Abstract
Context:
Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) are rare and knowledge of the natural history is limited.
Objective:
We aimed to describe baseline characteristics and outcomes of patients with malignant PHEO and PGL (PPGL) and to identify predictors of shorter survival.
Design:
Retrospective review of patients with malignant PPGL evaluated from 1960 to 2016.
Setting:
Referral center.
Patients:
The group comprised 272 patients.
Main Outcome Measures:
Baseline description, survival outcomes, and predictors of shorter survival were evaluated in patients with rapidly progressive (n = 29) and indolent disease (n = 188).
Results:
Malignant PPGL was diagnosed at a median age of 39 years (range, 7 to 83 years), with synchronous metastases in 96 (35%) patients. In 176 (65%) patients, metastases developed at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis. Median follow-up was 8.2 years (range, 0.01 to 54.1 years). Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex (P = 0.014), older age at the time of primary tumor (P = 0.0011), synchronous metastases (P < 0.0001), larger primary tumor size (P = 0.0039), elevated dopamine (P = 0.0195), and not undergoing primary tumor resection (P < 0.0001). There was no difference in the type of primary tumor or presence of SDHB mutation.
Conclusions:
The clinical course of patients with malignant PPGL is remarkably variable. Rapid disease progression is associated with male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of primary tumor. An individualized approach to patients with metastatic PPGL is warranted.
We studied patients with malignant pheochromocytoma and paraganglioma. Overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Patients had a markedly variable clinical course.
Pheochromocytoma (PHEO) and paraganglioma (PGL) are neuroendocrine tumors arising from chromaffin cells of the adrenal medulla and extra-adrenal autonomic paraganglia, respectively. The combined estimated annual incidence of PHEO and PGL (PPGL) is ∼0.8 per 100,000 person-years (1), and there are ∼500 to 1600 new cases in the United States per year (2). Patients with catecholamine-secreting PPGL frequently present with symptoms of catecholamine excess, whereas nonfunctioning PPGL may cause local compressive symptoms due to bulky disease (3, 4). More than 30% of patients with PPGL have a hereditary predisposition, and up to 50% of patients with metastatic disease have certain hereditary germline mutations (3, 4). Syndromic PPGL is seen as a part of multiple endocrine neoplasia (MEN) type 2, von Hippel–Lindau (VHL) disease, and neurofibromatosis type 1 (NF1). Hereditary PPGL is mainly seen with mutations in succinate dehydrogenase (SDH) subunits (5, 6). Less common germline mutations associated with PPGL include mutations in transmembrane protein 127 (TMEM127), myc-associated factor X genes, somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2α, and pathogenic germline mutations in the FH gene encoding fumarate hydratase (7–10).
According to the World Health Organization, the diagnosis of malignant PPGL requires evidence of metastases at nonchromaffin sites distant from the primary tumor, such as lymph nodes, bones, liver, lung, brain, and others (11). Malignant disease has been reported in 2% to 13% of patients with PHEO and 2.4% to 50% with PGL (12–14). At least 11% of all patients with PPGL and up 31% of patients with PPGL in the setting of predisposing genetic mutation present with synchronous metastatic disease at the time of primary tumor diagnosis (15, 16). Predicting malignant disease in patients presenting with primary tumor without metastases is difficult, and there are no reliable clinical, molecular, histopathological, or biochemical markers of malignant potential. Mitotic activity, cellular atypia, or vascular invasion do not reliably predict malignant predisposition of these tumors. Moreover, the extent of local invasion to adjacent tissues does not necessarily indicate higher risk toward development of metastases (4).
Owing to the rarity of PPGL in general, and metastatic disease especially, current evidence on the natural history of malignant PPGL is scarce. Limited data exist with regard to clinical outcomes of patients with malignant disease; most reports are based on small, highly selected cohorts of patients. The objectives of the present study were to assess overall and disease-specific survival rates of patients with malignant PPGL. We also aimed to describe baseline characteristics and outcomes of patients with malignant PPGL and to identify prognostic factors influencing the course of the disease.
Subjects and Methods
Subjects
To examine the predictive features associated with shorter overall and disease-specific survival, we retrospectively reviewed a consecutive cohort of patients with malignant PPGL evaluated at the Mayo Clinic (Rochester) between 1 January 1960 and 30 September 2016. The study was approved by the Institutional Review Board of the Mayo Clinic. The Mayo Clinic PPGL database was reviewed to identify patients with malignant PPGL. Of 3280 patients, 272 (8.3%) had malignant disease. Diagnosis was confirmed by reviewing clinical, histopathological, and biochemical data. PGL was categorized according to the location of the primary tumor. Patients with both PHEO and PGL were included in the PGL group. Malignant disease was defined in accordance with the 2004 World Health Organization criteria (17). Synchronous metastatic disease was defined as the presence of distant metastases at the time or within 3 months of the primary tumor diagnosis. Patients who developed metastatic disease ≥3 months after the diagnosis of the primary tumor were defined to have metachronous metastases. Patients were characterized to have a genetic mutation predisposing to PPGL if they had a documented genetic testing for major PPGL susceptibility genes, familial history of genetic mutation, or presence of at least two National Institutes of Health criteria for diagnosing NF1 syndrome.
