J. Endocrinol. Invest. 15.643-649,1992

Malignant pheochromocytoma: Aseries of 14 cases observed between 1966and 1990 R. Mornex*, C. Badet*, and L. Peyrin** *Service d'Endocrinologie, Pavillon X, H6pital Edouard Herriot, 69003 Lyon, and **Laboratoire de Physiologie, Faculte de Medecine, 8 avenue RockefeIler, 69008 Lyon, France than in benign forms (9/68). Diagnosis of malignancy was based on metastases in 12 cases (Iymph nodes in 5, bon es in 5, liver in 4, lung in 2, brain in 1) and on peritumoral extension in 2 cases. No biological specificity was detected in urinary excretion of catecholamines or its metabolites. In 6 patients so far studied, an uptake of 131 1MIBG was found in the tumor and/or metastases. Four patients received therapeutic doses of 131 1MIBG and in three of them, this treatment led to a good result within a follow-up range of 12 to 66 months. The general evolution of the eleven cases followed up consisted of 5 patients who deceased with a median of 2 yr (range 1-12 yr) and 6 patients with a long survival 6.5 yr (range 2-15 yr) after the diagnosis of malignancy which corresponds to an overall survival of 14 yr (range 6-24 yr).

ABSTRACT. We report 14 patients (9 males, 5 females) aged 15-59 years, treated for malignant pheochromocytoma. These patients were observed during the 1966-1990 period along with 68 other patients presenting benign pheochromocytomas. From the initial general presentation of the 14 patients, two groups could be individualized. In seven patients, the initial presentation seemed benign. After the excision, the recovery was complete, but patients recurred on average 7.8 yr later (range 1-22 yr). Tumors were intraadrenal in six cases (5 single, 1 bilateral) and extraadrenal in one case. In the seven remaining patients, malignancy was evident from the first examination. The tumors were intraadrenal in 2 cases, extraadrenal in 5 cases. Frequency of extraadrenallocations (6/14) was in this se ries significantly higher

INTRODUCTION

served during the last 24 yr, 14 were found to be malignant. In 12 cases, malignancy was assessed by the development of metastases. In 2 cases" malignancy was assessed by locoregional invasion. Not only capsular and vascular invasion was observed but also massive peritumoral extension preventing complete resection during surgery. The biochemical determination of catecholamine metabolites and precursors varied along this period. Before 1986, the diagnosis relied on the determination, by fluorimetric methods (10), of urinary vanillyl mandelic acid (VMA), homovanilic acid (HVA), normetanephrine (NMN), metanephrine (MN), methoxytyramine (MT), epinephrine (E), norepinephrine (NE) and dopamine (DA). Since 1986, these substances are measured by high pressure liquid chromatography (11, 12). Classical imaging methods were used for the localization of the tumor. Since 1984, scintigraphy with I metaiodobenzylguanidine (MIBG) was carried out after iv injection of 18.5 to 74 mBq (0.5 to 2 mCi) 1311-MIBG (Cis International Gif-sur-Yvette, France) after blockade of thyroid uptake by iodide. For treatment, a standard dose of 100 mCi was administered to 4 patients every 6-12 months while a persistent tumoral uptake was detectable. Responses to ther-

It is generally accepted that 10% of pheochromocytomas are malignant, but this figure varies in different series (1-7). These discrepancies are due to the lack of histopathologie criteria (8, 9), which makes the diagnosis ambiguous in the absence of achromaffin tumor in a zone normally devoid of embryologie residues (bones, liver, lung, Iymphatic nodes, brain). Moreover, with insufficient survey, some malignant tumor might be missclassified. Finally, the approach could vary when the patients are referred for surgery or for evident malignancy. This report is based on a medical ward activity between 1966 and 1990. During this period 68 benign pheochromocytomas were treated by the same group. PATIENTS AND METHODS Out of 82 patients with pheochromocytoma ob-

Key-words.· Malignant pheochromocytoma, metaiodo-benzylguanidine, metastases, survival. Correspondence.· R. Mornex, MD, Pavillon X, Höpltal Edouard Herriot, 69003 Lyon, France.

Received September

2, 1991, accepted June 4, 1992.

