| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Division of Endocrinology (G.D., C.S., E.A.) and Department of Urology (O.N.), Bnai Zion Medical Center, Haifa, Israel, and Department of Chest Surgery, Rambam Medical Center (L.-A. B.), Haifa, Israel
Address all correspondence and requests for reprints to: Gabriel Dickstein, Division of Endocrinology, Bnai Zion Medical Center, P.O. Box 4940, Haifa, 31048, Israel.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and TreatmentsResults and DiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and TreatmentsResults and DiscussionReferences |
|---|
It is also accepted that radical excision with en bloc resection of any local invasion offers the best chance for cure, and prolongs life significantly (5). Little is, however, agreed on about other means of treatment to improve survival and cure in this grave disease. The most accepted chemotherapic agent used is o,p'-DDD (mitotane), a specific adrenolytic agent (6). Its common mode of use is in high doses of 6–10 g/day, which cause severe side effects, and besides some encouraging results, there are many disappointing ones. These are well summarized in a review article by Barzilai and Pazianos (7).
There are suggestions in the literature that administering much lower, well-tolerated doses of o,p'-DDD, as adjuvant treatment to surgery after the primary tumor and metastasis were resected, may offer much greater advantages regarding survival and remission (8, 9). We treated four patients with adrenocortical carcinoma this way, and herein report our results, adding some information about this challenging disease.
|
Patients and Treatments |
|---|
|
TopAbstractIntroductionPatients and TreatmentsResults and DiscussionReferences |
|---|
Patient 1
A 57-yr-old woman was evaluated in another hospital for severe
new-onset hirsutism. Elevated levels of testosterone were found (6.5
nmol/L; normal, <5.0), and on abdominal computerized tomography
(CT) scan a left adrenal tumor of 8.0 cm in size was demonstrated. The
tumor was resected and was described as a benign adrenal adenoma,
because it demonstrated no features suggestive of malignancy. One year
later, hirsutism recurred. The patient was reevaluated by us. Elevated
testosterone levels were found (7.8 nmol/L). On CT scan was found a
recurrence of the left adrenal tumor, and multiple lung lesions were
found. In two surgical procedures an adrenal tumor of 7.0 cm in size
and 13 lung metastases were removed from both lungs. The histology of
the tumors resected from both lungs was consistent with adrenocortical
carcinoma. Repeated CT scan (3 months later) showed no evidence of
residual tumor tissue. Testosterone levels returned to normal (2.0–2.5
nmol/L), as did dehydroepiandrosterone sulfate levels (0.2–0.3
µmol/L). The patient was put on o,p'-DDD treatment of up to 5.0
g, which she could not tolerate because of nausea and weakness. Within
2 months the dose was tapered down to 1.5 g, and she remained on
this dose, which was well tolerated, for 48 months. Her follow-up
included testosterone and cortisol measurements, as well as liver
function tests and complete blood counts. CT scans were repeated every
6 months. All these tests were negative for 4 yr. After that time, a
repeat CT showed two lesions in the left lung. These were resected and
were found to be consistent with adrenocortical carcinoma. Three months
later a repeat chest CT was normal (Fig. 1B
) and has remained so after 6
months.
|
A 67-yr-old man was evaluated for microhematuria and weight loss
of 5 kg in 2 months. On CT scan a left adrenal tumor of about 12 cm in
size was demonstrated. Urinary free cortisol level was elevated
to 253 µg/24 h. No further endocrine evaluation was done
before resection of the tumor. On surgery, the tumor was found to be
very friable and ruptured in situ, spilling a large quantity
of fluid. The tumor was found to be an adrenal tumor, 9.0 x 9.0
cm in size (Fig. 2). In two places the
surface was cut, and it seemed that much of the internal contents was
lacking. The tumor weighed 190 g (without the fluid spilled on
surgery). It showed invasion of anaplastic cells with significant
pleomorphism. Many cells had multiple nuclei with bizarre shapes. There
were areas of bleeding in the tumor. The fibrotic capsule included
hemosiderine pigment. The tumor’s capsule was invaded by tumor cells.