All PPGL tumors were defined as functional when urine or plasma-fractionated catecholamines or fractionated or total metanephrines were elevated above the upper limit of respective reference ranges. The reference intervals for plasma concentrations were established at the Mayo Clinic (18). The tumors were considered nonfunctional when the levels of plasma or urine metanephrines/catecholamines remained within the reference ranges. Tumors hypersecreting primarily epinephrine/metanephrine or norepinephrine/normetanephrine were termed adrenergic and noradrenergic, respectively. We separately evaluated for dopamine hypersecretion in all tumors and termed them dopaminergic. To investigate whether the time period of diagnosis played a role in baseline characteristics and outcomes of patients with malignant PPGL, we analyzed the variables based on year of diagnosis using the following arbitrary time intervals: 1960 to 1990 and 1991 to 2016. Additionally, for more detailed evaluation of prognostic factors for disease progression, we identified the patients with at least 5 years of follow-up from the primary tumor diagnosis, unless preceded by death due to malignant PPGL, and divided the cohort into two groups: patients with rapidly progressive disease who died of malignant PPGL within 5 years of the primary tumor diagnosis, and patients with indolent disease with at least 5-year disease survival. Patients with <5 years of follow-up, or those who died of other causes within 5 years of primary tumor diagnosis, were excluded from this analysis.
Data analysis
Descriptive statistics were used to provide a summary of the data. Categorical data were given as absolute and relative frequencies (percentages). Continuous data were presented as median, minimum to maximum range. To compare medians between two independent groups, we used the nonparametric Wilcoxon rank sum test. In patients with at least 5 years of follow-up after primary diagnosis, logistic regression models were used to estimate association of risk factors of dying within 5 years. Because there were 29 deaths in the rapidly progressive group, a multivariate logistic regression model was fit using three predictors, based on 10 events per predictor rule. The variables chosen to be in the multivariate model were based on those reported in prior studies. All tests were two-sided, and P values < 0.05 were considered statistically significant. All statistical analyses were conducted using JMP version 10 (SAS Institute, Cary, NC).
Results
Patient demographics
Between 1960 and 2016, 272 patients (138, 51% women) were diagnosed with malignant PHEO (n = 97, 36%), PGL (n = 159, 58%), or both (n = 16, 6%) (Table 1). Patients presented with the primary tumor at the median age of 39 years (range, 7 to 83 years).
Table 1.
Patient Characteristics
| Characteristic | Data |
|---|---|
| N | 272 |
| Male | 134 (49%) |
| Female | 138 (51%) |
| PHEO | 97 (36%) |
| PGL | 159 (58%) |
| Botha | 16 (6%) |
| Tumor location | |
| Abdomen/pelvis | 110 (40%) |
| Adrenalb | 106 (40%) |
| Skull base and neck | 31 (11%) |
| Thorax | 19 (7%) |
| Other | 6 (2%) |
| Genetic status | |
| Familial (including patients with NF1 and confirmed germline mutation) | 66 (24%) |
| Probably familial (nonconfirmed germline mutation but strong family history) | 15 (6%) |
| Tested negativec | 36 (13%) |
| Not done/insufficient information | 155 (57%) |
| Age at primary tumor diagnosis, y | 39 (7–83) |
| Synchronous metastasis | 96 (35%) |
| Regional metastasis (proximal lymph nodes and soft tissues) | 28/96 (29%) |
| Distant metastasis | 68/96 (71%) |
| Age at diagnosis of metastases, y | 44 (7–84) |
| Time to metachronous metastases, y | 5.5 (0.3–53.4) |
| Duration of follow up from primary diagnosis, y | 8 (0–54) |
| Duration of follow-up from metastases, y | 4 (0–40) |
| Status | |
| Alive with disease | 154 (57%) |
| No evidence of disease | 18 (6%) |
| Died of disease | 73 (27%) |
| Died of other causes | 27 (10%) |
| Age at death, y | 54 (7–91) |
Categorical data are presented as absolute and relative frequencies (percentages). Continuous data are presented as median (minimum–maximum range).
For statistical analysis, patients with both PHEO and PGL were included in the PGL group (PHEO 97, 36% and PGL 175, 64%).
Fifty (47%) patients had right PHEO, 50 (47%) patients had left PHEO, and 7 (6%) patients had bilateral PHEO. One patient with bilateral PHEO also had PGL and was included in the PGL group.
Of 36 patients, 30 (83%) patients tested negative for an SDHB mutation.
Although most cases of PPGL were apparently sporadic (191 patients, 70%), in 81 (30%) patients PPGL occurred in the context of a hereditary syndrome: 42 (15.4%) patients with SDHB mutation; 7 (2.6%) with SDHD mutation; 4 (1.5%) with NF1; 3 (1.1%) with VHL disease; 3 (1.1%) with MEN type 1 (MEN1); 3 (1.1%) with MEN type 2A; 2 (0.7%) with SDHC; 1 (0.4%) with Carney triad; and 1 (0.4%) with a TMEM127 mutation. Fifteen patients (5.5%) were diagnosed with familial PPGL based on family history (Table 1).