643

R. Mornex, C Badet, and L. Peyrin

apy were evaluated using uniform criteria and were devided in two categories i) tumor responses were classified as 1) complete response: complete regression of all measurable tumor, 2) partial response: at least 50% of reduction of all measurable tumor, 3) minimal response: between 25 and 50% reduction of all measurable tumor, 4) no change, 5) progression: appearence of new lesions or an increase of 25% a more of all measurable tumor; ii) hormonal responses were evaluated by 24 h urinary elimination of metanephrines and classified as 1) complete response: normal elimination, 2) partial response: at least 50% reduction, 3) minimal response: between 25 and 50% reduction, 4) no change, 5) progression: at least 25% increase.

part of aMEN Ila syndrome (case no. 2). The remaining 13 cases were sporadic pheochromocytomas.

Clinical presentation Out of 11 patients with high blood pressure, 7 had permanent hypertension, 4 had paroxysmal hypertension and in 3 of them an orthostatic drop of blood pressure was detectable. The remaining 3 patients had anormal blood pressure, but 2 of them had atypical crises. Classical manifestations, such as palpitations, pulsatile headaches or sweating were present in 11 patients and an abdominal mass was palpable in 3 of them. Biochemical pattern (Tables 2 and 3) We had no initial qualitive data for 4 patients (cases no. 3, 5, 7, 12). The urinary excretion of catecholamines and/or metabolites was clearly increased in 13 patients. In one patient (case no. 3),

RESULTS

These 14 patients (9 men, 5 women) had a mean age of 37 yr (15-59) (Table 1). Only one case was

Table 1 - Characteristics of 14 patients with malignant pheochromocytoma. Patients Age (no) (yr)

Sex

Date 01 initial Initial diagnosis surgery

Tumor localization

Date 01 recurrence

Metastases locoregional invasion

Evolution

Cause 01 death

31

M

1966

1975

bones

Alive

2

F

1966

B B

Ad

27

Ad (bilat)

1988

locoregional invasion

Alive

3

47

F

1970

M

EAd

locoregional Invasion liver

dead 1982

Liver metastases

4

47

M

1970

M

Ad

locoregional invasion bones

dead 1972

Tumoral progression

5

49

M

1971

B

Ad

locoregional invasion Iymph nodes lung brain

dead 1987

intracran!um hypertension

liver

dead 1976

Ilver metastases

locoregional invasion liver

lost lor lollow up 1977

1979

6

41

M

1974

M

EAd

7

37

M

1974

B

Ad

1977 1983

8

20

M

1976

B

EAd

9

23

M

1977

M

EAd

10

59

F

1980

B

Ad

11

43

F

1981

M

Ad

12

31

M

1984

M

13

15

M

1984

14

50

F

1984

Iymph nodes

alive

bones Iymph nodes

lost lor lollow up 1982

liver - bones lung

dead 1981

locoregional invasion Iymph nodes

allve

EAd

bones (medullary compression)

lost lor lollow up 1985

M

EAd

locoregional invasion

allve

B

Ad

Iymph nodes

alive

1981

1988

M = male, F = female, B = benign, M = malignant. Ad = adrenal, EAd = extraadrenal

644

remar~

±

MEN Ila

liver metastases

Ma/ignant pheochromocytoma

Table 2 - Urinary catecho/amines and metabolites at the first examination. Patients Initial (no) diagnosis 1

E NE (10-5O l1g** (50-200 I1g** /24 h) /24 h)

MN (50-300 I1g ** /24 h)

NMN (50-300 I1g** /24 h)

VMA (2-4 mg** /24 h)

B

80

526

211

1163

9.6

192

292

10991

6887

23.7

0

1784

294

34801

55.7

118

4340

267

11600

210

53

3160

594

1900

39.1

367

2

B

3

M

4

M

5

B

6

M

7

B

8

B

HVA (2-4 mg** /24 h)

DA « 15OO l1g** /24 h)

MT (90-100 I1g** /24 h)

7640

355

2230

604

1974

408

3254

1625

45000*

9

M

59

2412

10

B

178

1118

11

M

1004

1861

12

M

13

M

14

B

2

12500 7000*

26.8

850

11295

40.0

160

9200

49.5

150

2310

12

52.8 64

1400

1342

*Sum 01 MN + NMN "Normal range

Table 3 - Urinary catecho/amines and metabo/ites after ma/ignant recurrence of 7 apparent/y benign pheochromocytomas. Patients (no)