There was a large number of mitosis, partially pathological.
|
Patient 3
A 29-yr-old man was found to have a right adrenal tumor
on CT scan performed as part of workup for abdominal pain, diarrhea,
and weight loss of 6 kg in 3 months. The tumor was resected and found
to be 11.0 x 8.0 x 6.0 cm in size and weighed 320 g
(Fig. 3). The tumor cells showed
pleomorphism and anaplsticity (grade 3–4). About one third of the
tumor grew in a diffuse manner without any organization.
|
Patient 4
A 45-yr-old woman was evaluated for new-onset hirsutism. Elevated testosterone levels (8.2 nmol/L) were found, whereas dehydroepiandrosterone sulfate was in the normal range (9.7 µmol/L). On CT a large right adrenal tumor was demonstrated. The tumor was resected and found to be 7.5 x 5.0 x 4.0 cm in size. It weighed 53 g. Some tumor zones were composed of large cells with eosinophilic cytoplasm and large hyperchromatic nuclei separated by fibrovascular septa. Occasional mitotic divisions were seen, as was focal tumor necrosis. There was evidence of focal vascular and capsular invasion. In one place, the tumor was not totally resected.
The patient was put on o,p'-DDD 1.5 g/day, a dose that she tolerates well. Testosterone levels dropped post surgery to normal, and remained so since (0.5–0.7 nmol/L). Cortisol levels became low on o,p'-DDD treatment, and replacement therapy with dexamethasone was started. The patient is doing well with no side effects, complications, recurrence of the tumor, or development of metastases for the past 21 months.
|
Results and Discussion |
|---|
|
TopAbstractIntroductionPatients and TreatmentsResults and DiscussionReferences |
|---|
One may question the diagnosis of adrenal carcinoma in our patients. This diagnosis is indeed difficult to make, and the literature on this subject is controversial. It is well known that histology may be misleading. A recent review (5) summarized the histological features suggestive of carcinoma. Among these are frequent mitoses (patient 2), marked cellular pleomorphism (patients 2 and 3), nuclear atypia (patient 2), and invasion of the capsule (patients 2 and 4) or vascular invasion (patient 4). Using the criteria for size as predictor of malignancy in adrenocortical tumors, our patients fulfill the criterion of tumors larger than 5 cm and of volume greater than 200 cm3 (2). Patients 1 and 4 had virilizing-only tumors without clinical or biological Cushing’s syndrome. This feature was found in the widely quoted study by Bertaga and Orth (1) to be relatively common in adrenocortical carcinoma (7 out of 32 patients or 22%) but very uncommon in adrenocortical adenoma (1 out of 26 patients or 4%).
Patient 1 exhibited a very unusual course. Despite multiple lung metastasis, she experienced 4 yr of remission. It is our belief that the combination of careful removal of all tumorous lesions together with prophylactic use of low doses of o,p'-DDD allowed this long remission period. After recurrence of the two lung lesions, which were successfully and uneventfully removed, the o,p'-DDD dose was raised to 3.0 g, and thus far no recurrences were observed. We were able to find one similar case in the literature (10). That patient started out with an even worse situation (the primary tumor being much more widespread), but did well on a combination of repeated surgeries and 3.0 g of o,p'-DDD. In that case the authors contributed the success to the repeated surgical procedures, and, in our view, underscored the possible effect of the adjuvant medical treatment.
The role of mitotane in treatment of adrenocortical carcinoma is controversial (1, 5, 6, 7, 8). Besides the problem of diagnosing adrenal carcinoma and separating it from adenoma, there is also a lack of controlled studies. In most cases mitotane was added in high doses, at different stages of the disease, with or without tumor removal. Schtiengart et al. (8) were the first to suggest the beneficial effects of low doses of mitotane given immediately after tumor resection. Their results were also supported by a later study (9). One study that may suggest a clear benefit from use of adjuvant treatment with mitotane appeared recently (11). It showed that out of 26 patients who were treated with surgery + mitotane, the survival rate was 46% (12 patients), whereas in those who only were operated on, only 28% survived. In the group that received mitotane adjuvantly, 13 were started immediately post operatively, whereas in 13 the treatment was delayed for 3–15 months. Comparing these two groups, survival rate in the first was 10 out of 13 (77%), whereas in the second it was only 2 out of 13 (15%). These data strongly suggest that there is a positive role for treatment with low doses of mitotane only when started shortly after tumor resection. Schtiengart et al. (8) data showed that patients who received mitotane as adjuvant therapy before evidence of metastases was noted, and in those who were treated with mitotane and underwent subsequent surgery for recurrent tumor, had a significantly longer survival (74 ± 33 months) than those who got no mitotane treatment (10.3 ± 8.7 months). Other studies concerning this subject are in process (2).
