World Journal of Surgery

, 32:2520

Pheochromocytoma in MEN 2A Syndrome. Study of 54 Patients

Authors

    • Endocrine Surgery UnitVirgen de la Arrixaca University Hospital
  • Maria Balsalobre
    • Endocrine Surgery UnitVirgen de la Arrixaca University Hospital
  • Jose L. Ponce
    • Endocrine Surgery UnitLa Fé University Hospital
  • Antonio Ríos
    • Endocrine Surgery UnitVirgen de la Arrixaca University Hospital
  • Nuria M. Torregrosa
    • Endocrine Surgery UnitVirgen de la Arrixaca University Hospital
  • Javier Tebar
    • Endocrine Surgery UnitVirgen de la Arrixaca University Hospital
  • Pascual Parrilla
    • Endocrine Surgery UnitVirgen de la Arrixaca University Hospital
Article

DOI: 10.1007/s00268-008-9734-2

Cite this article as:
Rodriguez, J.M., Balsalobre, M., Ponce, J.L. et al. World J Surg (2008) 32: 2520. doi:10.1007/s00268-008-9734-2
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Abstract

Background

Pheochromocytoma occurs in nearly 50% of MEN 2A (multiple endocrine neoplasia, type 2A) cases. Many issues related to this tumor are still the subject of debate: the diagnostic management in patients who have had positive genetic study results (RET mutation), variations related to mutation, the best surgical option, and the real relapse rate during long-term follow-up. The aim of this study is to present our experience with this unusual disease, looking for answers to some of these questions.

Patients and methods

Of 169 patients belonging to 19 MEN 2A families, 54 (32%) presented with pheochromocytoma. The following variables have been studied: (1) clinical and diagnostic data [age, mutation, clinical features, results of catecholamines and catabolites in a 24-h urine sample, computerized tomography (CT) scan and iodine-131 meta-iodobenzylguanidine (MIBG) scintigraphy results, and the means of diagnostic, clinical, or genetic screening]; (2) surgical treatment; and (3) follow-up and recurrence. The mean follow-up time was 92.5 months (range: 12–120 months).

Results

The mean age of the 54 patients was 37.9 years (range: 14–71 years); 33 were women. Most (96.3%) mutations were found in exon 11. The most frequent mutations were Cys634Tyr (in 33 cases [61.1%]) and Cys634Arg (in 14 [25.9%]). The diagnosis of pheocromocytoma was made after the diagnosis of MTC in 26 cases (48.2%), simultaneously in 21 (38.9%), and prior in the 7 remaining cases (12.9%). At the time of diagnosis 28 patients (51.8%) were asymptomatic and 26 (48.2%) had clinical features related to pheochromocytoma. In 6 patients (11.1%), the values of catecholamines and catabolites in urine were normal. In the cases with high values, the most useful isolated determination was that of metanephrines (82%), followed by adrenaline (76%). The CT scan did not provide a correct diagnosis in 6 patients with bilateral lesions, and one patient with a bilateral tumor was not diagnosed by MIBG. The combination of CT scan and MIBG diagnosed 100% of cases. The pheochromocytoma was bilateral in 27 cases, with a total number of 81 pathological glands detected. A laparascopic approach was used in 30 cases and a laparotomy in 24. The mean tumor size was 4.5 cm (range: 1–18 cm). Five patients with unilateral resection relapsed (18.5%), and the mean relapse time was 43.2 months (range: 12–120 months). There was a greater frequency of pheochromocytoma in those subjects who had the Cys634Arg mutation (p < 0.03). In addition, the Cys634Arg mutation is more frequent in bilateral cases. There are no prognostic factors for recurrence.

Conclusions

Pheochromocytoma in MEN 2A is related to the type of mutation, which can be early onset and is frequently asymptomatic. Its diagnosis requires catecholamines determinations as well as a CT scan. Correct diagnosis of bilaterality is established by CT and MIBG. Laparoscopic adrenalectomy is the treatment of choice.