E (10-5O l1g** /24 h)

NE (50- 2OO l1g /24 h)

20

292

113

MN (50-3OO l1g /24 h)

NMN (50-300I1g /24 h) 1027

VMA (2-4 mg /24 h)

HVA (2-4 mg /24 h)

4.0

4.0 5

DA « 15OO l1g /24 h)

MT (50- lOO l1g /24 h)

960

62

2

150

181

1394

656

6.6

5

22

4400

667

4305

15.95

1250

7

118

3900

560

31100

50

6094

8

106

1782

106

1929

2280*

10 14

18

533

111

11

696 587

2

15.6 7699

6.6

2800

*Sum 01 MN + NMN "Normal range

in spite of liver metastases eonfirmed by the pathologist, urinary exeretion was normal in the one oeeasion it was evaluated. The biologieal pattern showed in general NE seereting tumors. Only 2 patients (eases no. 2 and 11) had a simultaneous hyperseeretion of E and NE. There were no exelusively E- or DA-seereting tumors. Independently of the period (initial or reeurrenee), DA or its metabolites were not systematieally increased: MT (5/6), DA (7/10), HVA (3/5). The profile of eateeholamines and metabolites ex-

eretion was not different during the reeurrence of pheoehromoeytomas initially elassified as benign eompared to the first examination (Table 3). General evolution The general evolution of our patients ean be related to two different presentations. a) Benign presentation In 7 cases, the pheochromoeytoma was eonsidered to be benign after the first surgieal proeedure. The gross histopathologie

645

R. Mornex, C. Badet, and L Peyrin

characteristics did not differ from the majority of our benign tumors: - 6 tumors were intraadrenal 5 single adrenal tumors and 1 multiple bilateral tumor (case no. 2), - 1 tumor was located at the renal artery level. Tumor size ranged from 10 - 550 g. After surgical excision, patients were apparently cu red and urinary exeretion of all substances normalized in ali patients. The majority of patients were not submitted to a systematie foliow-up and the malignant nature of the tumor was revealed by reeurrenee with 10coregional invasion and metastases. The mean delay for reeurrence was 7.8 yr (1-22 yr). Clinical manifestations were roughly superimposable to those seen at the beginning and a eonsequenee of hypersecretion of cateeholamines by both tumor and metastases. The biological qualitative profile was generally the same as that of the initial period. However, we observed one patient who had normal DA exeretion at the first presentation and elevated DA exeretion during recurrenee (case no. 14). Reeurrence with loeoregional invasion was observed in 3 patients (eases no. 2, 5, 7). Metastases were located in bone (n=3), liver (n=2), Iymph nodes (n=3), lung (n=2), or in brain (n=1). After diagnosis of reeurrence, 1 patient was lost from the follow-up, 2 patients died (6 months and 8 yr later). The overall survival was 13.4 yr (median 15 yr). Four patients are still alive 7, 15, 25, 25 yr after the first diagnosis and 2, 2, 7, 15 yr after reeurrenee.

tumors were intraadrenal and 5 tumors were extraadrenal (3 pararenal, 1 in organ of Zuckerkandl, 1 in prostate gland). Metastases were loeated in Iymph nodes (n=2), liver (n=3), bones (n=3). Four patients had loeoregional invasion, 2 patients were lost for follow-up after 1 and 3 yr, 3 patients died 1, 2 and 12 yr after diagnosis, 2 patients are still alive 6 and 9 yr later. Loca/ization 1311-MIBG evaluation was carried out in 9 patients and an uptake was found in 9 out of 15 loeations (tumor or metastases), 3 patients had no uptake. The metastatie distribution was also determined with the aid of ultrasonography, CT sean, arteriography and vena cava catheterization. Treatment In all cases, the initial tumor was resected generally in one proeedure. Surgery was also performed on distant metastases in first intention when they were aceessible. Thus, hepatic metastases were resected in 1 patient (case no. 7) rib metastasis in 1 patient (ease no. 9), vertebral metastases in 1 patient (case no. 12) and Iymph nodes in 4 patients (eases no. 5, 8, 9, 14). No complete eure was obtained with surgery alone. Four patients received 1311-MIBG therapy. One (ease no. 12) was lost from follow-up after the first 100 mCi dose. Results in the remaining 3 patients are summarized in Table 4. Tumoral response was less impressive than biological response with a complete normalization of urinary eateeholamine exeretion in patient no. 11 and a reduction of more than 50% in patient 8. A clinieal improvement was also observed in the 3 eases. Chemiotherapy was given to 4 patients (cases no. 1, 3, 6, 10) eonsisting of iv administration of doxorubieine (100 mg) onee a month for 2-9