PPGL was preceded by adrenergic symptoms (e.g., spells, hypertension, headache, palpitations) in 137 (50%) patients, by tumor-related mass effect (lump, pain, compression of surrounding structures) in 70 (26%) patients, or discovered incidentally on imaging in 65 (24%) patients. Median size of the primary tumor at the time of the initial diagnosis of PPGL was 7.0 cm (range, 0.9 to 26.0 cm). Of 248 patients with sufficient biochemical testing data, catecholamine hypersecretion was observed in 197 (79%) patients (Table 2).
Table 2.
Tumor Characteristics
| Characteristic | Data |
|---|---|
| Primary tumor size, cm | 7.0 (0.9–26.0) |
| Multifocal PHEO/PGL | 66 (24%) |
| Functionala | 197/248 (79.4%) |
| Noradrenergic | 113/177 (63.8%) |
| Adrenergic | 61/177 (34.5%) |
| Dopaminergicb | 72/172 (42%) |
| Nonfunctional | 51/248 (21%) |
| Mode of discovery of primary tumor | |
| Asymptomatic/incidental | 65 (24%) |
| Adrenergic symptoms | 137 (50%) |
| Mass effect symptoms | 70 (26%) |
| Recurrence at the primary tumor site | 90 (33%) |
| Time to recurrence, y | 4.1 (0.2–34.9) |
| Surgical resection of the primary tumor | 243 (89.3%) |
| Unresectable | 28 (10.3%) |
| Poor surgical candidacy due to comorbidities | 1 (<1%) |
Categorical data are presented as absolute and relative frequencies (percentages). Continuous data are presented as median (minimum–maximum range).
Of 272 patients, 248 patients underwent biochemical testing and 24 (9%) patients did not complete testing. Of 248 patients, biochemical profile was uncharacterizable in 20 (8%) patients.
Sufficient laboratory data on dopamine hypersecretion was available in 172 patients.
Ninety-six (35%) patients presented with synchronous metastases, whereas 176 (65%) patients developed metachronous metastases at a median of 5.5 years (range, 0.3 to 53.4 years) after the primary tumor diagnosis (Table 1). The most common locations of metastases were bone (n = 161, 59.1%), lymph nodes (n = 127, 46.7%), liver (n = 99, 36.4%), lungs/thorax (n = 103, 37.9%), and abdomen/pelvis (n = 86, 31.6%).
Surgery was the most common treatment of primary tumors (n = 243, 89.3%). Twenty-eight (10.3%) patients were determined to have unresectable tumors; one (0.4%) patient was a poor surgical candidate due to comorbidities. Out of 164 patients, 159 (97%) patients underwent additional surgical resection (for reoperation of primary tumors or metastasectomy). Palliative radiotherapy was performed in 128 (47%) patients. Ninety-five (35%) patients received chemotherapy and targeted molecular therapy (cyclophosphamide, vincristine, dacarbazine, everolimus, sunitinib, sorafenib, pazopanib, lenvatinib, and others), 25 (9%) had radiofrequency ablation, 24 (8.8%) had 131I-metaiodobenzylguanidine treatment, 16 (5.8%) had embolization procedures, 13 (4.7%) had stereotactic radiotherapy, 11 (4%) had cryoablation, and 2 (0.7%) had percutaneous ethanol injection.
Patients were followed for a median of 8.2 years (range, 0.01 to 54.1 years) from the initial diagnosis and for a median of 4.0 years (range, 0.01 to 40 years) from the time of metastatic spread. Among patients with <1 year of follow-up (n = 15, 6%), 53% died of disease, 7% died of other causes, and 40% were alive at last follow-up. Among patients with 1 to 5 years of follow-up (n = 69, 25%), 31% died of disease, 7% died of other causes, and 62% were alive at last follow-up. Of those with 5 to 10 years of follow-up (n = 66, 24%), 26% died of disease, 10% died of other causes, and 64% were alive with disease. One hundred twenty-two patients (45%) had >10 years of follow-up: 22% died of disease, 12% died of other causes, and 66% were alive with disease at last follow-up (Fig. 1).
Figure 1.
Outcomes of patients with malignant PPGL based on the duration of follow-up. Duration of follow-up was <1 year in 15 (6%) patients, 1 to 5 years in 69 (25%) patients, 5 to10 years in 66 (24%) patients, and >10 years in 122 (45%) patients.
Among patients alive at last follow-up, median duration of follow-up was 8.8 years (range, 0.01 to 54.1 years) and 4.7 years (range, 0 to 38.0 years) from the initial tumor diagnosis and metastases, respectively. At the conclusion of the study, 154 (57%) patients were alive with disease and 18 (6%) patients had disease remission. One hundred (37%) patients died during follow-up; 73 (27%) patients died of malignant PPGL and 27 (10%) patients died of causes unrelated to PPGL. In 73 (27%) patients who died of malignant PPGL, the median survival was 6 years (range, 0.01 to 41 years) and 3 years (range, 0.01 to 17 years) from primary diagnosis and development of metastasis, respectively (Table 1).
Year of diagnosis
Of 272 patients, 97 (54.6% women) were diagnosed between 1960 and 1990, and 175 patients (48.6% women) were diagnosed between 1991 and 2016. Among those diagnosed before 1990 vs after 1990, more patients presented with adrenergic symptoms (n = 61, 62.9% vs n = 76, 43.4%; P = 0.002), a similar proportion presented with mass effect symptoms (n = 24, 24.7% vs n = 46, 26.3%; P = 0.78), and fewer were diagnosed incidentally (n = 12, 12.4% vs n = 53, 30.3%; P = 0.0006) (Supplemental Table1 (28.9KB, docx) ).