Introduction

Approximately 50% of patients with multiple endocrine neoplasia (MEN) type 2A develop pheochromocytoma during their lifetime [1, 2]. Its diagnosis was mainly clinical until genetic screening techniques were introduced. In this context, in retrospective studies it has been considered that mortality due to pheochromocytoma in MEN 2 could be as high as 60% [2]. At present, a follow-up protocol allows for an almost preclinical diagnosis of pheochromocytoma, in much younger patients [3].

Moreover, surgical treatment has undergone changes, not the least because of the general use of laparoscopy as a standard procedure. Adrenalectomy of only the macroscopically pathological gland or even subtotal adrenalectomy are among the treatment options suggested in recent years.

These changes in the clinical and surgical framework of pheochromocytoma in patients with MEN has also led to controversy. Moreover, the published series are scarce and heterogeneous. The following issues need to considered: the diagnostic management of patients who have had positive genetic study results, the variations related to mutation, the best surgical option, and the real relapse rate in long-term follow-up.

The objective of this study is to report our experience in 54 cases of pheocromocytoma diagnosed and treated in patients with MEN 2A syndrome.

Patients and method

A study has been made of patients with pheochromocytoma belonging to families with MEN 2A that were diagnosed and treated in two University Hospitals in Spain (Virgen de la Arrixaca of Murcia and La Fe of Valencia). This is a retrospective analysis of a prospective collected data. A total of 169 patients were studied, belonging to 19 families with MEN 2A syndrome. The MEN 2 diagnosis was established either from a genetic study showing mutations of the RET proto-oncogene, or, in early cases, from a clear family history conducted according to the international MEN study group criteria [4]. All of the patients have fulfilled the same therapeutic and clinical protocol. In all patients with MEN 2A syndrome an initial clinical study and biological monitoring was carried out and was repeated annually. We have included basal and post-stimulus calcitonin determinations used for confirming medullary thyroid carcinoma (MTC), and calcium and parathormone for the early diagnosis of hyperthyroidism (HPT).

For the diagnosis of pheochromocytoma, it was necessary to carry out 24-h urinary determinations of total and fractionated catecholamines (adrenaline, noradrenaline, and dopamine), metanephrines and normetanephrines, and vanillyl mandelic acid, annually from the age of 15. We carry out annual computed tomography (CT) and meta-iodobenzylguanidine (MIBG) scintigraphy, if the catecholamines are elevated. When they were normal, CT and MIBG were carried out every 1.5/2 years.

A pheochromocytoma was diagnosed in 54 of the 169 patients (32%) with MEN 2A syndrome. All of these patients have undergone operation. In all cases preoperative preparation was carried out using as α-blockers, varying doses of phenoxybenzamine. When there were tachycardia or palpitations, treatment was related to β-blockers (usually propranolol). Adrenalectomy was unilateral or bilateral depending on the imaging studies. Until 1998, adrenalectomy was carried out via a laparotomy, and after that date, via the laparoscopic approach. Mean follow-up after surgery was 92.5 months (range: 12–178 months).

The following variables have been studied in all patients: clinical and diagnostic data, type of operation, and extent of follow-up.

Clinical and diagnostic data

A broad range of diagnostic features were studied, including age at diagnosis of the pheochromocytoma; type of RET mutation; and clinical findings dividing the patients according to those who were symptomatic and those who were asymptomatic. The clinical variables studied were hypertension, palpitations, perspiration, headache, chest pain, tremulousness.

Laboratory data included 24-h urinary determinations of total and free catecholamines (adrenaline, noradrenaline, and dopamine), metanephrines, and vanillyl mandelic acid.

Results of the adrenal CT scan and I131-MIBG scintigraphy were also evaluated. Computed tomography was considered to be positive if adrenal nodular tumors were identified, and MIBG scintigraphy was considered to be positive if there was clear increased uptake in the adrenal region. We studied the reliability of the MIBG study for the diagnosis of unilaterality versus bilaterality.

Finally, the method of diagnosis was evaluated, based on the clinical symptoms or on genetic or familial screening.

Surgical treatment

The study included evaluation of the approach to operation—open or laparoscopic—and extended to consider the full range of complications.