b) Ma/ignant presentation In 7 cases, malignancy was discovered before, du ring or immediately after the first surgical procedure. Patient no. 12 had bone metastases with spinal eord eompression before the diagnosis of pheoehromocytoma. In patient no. 4, catecholamine exeretion remained high after surgery whieh led to the finding of metastases. Two

Table 4 - Hormone and tumor response in 4 patients treated with 737/-MIBG. Cumulatlve dose (mCi)

Clinical response

Tumor response'

Hormonal response"

300

+

no change stabilisation

no change

8

307

+++

no change

partial

II

470

+++

minimal

complete

12

100

Patients (no.)

Evolution after treatment no relapse after 48 months no relapse after 12 months Relapse after 46 months with tumoral recurrence. liver meta, and catechol elimination lost to follow-up

'Tumor response: complete: complete regression 01 all measurable tumor; partial: at least 50% reduction 01 all measurable tumor; minimal: between 25 and 50% reductlon 01 all measurable tumor; no change, progression: appearence of new lesions or increase 01 25% 01 all measurable tumor "Hormonal response: evaluation on 24 h urlnary elimination 01 catecholamines and metanephrines; complete. normal elimination, partial: at least 50% reduction 01 elimination; minimal; between 25 and 50% reductlon; no change; progression. at least 25% increased.

646

Malignant pheochromocytoma

nant pheochromocytomas were extraadrenal at the first presentation (42%), whereas 9 of 68 benign tumors were extraadrenal (13%). The high percentage of malignancy in extraadrenal tumors is in good agreement with data of the literature (Table 5). The present study emphasizes the lack of clinical markers for malignancy. In fact, clinical expression with paroxysmal hypertension (25%), permanent hypertension (50%), atypical presentation (25%) is roughly the same than in the benign form. Considerable variations in excretion patterns of catecholamines and metabolites were observed, but no tumor was exclusively or predominantly DA-secreting wh ich is contradictory with previous findings (4, 20). Malignant pheochromocytoma might represent an intermediary situation between neuroblastoma where DA excretion is frequently increased and benign pheochromocytoma where DA excretion is frequently normal. Both derive from the neural crest: malignant pheochromocytoma seems to be sometimes closer to the former, sometimes closer to the latter. However, we must point out the fact that we were unable to measure certain peptides (e.g., neuropeptide Y, neurospecific enolase), which are supposed to be good markers of malignancy (21,22). The general evolution of malignancy allows us to distinguish two different situations. According to the literature as weil as to our own experience, roughIy half of malignant pheochromocytomas are apparently benign when first discovered. After excision they are clinically and biologically cured. Thus, at this stage, no specific clinical or biological profile can be detected. Nevertheless, malignant recurrence occurs 7-8 yr later on average, but this period of time may be as long as 22 yr as with one of our patients. The second half of the patients with malignant pheochromocytoma will have from the beginning signs of malignancy and metastases. The localization of recurrent tumors was sometimes possible with simple imaging procedures. Scintigraphy with 1311-MIBG was useful in 6 cases but not informative in 3. The lack of sensitivity is higher than 10-15% reported by Shapiro et al. (23) or Chatal et al. (27). In some cases, vena cava

months. A 2-yr survival with clinical improvement was observed in one patient (case no. 3), who had liver metastases and received 9 doses, while no response was seen for the remaining patients with bone or liver metastases. To improve the clinical paroxystic manifestations and hypertension, patients were treated successfully with phenoxybenzamine in 2 cases, with alpha-beta or beta blockers in 4 cases. Alpha methylparatyrosine was used in 2 cases (dose range: 500 - 1500 mg daily) for 1 and 3 yr, respectively, to control hypertension. DISCUSSION