There was no between-group differences in tumor size (P = 0.57), rate of surgical resection of primary tumor (P = 0.89), functional PPGL (P = 0.22), or proportion of patients with rapid disease progression (P = 0.34) (Supplemental Table 1 (28.9KB, docx) ).
Primary tumor type
Patients with malignant PHEO (n = 97, 36%) and PGL (n = 175, 64%) had similar sex distribution (P = 0.58). Compared with PGL, PHEOs were larger [median size 9.0 cm (range, 3.0 to 26.0 cm) vs 5.8 cm (range, 0.9 to 19.1 cm); P < 0.0001], more frequently functional (91% vs 72%; P = 0.0001), and less commonly associated with SDHB mutation (1.0% vs 23.4%; P < 0.0001). Additionally, both groups had a similar rate of surgical resection of primary tumors (94% vs 87%; P = 0.064) and time interval from primary tumor to discovery of metastases [2.7 years (range, 0 to 34.2 years) vs 2.1 years (range, 0 to 53.4 years); P = 0.21] (Supplemental Table 2 (29.2KB, docx) ).
Compared with PHEO, PGL was more commonly diagnosed at a younger age [median, 36 years (range, 7 to 82 years) vs 46 years (range, 11 to 83 years); P < 0.0001]. Additionally, patients with PGL were more likely to have a noradrenergic biochemical phenotype (76.0% vs 50.0%; P = 0.0004), more likely to have synchronous metastatic disease (41% vs 26%; P = 0.013), and more likely to have multifocal disease (33% vs 8%; P < 0.0001) (Supplemental Table 2 (29.2KB, docx) ).
Patients with malignant PGL had more bone (67% vs 45%; P = 0.0006) and lymph node (53% vs 35%; P = 0.004) metastases compared with PHEO, whereas liver metastases were more common in patients with PHEO (49% vs 30%; P = 0.002). There were no differences in the rates of lung/thoracic, abdominal/pelvic, or brain metastases between groups (P > 0.05). Importantly, there were no differences between rapidly progressive and indolent metastatic disease among PHEO and PGL (P = 0.14) and disease-specific mortality (P = 0.07) (Supplemental Table 2 (29.2KB, docx) ).
Risk of rapid disease progression
Among patients with sufficient follow-up, 29 patients had rapid disease progression (<5 year survival from the time of primary tumor diagnosis) and 188 patients had indolent disease (alive for at least 5 years from the time of diagnosis) (Table 3). Univariate analysis demonstrated that rapid disease progression was associated with male sex (n = 20, 69% vs n = 84, 45%; P = 0.014), older age at primary tumor diagnosis [50 years (range, 7 to 70 years) vs 36 years (range, 9 to 83 years); P = 0.0011], synchronous metastases (n = 22, 76% vs n = 40, 21%; P < 0.0001), larger primary tumor size [10.0 cm (range, 1.0 to 19.1 cm) vs 6.4 cm (range, 0.9 to 22.0 cm); P = 0.0039], elevated dopamine levels (n = 10, 71% vs n = 49, 39%; P = 0.0195), and not undergoing surgical resection of primary tumor (19, 66% vs 181, 96%; P < 0.0001) (Table 4). None of the patients with skull base and neck PGL had rapid disease progression. Additionally, patients with rapidly progressive disease more frequently developed lung/thoracic metastases (n = 17, 59% vs n = 67, 36%; P = 0.0197). There was a similar distribution among other metastatic sites between the groups.
Table 3.
Characteristics of Patients With Rapidly Progressive and Indolent Disease Course
| Rapidly Progressive (n = 29) | Indolent (n = 188) | P Value | |
|---|---|---|---|
| Male | 20 (69%) | 84 (45%) | 0.014 |
| Female | 9 (31%) | 104 (55%) | |
| Primary tumor type | 0.1433 | ||
| PHEO | 14 (48%) | 64 (34%) | |
| PGL | 15 (52%) | 124 (66%) | |
| Location of primary tumor | |||
| Adrenal | 15 (52%) | 71 (38%) | 0.1568 |
| Abdomen/pelvis PGL | 12 (41%) | 77 (41%) | 0.9657 |
| Thorax | 1 (3%) | 13 (7%) | 0.4455 |
| Skull base and neck | 0 | 25 (13%) | 0.0057 |
| Other | 1 (3%) | 2 (1%) | — |
| Mode of discovery | |||
| Adrenergic symptoms | 11 (38%) | 109 (58%) | 0.0436 |
| Mass effect | 10 (34%) | 43 (23%) | 0.190 |
| Incidental/asymptomatic | 8 (28%) | 36 (19%) | 0.309 |
| Genetic status | |||
| Sporadic | 24 (83%) | 123 (65%) | 0.0512 |
| SDHB | 3 (10%) | 32 (17%) | 0.340 |
| SDHC | 0 | 2 (1%) | — |
| SDHD | 0 | 7 (4%) | — |
| Familial | 0 | 14 (7%) | — |
| MEN1 | 1 (3%) | 2 (1%) | — |