Follow-up

All patients were evaluated at follow-up for tumor recurrence. A study was made of the relationship between the type of mutation and the presence of pheochromocytoma. An evaluation was also made of the factors related to clinical variables, bilaterality, and contralateral relapse. For statistical purposes, contingency table analysis was applied using the chi-square test complemented by an analysis of remainders, Student’s t-test, and logistical regression analysis.

Results

The mean age for the diagnosis of pheochromocytoma is 37.4 years (range: 14–71 years). Thirty-one patients (57.4%) were women. The 54 patients with pheochromocytoma belong to 19 families with MEN 2A syndrome. The following mutations of the RET protooncogene were found in these subjects: Cys634Tyr exon 11 in 33 cases (61.1%), Cys634Arg exon 11 in 14 cases (25.9%), Cys634Ser exon 11 in 4 cases (7.5%), Val804Met exon 14 in 2 cases (3.7%), and Cys634Trp in 1 case (1.8%).

Pheochromocytoma diagnosis was made after the diagnosis of MTC in 26 cases (48.2%), simultaneously in 21 cases (38.9%), and prior to the diagnosis of MTC in the seven remaining cases (12.9%). In the youngest patient, aged 14 years, diagnosis was simultaneous.

At time of diagnosis, 28 patients (51.8%) were asymptomatic and 26 (48.2%) presented with clinical variables related to pheochromocytoma. The presence of HTA was the most frequent clinical characteristic being present in 50% of patients, followed by the presence of palpitations (37.5%) and perspiration (31.2%). The rest of the signs and symptoms are expressed in Table 1.
Table 1

Clinical symptoms and signs of the patients with pheochromocytoma

Symptoms

N (%)

Hypertension

13 (24)

Palpitations/tachycardia

10 (18.5)

Perspiration

8 (14.8)

Headache

5 (9.2)

Chest pain

3 (5.5)

Tremulousness

3 (5.5)

Asymptomatic

28 (51.8)

In six (11.1%) of the 54 patients, the determination of catecholamines and catabolites in urine showed normal values. In the 48 cases with high values, the most useful individual determinations were metanephrines (high in 82%), followed by adrenaline (76%). Adrenaline and/or noradrenaline and/or metanephrine were high in 91% of cases. In Table 2 the laboratory results are shown.
Table 2

Twenty-four hour urinary determinations of catecholamines

Normal catecholamines

6 (11.1%)

High catecholamines

48 (88.9%)

Adrenaline

36/48 (76%)

Noradrenaline

28/48 (59%)

Dopamine

25/48 (53%)

Metanephrines

39/48 (82%)

Normetanephrines

33/48 (75%)

Vanillyl mandelic acid

28/48 (59%)

Adrenaline + noradrenaline + dopamine + metanephrines

44/48 (91%)

All of the patients were given a CT scan that correctly diagnosed unilateral or bilateral occurrence in 48 cases, but unilateral tumor diagnosis was made in 6 patients who were later found to have bilateral lesions. In 51 patients MIBG scintigraphy was carried out, correctly identifying unilaterality or bilaterality in 50 patients; in the remaining patient, bilateral tumors were diagnosed by CT and not by MIBG. The combination of CT scan and MIBG diagnosed 100% of cases.

The diagnosis was made according to clinical features suggestive of pheochromocytoma in 11 patients, and according to familial screening in 43 others (15 also had clinical features of the disease).

The surgical approach was laparoscopy in 30 cases (19 unilateral and 11 bilateral), and open surgery in 24 cases (16 bilateral and 8 unilateral). The laparoscopic approach was lateral transperitoneal in all cases. Conversion to an open procedure was necessary in three patients, one who developed a hemorrhage and two because of technical problems.

The conversion rate is 7.3% of the cases with a laparoscopic approach (3 of 41). No serious perioperative complications were recorded. Two patients with bilateral adrenalectomy suffered Addisonian crisis, in spite of hydrocortisone and fludrocortisone treatment.

In the 54 patients of this study, 81 glands have been extirpated, 37 from the right side and 44 from the left. The mean size of the resected tumors was 4.5 cm. (range: 1–120 cm). None of the tumors were malignant.