The number of patients we present is too small to draw final conclusions. However, the results are very encouraging and suggest the importance of further study into this matter. Thus far there is no better mode of treatment other than surgery only to offer to patients. Mitotane in doses of 1.5–3.0 g causes very little and well-tolerated side effects (some nausea and dizziness) without any complications. There is a need for cortisol and, later on, mineralocorticoid replacement therapy. The fact that three of our patients (grade 2) show no tumor recurrence after 68, 54, and 18 months of treatment, and one (grade 4) patient developed treatable recurrence at 48 months, strongly suggests a positive role of mitotane under these circumstances.
Despite the limitations mentioned above, we feel that low-dose mitotane treatment adjuvantly to surgical resection offers clear benefits in an otherwise grave disease. Unlike what is typically employed, mitotane treatment has to be started very shortly after surgery, and be continued for a very long time; how long is as yet undetermined. These low doses of mitotane are well tolerated and do not influence patients’ daily routine. This in contrast to the high doses needed, with very limited effect if treatment is started only when the tumor recurs. Further studies are needed to define the exact positive role of this mode of treatment.
|
Revised May 22, 1998.
Accepted June 4, 1998.
|
References |
|---|
|
TopAbstractIntroductionPatients and TreatmentsResults and DiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  F. Daffara, S. De Francia, G. Reimondo, B. Zaggia, E. Aroasio, F. Porpiglia, M. Volante, A. Termine, F. Di Carlo, L. Dogliotti, et al. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly Endocr. Relat. Cancer, December 1, 2008; 15(4): 1043 - 1053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I G C Hermsen, H Gelderblom, J Kievit, J A Romijn, and H R Haak Extremely long survival in six patients despite recurrent and metastatic adrenal carcinoma. Eur. J. Endocrinol., June 1, 2008; 158(6): 911 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bertherat, J. Coste, X. Bertagna, G. Dickstein, C. Shechner, O. Nativ, J. E. Lee, A. Machens, H. Dralle, M. Terzolo, et al. Adjuvant Mitotane in Adrenocortical Carcinoma N. Engl. J. Med., September 20, 2007; 357(12): 1256 - 1259. [Full Text] [PDF]
|
|
|
|
|
|
M. Terzolo, A. Angeli, M. Fassnacht, F. Daffara, L. Tauchmanova, P. A. Conton, R. Rossetto, L. Buci, P. Sperone, E. Grossrubatscher, et al. Adjuvant Mitotane Treatment for Adrenocortical Carcinoma N. Engl. J. Med., June 7, 2007; 356(23): 2372 - 2380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Schteingart Adjuvant Mitotane Therapy of Adrenal Cancer -- Use and Controversy N. Engl. J. Med., June 7, 2007; 356(23): 2415 - 2418. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Nader, G. Raverot, A. Emptoz-Bonneton, H. Dechaud, M. Bonnay, E. Baudin, and M. Pugeat Mitotane Has an Estrogenic Effect on Sex Hormone-Binding Globulin and Corticosteroid-Binding Globulin in Humans J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2165 - 2170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Allolio and M. Fassnacht Adrenocortical Carcinoma: Clinical Update J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2027 - 2037. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Kendrick, R. Lloyd, L. Erickson, D. R. Farley, C. S. Grant, G. B. Thompson, C. Rowland, W. F. Young Jr, and J. A. van Heerden Adrenocortical Carcinoma: Surgical Progress or Status Quo? Arch Surg, May 1, 2001; 136(5): 543 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rainis, S. Ben-Haim, and G. Dickstein False Positive Metaiodobenzylguanidine Scan in a Patient with a Huge Adrenocortical Carcinoma J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 5 - 7. [Abstract] [Full Text]
|
|
|
|
|
|
L. Barzon, F. Fallo, and N. Sonino Comment--Is There a Role for Low Doses of Mitotane (o,p'-DDD) as Adjuvant Therapy in Adrenocortical Carcinoma? J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1488 - 1488. [Full Text]
|
|
|
|
|
|
G. Dickstein Is There a Role for Low Doses of Mitotane (o,p',DDD) as Adjuvant Therapy in Adrenocortical Carcinoma?--Authors' Response J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1488a - 1489. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