| NF1 | 0 | 3 (1.6%) | — |
| MEN2A | 1 (3%) | 2 (1%) | — |
| VHL | 0 | 1 (0.5%) | — |
| TMEM127 | 0 | 1 (0.5%) | — |
| Carney | 0 | 1 (0.5%) | — |
| Year of primary diagnosis | 1991 (1965–2012) | 1995 (1951–2011) | 0.8174 |
| Age at primary diagnosis, y | 50 (7–70) | 36 (9–83) | 0.0011 |
| Primary tumor size, cm | 10.0 (1.0–19.1) | 6.4 (0.9–22.0) | 0.0039 |
| Functional (n = 202 tested) | 21/27 (78%) | 141/175 (81%) | 0.7377 |
| Noradrenergic | 8/27 (29.6%) | 82/175 (46.9%) | 0.093–0.669 |
| Adrenergic | 8/27 (29.6%) | 45/175 (25.7%) | 0.0195 |
| Dopaminergic | 10/14 (71.4%) | 49/126 (38.9%) | |
| Biochemical profile at last follow-up | 20/21 (95%) functional | 117/141 (83%) functional | 0.1024 |
| Nonfunctional | 1/21 (5%) biochemical remission | 24/141 (17%) biochemical remission | 0.1570 |
| Uncategorizable | 6/27 (22.2%) | 34/175 (19.4%) | 0.7345 |
| 5 (18.5%) | 13 (7.4%) | 0.0598 | |
| Multifocal | 5 (17%) | 51 (27%) | 0.2400 |
| Surgical resection of primary tumor | 19 (66%) | 181 (96%) | <0.0001 |
| Recurrent tumors | 2 (7%) | 77 (41%) | <0.0001 |
| Time to recurrence, y | 1.4 (0.7–2.1) | 6.9 (0.2–34.9) | 0.0657 |
| Synchronous | 22 (76%) | 40 (21%) | <0.0001 |
| Regional vs distant | 1 (5%) vs 21 (95%) | 16 (40%) vs 24 (60%) | 0.0010 |
| Age at metastatic disease, y | 50 (7–70) | 43 (13–84) | 0.3004 |
| Time from diagnosis to metachronous metastasis, y | 0.5 (0.4–2.4) | 6.2 (0.4–53.4) | <0.0001 |
| Death related to disease | 29 (100%) | 44 (68%) | <0.0001 |
| Age at death, y | 54 (7–71) | 54 (26–91) | 0.0685 |
| Time to last follow-up/death, y | 1.6 (0.1–4.5) | 12.3 (5.0–54.1) | <0.0001 |
| Status | <0.0001 | ||
| Alive with disease | 0 | 107 (57%) | |
| No evidence of disease | 0 | 16 (9%) | |
| Died of disease | 29 (100%) | 44 (23%) | |
| Died of other causes | 0 | 21 (11%) |
Categorical data are presented as absolute and relative frequencies (percentages). Continuous data presented as median (minimum–maximum range).
Table 4.
Univariate and Multivariate Analyses for Risk of Rapidly Progressive Disease
| Variables | Univariate Analysis |
Multivariate Analysis |
||
|---|---|---|---|---|
| OR (95% CI) | P Value | OR (95% CI) | P Value | |
| Sex | ||||
| Males | 2.75 (1.22–6.65) | 0.014 | ||
| Females | 0.36 (0.15–0.81) | |||
| Age at diagnosis (per 1 y) | 1.04 (1.02–1.07) | 0.0018 | 1.04 (1.01–1.08) | 0.0047 |
| Tumor size (per 1 cm) | 1.14 (1.04–1.27) | 0.0039 | 1.12 (1.009–1.25) | 0.034 |
| Dopamine secretion | 3.93 (1.24–14.96) | 0.0195 | ||
| Synchronous | 11.63 (4.85–31.22) | <0.0001 | 10.24 (3.76–31.18) | <0.0001 |
| Not undergoing surgery | 13.61 (4.71–41.62) | <0.0001 | ||
There were no between-group differences in the year of primary tumor diagnosis (1995 vs 1991), type of primary tumor (48% vs 34% PHEOs, 52% vs 66% PGL), age at diagnosis of metastases (50 vs 43 years), or presence of SDHB mutation (10% vs 17%) (Table 3).
Fewer patients in the rapidly progressive group underwent reoperation of primary tumors or metastasectomy (n = 10, 35% vs n = 138, 73%; P < 0.0001). Patients with rapidly progressive disease more commonly received chemotherapy (n = 17, 59% vs n = 59, 31%; P = 0.0052).
Multivariate analysis showed that independent factors associated with rapid disease progression and mortality in patients with malignant PPGL included: older age at primary diagnosis [odds ratio (OR) = 1.04; 95% confidence interval (CI), 1.01 to 1.08; P = 0.0047, for 1 year age difference], larger tumor size (OR = 1.12; 95% CI, 1.009 to 1.25; P = 0.034, for each 1 cm increase in tumor size), and synchronous metastases (OR = 10.24, 95% CI 3.76 to 31.18; P < 0.0001) (Table 4).
Median overall survival was 24.6 years for patients with malignant PPGL (Fig. 2). The 5-year overall survival rate was 85.4% (79.2% for PHEO, 88.9% for PGL), 10-year overall survival rate was 72.5% (64.2% for PHEO, 77.3% for PGL), and 15-year overall survival was 65.4%. Median disease-specific survival was 33.7 years. Disease-specific survival rate was 88.1% at 5 years, 77.9% at 10 years, and 71.8% at 15 years. Overall and disease-specific survival rates were similar for patients with metastatic PHEO and PGL (P = 0.22 and P = 0.87).