After a mean follow-up of 92.5 months the presence of a contralateral tumor was detected (range: 12–178 months) in 5 (18.5%) patients who presented with unilateral pheocromocytoma. The mean time of appearance of this contralateral relapse was 43.2 months (range: 12–120 months). Two of the 5 patients had clinical symptoms. The diagnosis of relapse was made because of an increase in the 24-h urinary determinations of catecholamines in 4 cases. The remaining patient had evidence of an adrenal nodule on the CT scan, and a MIBG scintigraphy test with increased uptake, but with normal catecholamines. The mean size of the relapsed tumor was 1.9 cm. At present one of the 54 patients has slight hypertension with normal catecholamine levels and normal imaging test results.

Once the descriptive analysis had been made, we attempted to establish which factors were related to (1) mutation; (2) the presence of clinical symptoms: (3) unilaterality or bilaterality; and (4) recurrence. When we studied the relationship between the type of RET mutation and the presence of pheochromocytoma, we found higher frequency in the subjects who have the Cys634Arg in exon 11 mutation. There is no relationship in the rest of the mutations identified (Table 3). Moreover, on studying the “family trees,” we found no significant differences in the frequency of pheochromocytomas based on position in the pedigree.
Table 3

Relationship between RET mutation and the presence of pheocromocytoma (*p < 0.003)

 

Cys634Tyr

Cys634Arg

Val804Met

Cys634Trp

Cys634Ser

Pheocromocytoma

33

14*

2

1

4

Non-pheocromocytoma

88

11

2

6

4

If we study those factors that are related to the presence or absence of clinical symptoms, age is the only related factor. This means that older patients were more symptomatic than the younger ones (Table 4). In addition, in our series we have not found a relationship between clinical symptoms and any of the following factors: male or female sex, type of RET mutation, tumor size, diagnostic method, or urinary catecholamine values.
Table 4

Factors related to the presence of clinical symptoms in patients with pheochromocytoma

 

Asymptomatic

Symptomatic

pValue

Age at diagnosis, years

32.2 (10.9)

42.3 (14.1)

<0.03

Sex

    Female

18

13

ns

    Male

10

13

Mutation

    Cys634Tyr exon 11

16

17

ns

    Cys634Arg exon 11

8

6

    Val804Met exon 14

2

    Cys634Trp exon 11

2

2

    Cys634Ser exon 11

1

Method of diagnosis

    Clinical

3

8

ns

    Screening

23

5

    Screening + clinical

2

13

Mean tumor size (cm)

3.2

3.8

ns

High catecholamine

    No

4

2

ns

    Yes

24

24

With regard to unilaterality or bilaterality at the moment of diagnosis, we have found that bilateral pathology is more frequent in the Cys634Arg mutation and that unilateral pathology is more common in the Cys634Tyr mutation (p < 0.04) (Table 5). To evaluate whether there were any variables related to relapse, we studied the following parameters: age at diagnosis, sex, mutation, method of diagnosis, tumor size, and follow-up time. None of these factors are related to relapse (Table 6).
Table 5

Prognostic factors related with unilateral or bilateral pheochromocytoma Age at diagnosis (years)

 

Bilaterality

p Value

No

Yes

Age at diagnosis, years

36.4

38.1

ns

Sex

    Female

9

22

 

    Male

18

5

Mutation

    Cys634Tyr exon 11

22

11

<0.04

    Cys634Arg exon 11

2

12*

    Val804Met exon 14

1

1

    Cys634Trp exon 11

1

    Cys634Ser exon 11

1

3

Method of diagnosis

    Clinical

7

4

ns

    Screening

16

12

    Screening + clinical

4

11

Presence of clinical symptomas

    Asymptomatic

18

10

ns

    Symptomatic

9

17

24 h catecholamines in urine

    Normal

4

2

ns

    High

23

25

Table 6

Prognostic factors for recurrence

 

Recurrence

p Value

Yes

No

Age at diagnosis, years

35.2

36.8

ns

Sex

    Female

3

28

ns

    Male

2

21

Mutation

    Cys634Tyr exon 11

4

29

ns

    Cys634Arg exon 11

14

    Val804Met exon 14

2

    Cys634Trp exon 11

1

    Cys634Ser exon 11

1

3

Method of diagnosis

    Clinical

1

10

ns

    Screening

2

26

    Screening + clinical

2

13

ns

Mean tumor size (cm)

