Pheochromocytoma - from endocrinologist to surgeon
C. Poianã, M. Carsote, C. Chiritã, B. Stanescu, R. Bulata, R. Petrescu, C. Iosif, S. VerzeaClinical case, no. 6, 2009
* University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
* “C. I. Parhon” National Institute of Endocrinology, Bucharest, Romania
* Emergency Central Military Clinical Hospital, Bucharest, Romania
* “Victor Babes” National Institute of Research and Development of Pathology, Bucharest, Romania
Pheochromocytomas are rare neuroendocrine tumors, which originate in the cromaffin cells of the adrenal medulla. The incidence is between 2 and 8 cases per 1.000.000 people yearly. Apparently, 50% of cases were discovered at postmortem examinations (1-3). From all the hypertensions, pheochromocytomas are the cause of 0.1 to 1%. The lesion is usually unilateral, but 10% are bilateral, mostly seen in familial syndromes, like multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease or neurofibromatosis type 1. The frequency of malignant pheochromocytomas varies between 2.5 and 14% (4). There are no clinical, biochemical or radiological characteristics that can differentiate a benign tumor from a malignant one. The immunohystochemistry markers, like Ki67, a marker for cellular proliferation is highly suggestive, but malignancy is certain only in the presence of metastases. (1)
Case report
A 32 years old male patient, is evaluated one year after left laparoscopic adrenalectomy for a pheochromocytoma. His family history is unremarkable. At the age of 29 years, he underwent pulmonary lobotomy of the left inferior lobe, for a Hydatid cyst. A postoperative computed tomograph exam revealed a solid left adrenal tumor of 3.6 by 3.1 by 5.5 cm, with irregular borders. The patient was asymptomatic. The biochemical profile (including serum Potassium) was normal. The plasma cortisol (14.58 mg/dl – normal rage: 4.5 - 22 mg/dl) showed normal suppression during a low dose Dexametasone test. No hypogonadism was present. The surgical approach of the tumor was proposed, but the patient dropped out of follow up. After two years, a magnetic resonance exam showed again the left adrenal tumor of 4.5 by 4.5 by 7.0 cm, with a cystic area and with decreased intake of contrast, compared with the renal parenchyma and no metastases. (Fig. 1) Laparoscopic lateral transabdominal removal of the tumor was attempted, but because of the difficulty of dissecting the tumor, conversion to open surgery was decided. The patient had no hypertension or hypotension during the procedure and the postoperative evolution was uneventful. He was discharged after 10 days. The histological examination revealed a pheochromocytoma with aspects suggesting malignancy: capsular and adipose tissue invasion, frequent atypical cellular divisions, and nuclear pleyomorphism. The immunohystochemistry exam sustained the diagnosis: S100 positive, CROMO positive in different areas, ViM positive in a diffuse manner, INHIBIN A negative, CD 31 and ACT positive in blood vessels, negative in the tumor. The Ki 67 proliferation index of 5% is suggestive for well differentiated carcinoma. Reevaluation of the prior endocrinological investigations showed elevated plasmatic normetanephrines (NMN – 290 ng/ml, normal range between 15 – 90 ng/ml) and metanephrines (MN - 49 ng/ml, normal range between 10 – 45 ng/ml). After the surgical cure of the tumor the patient had normal levels of plasmatic metanefrines (NMN – 19 pg/ml, MN – 15 pg/ml). Chromogranin A, a marker of neuroendocrine tumors,was also normal (26 ng/ml, normal range up to 100 ng/ml). The normal values of PTH and calcitonin suggest the pheocromocitoma was not associated with parathyroid adenoma and thyroid medullar carcinoma as in a MEN2B syndrome. The patient underwent 123I-metaiodobenzylguanidine scintigraphy in order to identify metastatic or recurrent lesion that were not present. (Fig. 2) One year after the surgery, the patient had normal levels of metanefrines and chromogranin A, and the computed tomography exam showed no local or metastatic recurrence.
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Open questions and discussions
1. laparoscopic adrenalectomy - when?: Since it’s introduction in 1992, laparoscopic adrenalectomy is becoming the gold standard for the treatment of adrenal tumors, because of its low morbidity and mortality, and short recuperation period compared with open surgery (5). But it’s limits and applicability in cases of large (6) or supposedly malign tumors (7) is still matter of debate.
A recent review of laparoscopic adrenalectomy for malign tumors found similar recurrence rates compared with open adrenalectomy, of almost 40%. This suggests that minimal invasive surgery can be used for selected adrenal cancers and metastases (8;9). Out of 9 patients who underwent laparoscopic adrenalectomy and in which the histopathologic exam proved malignancy, only one died of metastatic disease and two had local recurrences (10).
For larger tumors (bigger than 6 cm) there are some authors who report their successful removal (up to 13 cm) (9,11). For these larger tumors, in some studies, but not in all, the operating time was significantly longer (11,12). Even larger tumors have been operated, up to 20 cm, with hand-assisted laparoscopic adrenalectomy (13).