The 17% prevalence of malignant forms of pheochromocytomas found in the present se ries is higher than that generally reported. As a matter of fact, arecent review of the literature gathering more than 1000 cases (13) found that approximatively 10% of lesions aremalignant.Aninteresting aspect of our study is the medical approach and the fact that long term follow-up allows us to classify the pheochromocytomas with greater accuracy. The relapse occurring after 22 yr represents one of the longest reported delay. Assessment of malignancy was based on the invasion by chromaffin tumor of organs where no embryologic residues can be found such as Iymph nodes, liver, lung, bone, brain. This type of pattern is clearly different from the multifocal primary lesions or recurrent multiple pheochromocytomas occuring in anormal site. Capsular or vascular local invasion occur frequently and may be associated with a poor prognosis. In 2 patients (cases no. 3 and 11), this was associated with metastases and in 2 other patients (cases no. 2 and 13) this feature, together with the locoregional invasion, was the basis for assessment of malignancy. In spite of the absence of metastases in the latter two cases, diagnosis of malignancy was accepted because we have seen the same locoregional invasion in 5 additional patients with metastases, whereas we have never seen this feature in the 68 benign pheochromocytomas. Histologic features, such as mitosis, giant cells and nuclear pleomorphism are not specific of malignancy. Therefore, there is no correlation between these cellular characteristics and the likelihood of metastases (8). Flow cytometry with DNA analysis is a new tool that may predict malignant evolution if the histogram is abnormal (15). In our series, some tumors weighed less than 100 9 and were not greater than 6 cm in diameter. For this reason, we cannot agree with the classical statement that size is a criterion for the diagnosis of malignancy (3, 4). On the other hand, 6 of 14 malig-

Table 5 - Localization of 587 pheochromocytomas from 8 series of literature (1-4, 16-19)

647

Benign pheochromocytoma

Malignant pheochromocytoma

Adrenal

439

35

Extraadrenal

74

39

R. Mornex, C Badet, and L. Peyrin

REFERENCES

catheterization was necessary to locate the part of the body in which a selective arteriography would then be able to detect ectopic recurrent tumor. The evolution of malignant pheochromocytoma is very variable with survival ranging from months to decades; prolonged survival even with widely metastatic disease is not uncommon: one of our patients survived with bone metastases for 15 yr. Nevertheless, in spite of this great variability, two different groups can be distinguished. One is composed of aggressive pheochromocytomas with disseminated metastases (especially to lung, liver and brain) and tumor progression: the prognosis is very poor, with a survivalless than 2 yr. Conversely, some pheochromocytomas show a relative malignancy and a slow evolution (especially with bone and Iymph node metastases). From a therapeutic point of view, surgery remains the best treatment. When distant metastases have occured, if complete surgical resection of metastatic tumors is not possible, then an effort should be made to reduce the size of the tumor and, consequently, catecholamines levels. Multiple resections mayaiso be required (28). The experience with radiation therapy (29) and chemotherapy (30) is anecdotal. However, arecent trial with cyclophosphamide, vincristine and dacarbazine every three wk showed a complete or partial tumoral response in 57% and a complete or partial humoral response in 80% of patients (31). MIBG therapy is an attractive new possibility. Our experience concerned only 4 patients, with an adequate follow-up in 3. We noticed a clinical improvement in the 3 patients, but also a biological normalization in one and a partial biological regression in other. We considered these results quite encouraging. These 3 patients are included in multicenter French study recently reported by the French MIBG Cooperative Group (32). In this study 15 patients with malignant pheochromocytomas were treated with MIBG. A beneficial effect was observed in 9 patients (60%), with 5 partial tumor responses, 4 complete hormonal responses and 3 partial hormonal responses, but no complete remission was seen. In other series, Sisson et al. treated 12 malignant pheochromocytomas with 131 1_ MIBG, obtaining partial biological responses in 5 patients, 2 of whom showed a partial humoral response (33). This partial effectiveness of MIBG even in the absence of side effects put it in second place after surgery, as far as therapy is concerned. The use of adrenolytic agents to minimize the cardiovascular effects of catecholamines is also important. Such therapy allows prolonged survival and a good quality of life despite widely disseminated tumor.

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24. Shapiro B., Copp JE, Sisson Je, Eyre PL, Wallis J, Beierwaltes WH lodine 131 metaiodobenzylguanidine for the locat-

649