Figure 2.
Overall and disease-specific survival in patients with malignant PPGL. (a) Overall survival in patients with malignant PPGL. (b) Disease-specific survival in patients with malignant PPGL.
Discussion
We found that the clinical behavior of malignant PPGL is remarkably variable. For example, whereas in some patients discovery of metastases precedes discovery of the primary tumor, others develop metastases >50 years after the initial diagnosis.
We observed a median overall survival of 24.6 years and a median disease-specific survival of 33.7 years. Previous reports on the clinical course of metastatic PPGL have been widely inconsistent, with the 5-year survival rates ranging from 12% to 84% (4, 19–23). Without treatment, the 5-year survival rate has been reported to be generally <50% (24). In contrast, our study showed that overall and disease-specific 5-year survival rates were 85.4% and 88.2%, and 10-year overall and disease-specific survival rates were 72.5% and 77.9%, respectively. These results indicate that a substantial number of patients have an excellent prognosis despite having malignant PPGL. Similar to previous reports, we found that the course of the disease can be highly variable with some patients living >50 years after diagnosis (25, 26).
We found that male sex, older age at primary tumor diagnosis, dopamine hypersecretion, synchronous metastases, larger primary tumor size, and not undergoing surgical resection of the primary tumor were associated with an aggressive disease course and higher mortality risk. On the multivariate analysis, older age at primary tumor diagnosis, larger primary tumor size, and presence of synchronous metastases remained significant predictors of rapid disease progression and death. Comparable to our findings, others have previously reported that male sex (20), older age at the primary tumor diagnosis (age ≥ 76 years) (20, 27), and failure to undergo surgical resection of the primary tumor (20–22) were associated with shorter survival (20).
In our study, larger primary tumor size was associated with rapid disease progression and higher mortality risk. Similarly, larger tumor size (generally >4.5 to 5 cm) has been reported as a strong predictor of persistent or recurrent disease and mortality in several other studies (4, 20, 24, 28, 29). In one study, primary tumor size ≥ 6 cm was found to be an important independent risk factor for metastatic disease (30), and tumor size was significantly associated with worse overall survival after adjusting for age, sex, and tumor location (23). Another study reported that in SDHB-related PPGL the size of the primary tumor predicts development of metastatic disease and also affects patient survival (31).
We observed an association between dopamine hypersecretion and more aggressive malignant disease. High plasma and urinary levels of dihydroxyphenylalanine and dopamine, the immediate precursors of norepinephrine, are biochemical markers that may characterize malignant PPGL (24, 32, 33). These markers suggest a dedifferentiated state suggestive of malignant potential; however, they do not accurately discriminate benign from malignant disease.
Similar to our results, the timing of metastasis was an important determinant of prognosis in other studies (4, 20, 23). Presence of synchronous metastases has been associated with shorter survival, whereas onset of metastasis >6 months after the initial diagnosis or resection of the primary tumor had longer overall survival durations than in patients with synchronous metastasis.
In our study, patients with malignant skull base and neck PGL had indolent courses of disease with longer survival (overall 5-year survival rate was 85.4% and 5-year disease-specific survival rate was 88.2%). Among patients with sufficient follow-up, none with malignant skull base and neck PGL died of disease within 5 years of primary diagnosis. Similarly, others showed that 5-year overall survival was 88.1% for surgery alone and 66.5% for adjuvant radiation (P = 0.23) for 86 patients with malignant skull base and neck PGL (34). In contrast, another study that evaluated prognosis of 59 patients with skull base and neck PGL metastatic to regional lymph nodes and distant sites reported a much shorter 5-year relative survival rate of 59.5% (21).
Interestingly, we did not find that primary tumor type, multifocal PPGL, location of primary tumor (except skull base and neck), functional biochemical status, or presence of SDHB mutation played a significant role in the progression of malignant disease. Germline mutations of the SDHB gene are considered one of the most important risk factors for developing metastatic PPGL, with rates up to 50% to 90% in some studies (3, 23, 35–37). Previous studies have also reported that in cases of malignant PPGL, SDHB mutation was identified in 5% to 10% of patients (38). In contrast to our findings, these mutations have been associated with more aggressive tumor behavior than other PPGL types (3, 4, 23, 35–37). Patients with malignant SDHB-positive PPGL were reported to have a shorter overall survival (5-year survival probability 0.36, relative risk 2.6; P = 0.019) compared with patients with malignant PPGL not associated with SDHB mutations (35). Another retrospective review found that adult patients with SDHB mutations had statistically worse survival than did those with apparently sporadic disease (39).
We found no difference in survival rates among patients with malignant PHEO and PGL. In contrast to our findings, others have reported that patients with PHEO had longer overall survival (73.3% vs 54.0%; P = 0.001) compared with PGL, although disease-specific survival rates were similar (80.5% vs 73.5%, respectively; P = 0.118) (20).