3.9

4.2

Follow-up, months

69

64.1

ns

Discussion

Previous studies [1, 2, 5, 6] have reported a 50% frequency of pheochromocytoma in MEN 2A patients. The 32% registered in our study is probably a result of the low mean age of the patients, derived from the genetic diagnosis. The usual age at diagnosis is between 30 and 40 years, significantly younger than in the sporadic cases, as we have already demonstrated in previous studies. Nguyen and colleagues have already reported a mean age of 23.2 years, but with a frequency of only 16% [7]. Although variations have been described in the frequency of pheochromocytoma based on the proband’s position in the pedigree, in our series we have not found any differences in this regard. Table 7 provides a summary of the most significant characteristics of the various published series.
Table 7

Comparative study of the results of differences series

 

N

Genotype–phenotype correlatión (codon)

Asymptomatic

Unilateral

Recurrence

Mean time of recurrence (years)

Quayle et al. 2007 [12]

102

Yes (634)

40/102 (39.2%)

67/102 (66%)

Brunt et al. 2002 [16]

15

Yes (634)

2/15 (15.8%)

12/15 (80%)

4/12 (33%)

4.5 ± 0.7

Nguyen et al. 2001 [7]

14

Yes (634)

5/14 (35.7%)

5/14 (35.7%)

2/5 (40%)

4.5 y 6

Maia et al. 2005 [23]

29

Yes (634)

20/29 (6.9%)

2/20 (10%)

6

Machens et al. 2005 [11]

32

Yes (918/634)

23/32 (71.9%)

8/23 (34.8%)

4.8 (1–14)

Lairmore et al. 1993 [34]

49

4/49 (7%)

23/49 (46.9%)

12/23 (52%)

11.9 ± 2

Modigliani et al. 1995 [2]

300

119/300 (39.7%)

58/119 (48.4%)

Rodríguez et al. 2008 (present study)

54

Yes (634)

28/54 (51.8%)

27/54 (50%)

5/27 (18.5%)

3.6 (1–10)

A genotype–phenotype relationship has been demonstrated between RET mutations and pheochromocytoma [8]. To be more precise, the mutation in codon 634 is the most frequents[813], and this should be taken into account when clinical screening is carried out. The RET mutation can also often be located in codons 918 and 883. In this study, in 52 of the 54 cases, the RET mutation was located in codon 634, although the most frequent amino acid change was Cys634Tyr. In the two remaining cases the mutation was located in codon 804 of exon 14.

Pheochromocytoma is usually diagnosed at the same time as MTC (35%–73% of cases) [1, 6, 9], and as the first sign of MEN 2A in 9%–27% of cases [1, 14, 15]. In contrast, in our study, the diagnosis was made after diagnosis of MTC in 48.2% of the cases.

Between 30% and 50% of pheochromocytomas in MEN 2A patients are asymptomatic [7, 16], given that the tumors are diagnosed by screening. However, the actual percentage is probably lower, given that most series do not undertake measurements of arterial tension or 24-h electrocardiograms. However, because pheocromocytoma in MEN 2A patients has a high capacity to synthesize hormones, especially adrenaline, with a great capacity for its storage in tissue, the hypertension is more paroxysmal than maintained [17, 18]. Also, other minor symptoms are less frequent than in the sporadic cases [19].

Patients with pheochromocytoma usually have high levels of metanephrines in blood and urine. In our study, as in most groups, we have carried out the determination of catecholamines and metanephrines in fractionated 24-h urine for the biochemical diagnosis. Peplinski and Norton [20] suggest that the 24-h urinary metanephrine level is the single best biochemical indicator of pheochromocytoma. The fact that there is episodic secretion of adrenaline and noradrenaline means that the determinations in blood as well as in urine could be normal in some cases. This occurred in six of our patients who also had small tumors. Some authors [21, 22] believe that the most sensitive technique is the determination of plasma metanephrines, although the results of this test are also debatable [20] and it is not available in all laboratories.