There are different types of approaches for laparoscopic adrenalectomy, but the most frequently used ones are the lateral transperitoneal approach and the lateral retroperitoneal access. The retroperitoneal approach has the advantage of not being influenced by previous abdominal surgery and does not have the risk of carbon dioxide poisoning due to the insufflation gases. It also permits a good access to the adrenal gland (14,15). The operation tends to last longer and the blood loss is increased compared with the transabdominal approach (16). The transperitoneal laparoscopy permits a larger working area, and the anatomical hallmarks are easier to identify. The skill of the surgical staff and the previous pathology of the patient should determine the choice of the procedure.
The conversion rate is low, between 4.3% to 8.5% and should be considered in case of difficult dissection (like in our case), significant hemorrhage or local adheresions. Also if signs of malignity are discovered, (like capsular disruption during dissection or local invasion), conversion is recommended (11). The complication frequency is around 6% (9,17). Intraoperative complications include damaging the nearby organs (spleen, liver, pancreas, the bowels or the diaphragm), the blood vessels or the peritoneum. Late morbidity, such as deep vein thrombosis, peritoneal effusions or local recurrence has also been described (9,17).
2. pheochromocytomas – how do they differ? Because of the risk for hypertension at the mobilization of the tumor, pheochromocytomas are just starting to be operated laparoscopicaly.
In different patient series, pheochromocytomas comprise between 20 % (17) and 37.5 % (18) of all indications for adrenalectomy. Special care must be taken for these patients, especially in the preoperative care, when hypertension and volume contraction have to be normalized. The common protocol comprises alpha blockade with phenoxybenzamine. A Canadian study comparing 14 open adrenalectomies for pheochromocytomas with the 30 laparoscopic interventions found a statistically significant shorter postoperative hospital stay in the minimally invasive group. There was no difference in the frequence of intraoperative complications or recurrence rate (19).
In patients with pheochromocytomas larger than 6 cm the frequency of hypertensive events was almost three times higher compared with patients with smaller tumors (20). Another study found a higher rate of hypotensive and hypertensive crisis in patients with open adenalectomy compared with the laparoscopic approach (21). This seems to be related to the preoperative preparation of the patient or the timing for the clipping of the adrenal vein, because this was not confirmed by other authors (11;12). If some authors report a high cure rate of hypertension, of up to 75 – 100% (22), others are less optimistic, with 64% patient showing only an amelioration of blood pressure after surgery and only 33 % becoming normotensive (23). Still, their survival seems to be decreased mostly because of their risk of developing metastases (23).
Partial adrenalectomy, with conservation of normal adrenal tissue can be atempted in patients with bilateral lesions, in order to preserve cortical function. A large study, comparing 225 total laparoscopic adrenalectomy with 100 partial ones, for primary benign tumors, found after a mean follow up of 51 month, 6 relapses or local recurrences in the first group and none in the second one. The authors conclude that partial laparoscopic adrenalectomy is safe and can preserve cortical function in patients with bilateral adrenomectomy (24).
3. asymptomatic pheochromocytomas versus symptmatic The incidence of pheochromocytomas among theincidentally discovered adrenal masses is between 5 and 7%, and about 10% are diagnosed at an imagistic investigation performed for another pathology (10). In a retrospective study of patients with pheochromo-cytoma, investigated over a perios of 21 years at a teaching hospital in Northern Ireland, 10% were asymptomatic (4). Smaller tumor (< 1 cm) tend to be more frequently asymptomatic, but cases of larger tumors with no clinical signs have been described (10). Also, cystic pheochromocytomas, like in our case, tend to be more frequently asymptomatic. In one study, 3 out 6 cases of cystic pheochromocytomas operated between 2000 and 2007, were asymptomatic and had normal hormonal levels (25).
4. Follow up: because metastases can appear in pheo-chromocytomas considered initially benign a long time after surgical removal of the primary tumor, these patients require life long follow-up. This includes weekly measurements of blood pressure. Tumor markers (plasmatic or urinary metanephrines, urinary catecolamines) should be measured three months after surgery and then, every 6 months for the next three years. After that, the interval between testing may be increased to one year. Some authors recommend that the first dosage of the tumor markers should be two weeks after the surgery (1).
If the symptoms persist or the tumor markers are increased, imagistic studies are recommended. The most available ones are computed tomography and magnetic resonance. Usually, a whole body 123I metaiodobenzylguanidine scintigraphy is reserved for cases in which the tumor can not be located, or when searching for metastatic disease, (for example in large tumors or with signs of malignancy, like in our case). Its sensitivity for detecting the primary lesion or metastasis is around 83% and its specificity, 100%. Newer techniques, like the 6-[18F]-fluorodopamine positron emission tomography have a better sensitivity at detecting metastases (26).
Conclusions
usually, pheochromocytomas start as an endocrinological issue and end in surgery, and only rarely the pathway is the other way. Nevertheless, the surgical approach marks the prognosis as it is the only possibility to cure the disease. It also provides information regarding the histological profile. Recently, the immunohistochemistry markers as Ki67 became essential in pointing the aggressivity feature of the tumor resected
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