Our study included a large number of patients with malignant PPGL. Given the retrospective design of this study, follow-up of patients varied based on clinical and patient decisions. Nevertheless, the design of the study allowed for a long follow-up of patients, otherwise not feasible in a prospective study. Most patients with a rare malignant disease are followed at tertiary centers, and thus it is likely that our cohort is representative. It is possible that patients with more aggressive disease were more likely to be referred and followed at our institution. Additionally, differences between rapidly progressive and indolent cohort may in part be due to delayed presentation of patients with the rapidly progressive disease. The reasons for better prognosis in our cohort in comparison with others could be explained by referral bias, longer duration of follow-up than most other studies, and inclusion of a nonselective cohort.
Conclusion
In conclusion, patients with malignant PPGL have a markedly variable course of the disease and longer overall and disease-specific survival than previously reported. Although death can occur within a year of diagnosis, metastatic disease can be stable for >40 years. Detection of metastases can occur prior to the detection of primary tumors, but metastatic spread can also be discovered >50 years after the primary diagnosis. Therefore, lifelong follow-up of patients with PPGL is indicated. Larger tumor size, older age at diagnosis, and failure to undergo surgery could be indicators of delayed diagnosis and may be avoidable in some patients. Additionally, these factors, along with synchronous metastases and dopamine hypersecretion, could represent intrinsically more aggressive disease. Thus, a multidisciplinary and individualized approach to treatment of patients with metastatic PPGL is warranted.
Acknowledgments
We thank Ravinder J. Singh for comments that greatly improved the manuscript.
Acknowledgments
This work was supported by Grant UL1 TR000135 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
Acknowledgments
Author contributions: O.H. collected and analyzed data and wrote and revised the manuscript. W.F.Y. revised the manuscript and provided expert advice on disease. N.M.I.-A., N.E.K., L.G., C.B., and S.T. were responsible for data collection and revision of the manuscript. I.B. revised the manuscript and provided expert advice on disease and overall supervision.
Acknowledgments
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- CI
- confidence interval
- MEN
- multiple endocrine neoplasia
- NF1
- neurofibromatosis type 1
- OR
- odds ratio
- PGL
- paraganglioma
- PHEO
- pheochromocytoma
- PPGL
- pheochromocytoma and paraganglioma
- SDH
- succinate dehydrogenase
- TMEM127
- transmembrane protein 127
- VHL
- von Hippel–Lindau.
References
- 1.Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58(12):802–804. [PubMed] [Google Scholar]
- 2.Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS) . The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39(6):775–783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005;23(34):8812–8818. [DOI] [PubMed] [Google Scholar]
- 4.Jimenez C, Rohren E, Habra MA, Rich T, Jimenez P, Ayala-Ramirez M, Baudin E. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep. 2013;15(4):356–371. [DOI] [PubMed] [Google Scholar]
- 5.Dahia PL. Novel hereditary forms of pheochromocytomas and paragangliomas. Front Horm Res. 2013;41:79–91. [DOI] [PubMed] [Google Scholar]
- 6.Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res. 2012;44(5):328–333. [DOI] [PubMed] [Google Scholar]
- 7.Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Letón R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gómez-Graña A, de Cubas AA, Inglada-Pérez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernández-Lavado R, Díaz JA, Gómez-Morales M, González-Neira A, Roncador G, Rodríguez-Antona C, Benítez J, Mannelli M, Opocher G, Robledo M, Cascón A. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43(7):663–667. [DOI] [PubMed] [Google Scholar]
- 8.Lorenzo FR, Yang C, Ng Tang Fui M, Vankayalapati H, Zhuang Z, Huynh T, Grossmann M, Pacak K, Prchal JT. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med (Berl). 2013;91(4):507–512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, Boaretto F, Opocher G, Toledo RA, Toledo SP, Stiles C, Aguiar RC, Dahia PL. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010;42(3):229–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Castro-Vega LJ, Buffet A, De Cubas AA, Cascón A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Currás-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Letón R, Gómez-Graña A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;23(9):2440–2446. [DOI] [PubMed] [Google Scholar]
- 11.DeLellis RA. Pathology and Genetics of Tumours of Endocrine Organs. 3rd ed. Lyon, France: IARC; 2004. [Google Scholar]
- 12.Bravo EL. Pheochromocytoma: new concepts and future trends. Kidney Int. 1991;40(3):544–556. [DOI] [PubMed] [Google Scholar]
- 13.Plouin PF, Chatellier G, Fofol I, Corvol P. Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension. 1997;29(5):1133–1139. [DOI] [PubMed] [Google Scholar]
- 14.Goldstein RE, O’Neill JA Jr, Holcomb GW III, Morgan WM III, Neblett WW III, Oates JA, Brown N, Nadeau J, Smith B, Page DL, Abumrad NN, Scott HW Jr. Clinical experience over 48 years with pheochromocytoma. Ann Surg. 1999;229(6):755–764, discussion 764–766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc. 1981;56(6):354–360. [PubMed] [Google Scholar]
