomes is limited to overall survival. There were also no specific operative details regarding the approach (transperitoneal or retroperitoneal); therefore, the surgical cohort used in this study likely represents a heterogeneous sample. Similarly, the causes for conversion (eg, hemodynamic issues, blood loss, adhesions, suspected capsule rupture, etc.), are not available.
Information about why a particular surgical approach was selected (e.g., surgeon preference, hospital resources, patient factors, etc.) was also not available. Detailed patient comorbidities are not recorded, so the Charlson-Deyo score was used as a surrogate marker.
The NCDB receives data only from hospitals accredited by the Commission on Cancer , therefore, the findings of this work may not be applicable to all healthcare centers in the US. Despite these limitations, these data suggest that malignant pheochromocytoma can be treated with SMI in appropriately selected patients, such as those with tumors <6 cm.
In conclusion, patients with malignant pheochromocytomas can achieve prolonged survival with adrenalectomy.
SMI is associated with a shortening of the length of hospital stay, and other short- and long-term outcomes are comparable to SA for malignant pheochromocytomas <6 cm. For tumors ≥6 cm, this analysis did not identify a statistically significant risk for SMI, compared with SA, but robust recommendations regarding SMI cannot be made due to the limited sample size of this cohort.