The diagnosis of bilaterality is fundamental when adequate surgery has to be performed. The reported frequency of bilaterality is very variable in published reports, ranging between 35% and 80% [2, 6, 11, 12, 23, 24]. It is also known that the mutation in the codons 634 and 618 is related to bilaterality [12].

To locate a pheochromocytoma, CT scan and MRI have been used without distinguishing between the effectiveness of these modalities. A CT scan using fine cuts of 2 to 5 mm could detect adrenal lesions of 0.5 to 1 cm, and CT scan sensitivities of up to 98% have been recorded [25]. Six of our patients were diagnosed incorrectly as having unilateral involvement when in fact there were bilateral leasions. All were small tumors (of less than 1.5 cm), and 4 of the 6 occurred in the early years of the series.

Other authors prefer MRI, with or without gadolinium, and have reported a nearly 100% sensitivity [20, 26]. It is debatable whether MIBG needs to be carried out on all patients. Its use in cases of relapse and uncertain diagnosis seems obvious. For the diagnosis of bilaterality, some authors argue that by using scintigraphy it is difficult to distinguish between adrenal hyperplasia and small tumors [7]. In our experience this technique was useful in that it provided a diagnosis of bilaterality in 6 cases that were poorly diagnosed by CT scan. All our cases that were diagnosed as bilateral using MIBG were confirmed to be pheochromocytomas after the histological study and not simply areas of adrenal hyperplasia. We should also point out that there was one false-negative test result in the MIBG scintigraphy for bilaterality.

Given these results our protocol for pheochromocytoma screening recommends annual determinations of catecholamines and metanephrines in 24-h fractionated urine, as well as a CT scan every 1.5–2 years. For the diagnosis of localization, and to rule out bilaterality, we performed both a CT scan and a MIBG scintigram. With the most recent generation of CT technology, which uses 3-mm cuts and provides the possibility of three-dimensional reconstruction, we do not indicate MIBG. As mentioned earlier, given the relationship between phenotype–genotype that exists in MEN 2A, this exhaustive follow-up should be adhered to, especially in patients with mutations in codon 634, and even in the less frequent codons 918 and 883.

Preoperative preparation, in our case with phenoxybenzamine, is indicated even when the patient is asymptomatic, given that the clinical evaluation is often incorrect, as noted earlier. Having a normal test result should not exclude preoperative treatment either, given the episodic secretion of catecholamines and the possibility of false-negative results. The interoperative management is significantly better.

Laparoscopy is the choice of approach in surgical treatment [16, 27, 28]. Limitations only arise because of technical difficulties or tumor size. In our experience the maximum size was 9 cm, similar to that of other series [29]. In addition, it seems that the intraoperative secretion of catecholamines could be lower with laparascopy than with open surgery.

It seems to be clear that it is necessary to carry out only an adrenalectomy of the pathological gland. For this reason, the preoperative localization studies must be the most accurate as possible. There is some debate over which adrenalectomy technique should be used in bilateral cases. Subtotal adrenalectomy has been suggested as the technique of choice by some groups [3033], although the functioning of the gland cannot be guaranteed. We have carried out total adrenalectomy in all the bilateral cases, and there was no mortality in the follow-up, although there was a case of Addisonian crisis that required treatment.

With regard to the appearance of contralateral relapse in unilateral cases, we have registered a recurrence of 18.5% (5 of 27 unilaterally treated cases), during a mean follow-up of 92.5 months. This result is lower than that reported by Brunt [16],who recorded a 5-year follow-up period. Lairmore et al. [34], on the other hand, encountered a 52% relapse rate, but with a long-term follow-up of 10 years. Only one of our relapsed patients reported clinical features suggesting pheochromocytoma, although this patient did not have hypertension.

To conclude, pheochromocytoma in patients with MEN 2A requires a special diagnostic and therapeutic approach, involving early diagnosis, special follow-up in cases of patients with risk mutations, correct localization including bilaterality, and adequate laparoscopic surgical treatment.

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© Société Internationale de Chirurgie 2008