- 16.Ciftci AO, Tanyel FC, Senocak ME, Büyükpamukçu N. Pheochromocytoma in children. J Pediatr Surg. 2001;36(3):447–452. [DOI] [PubMed] [Google Scholar]
- 17.DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and Genetics of Tumours of Endocrine Organs. World Health Organization Classification of Tumours. Vol. 8. 3rd ed. Lyon, France: IARC Press; 2004. [Google Scholar]
- 18.Eisenhofer G, Lenders JWM, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, Linehan WM, Pacak K. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011;57(3):411–420. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Moskovic DJ, Smolarz JR, Stanley D, Jimenez C, Williams MD, Hanna EY, Kupferman ME. Malignant head and neck paragangliomas: is there an optimal treatment strategy? Head Neck Oncol. 2010;2:23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Goffredo P, Sosa JA, Roman SA. Malignant pheochromocytoma and paraganglioma: a population level analysis of long-term survival over two decades. J Surg Oncol. 2013;107(6):659–664. [DOI] [PubMed] [Google Scholar]
- 21.Lee JH, Barich F, Karnell LH, Robinson RA, Zhen WK, Gantz BJ, Hoffman HT; American College of Surgeons Commission on Cancer; American Cancer Society . National Cancer Data Base report on malignant paragangliomas of the head and neck. Cancer. 2002;94(3):730–737. [DOI] [PubMed] [Google Scholar]
- 22.Gimm O, DeMicco C, Perren A, Giammarile F, Walz MK, Brunaud L. Malignant pheochromocytomas and paragangliomas: a diagnostic challenge. Langenbecks Arch Surg. 2012;397(2):155–177. [DOI] [PubMed] [Google Scholar]
- 23.Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, Cote GJ, Perrier N, Phan A, Patel S, Waguespack S, Jimenez C. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab. 2011;96(3):717–725. [DOI] [PubMed] [Google Scholar]
- 24.John H, Ziegler WH, Hauri D, Jaeger P. Pheochromocytomas: can malignant potential be predicted? Urology. 1999;53(4):679–683. [DOI] [PubMed] [Google Scholar]
- 25.van den Broek PJ, de Graeff J. Prolonged survival in a patient with pulmonary metastases of a malignant pheochromocytoma. Neth J Med. 1978;21(6):245–247. [PubMed] [Google Scholar]
- 26.Yoshida S, Hatori M, Noshiro T, Kimura N, Kokubun S. Twenty-six-years’ survival with multiple bone metastasis of malignant pheochromocytoma. Arch Orthop Trauma Surg. 2001;121(10):598–600. [DOI] [PubMed] [Google Scholar]
- 27.Eisenhofer G, Timmers HJ, Lenders JW, Bornstein SR, Tiebel O, Mannelli M, King KS, Vocke CD, Linehan WM, Bratslavsky G, Pacak K. Age at diagnosis of pheochromocytoma differs according to catecholamine phenotype and tumor location. J Clin Endocrinol Metab. 2011;96(2):375–384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.O’Riordain DS, Young WF Jr, Grant CS, Carney JA, van Heerden JA. Clinical spectrum and outcome of functional extraadrenal paraganglioma. World J Surg. 1996;20(7):916–921, discussion 922. [DOI] [PubMed] [Google Scholar]
- 29.Kim KY, Kim JH, Hong AR, Seong MW, Lee KE, Kim SJ, Kim SW, Shin CS, Kim SY. Disentangling of malignancy from benign pheochromocytomas/paragangliomas. PLoS One. 2016;11(12):e0168413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, Mannelli M, Linehan WM, Adams K, Timmers HJ, Pacak K. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer. 2012;48(11):1739–1749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Schovanek J, Martucci V, Wesley R, Fojo T, Del Rivero J, Huynh T, Adams K, Kebebew E, Frysak Z, Stratakis CA, Pacak K. The size of the primary tumor and age at initial diagnosis are independent predictors of the metastatic behavior and survival of patients with SDHB-related pheochromocytoma and paraganglioma: a retrospective cohort study. BMC Cancer. 2014;14:523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Anton AH, Greer M, Sayre DF, Williams CM. Dihydroxyphenylalanine secretion in a malignant pheochromocytoma. Am J Med. 1967;42(3):469–475. [DOI] [PubMed] [Google Scholar]
- 33.Goldstein DS, Eisenhofer G, Kopin IJ. Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther. 2003;305(3):800–811. [DOI] [PubMed] [Google Scholar]
- 34.Sethi RV, Sethi RKV, Herr MW, Deschler DG. Malignant head and neck paragangliomas: treatment efficacy and prognostic indicators. Am J Otolaryngol. 2013;34(5):431–438. [DOI] [PubMed] [Google Scholar]
- 35.Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007;92(10):3822–3828. [DOI] [PubMed] [Google Scholar]
- 36.King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, Wesley R, Lodish M, Raygada M, Gimenez-Roqueplo AP, McCormack S, Eisenhofer G, Milosevic D, Kebebew E, Stratakis CA, Pacak K. Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol. 2011;29(31):4137–4142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C; European-American Paraganglioma Study Group . Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292(8):943–951. [DOI] [PubMed] [Google Scholar]
- 38.Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006;91(11):4505–4509. [DOI] [PubMed] [Google Scholar]
- 39.Turkova H, Prodanov T, Maly M, Martucci V, Adams K, Widimsky J Jr, Chen CC, Ling A, Kebebew E, Stratakis CA, Fojo T, Pacak K. Characteristics and outcomes of metastatic SDHB and sporadic pheochromocytoma/paraganglioma: an National Institutes of Health study. Endocr Pract. 2016;22(3):302–314. [DOI] [PMC free article] [PubMed] [Google Scholar]