Les paragangliomes retro-peritoneaux : diagnostic et prise en charge

25 septembre 2018

Auteurs : O. Karray, A. Saadi, M. Chakroun, H. Ayed, M. Cherif, A. Bouzouita, M.R.B. Slama, A. Derouiche, M. Chebil
Référence : Prog Urol, 2018, 10, 28, 488-494




 




Introduction


Paraganglioma, formerly called extra-adrenal pheochromocytoma, is an endocrine tumor, usually observed in young adults. Compared to more frequent locations, such as the carotid body and the truncus sympathicus, retro-peritoneum is an uncommon site [1]. Management of retro-peritoneal paraganglioma is multidisciplinary, implying radiologists, nuclear medicine physicians, anesthesiologists and urologists [2]. The major concern of the retro-peritoneal paraganglioma surgery are the cardio-vascular troubles and the risk of bleeding [3].


Methods


Authors studied retrospectively five cases of retro-peritoneal paraganglioma operated in the period from 2013 to 2017. The reported data concerned the past medical history, the clinical presentation, the hormonal assays, the radiological and imagery findings, the surgical procedure and the post-operative follow-up.


Results


The study is about 5patients, 2men and 3women (Table 1). The average age is 42.4years (25-62years). One patient had a history of polycythemia before the diagnosis of paraganglioma. Two patients consulted for a resistant hypertension, palpitation and increased sweating. Two other patients presented a lower back pain and voiding disorders. One patient was asymptomatic and the tumor was discovered in imagery as he suffered from a vaso-occlusive crisis related to a sickle-cell anemia. All the patients were explored by an abdominal CT-scan. Adrenal MRI was performed in two patients for whom the aspect wasn't clearly defined by CT-scan.


Three patients presented a unique tumor. Two of them consulted for non-specific symptoms; the third patient's tumor was discovered in imagery. In two cases, the tumor was peri-adrenal, measuring 12×3mm (right side) and 22×27mm (left side). Six months after diagnosis, an increase of the size of the nodules; 30mm and 34mm respectively; associated to a suspect wash out; measured at 40% and 20%; led us to operate. (Figure 1).


Figure 1
Figure 1. 

A heterogeneous tissular mass developed from the left adrenal gland. The Wash-Out is estimated at 20%.




In another patient, there was an aspect suggesting an upper urinary tract tumor in the right renal pelvis, measuring 20×14mm.


Patients with multiple-site tumors in CT-scan are those presenting catecholamine-excess symptoms and elevated urinary markers. The nodules, (2in a patient and 7for the other) were firmly adhering to the aorta and the inferior vena cava. (Figure 2).


Figure 2
Figure 2. 

Multiple hypervascularized lesions in the retro-peritoneum, firmly close to the aorta and the inferior vena cava.




MIBG scintigraphy was performed for both of them, showing a pathological fixation in the nodules. There were no other fixation sites than the masses viewed in scan. (Figure 3).


Figure 3
Figure 3. 

Pathological fixation of MIBG in two masses, adhering to large vessels.




Urinary markers were elevated in patients with catecholamine-excess symptoms and multiple-site tumors with pathological MIBG fixation. For those with non specific clinical signs and the asymptomatic patient, with a unique tumor, dosage was in the normal rate.


A 7days pre-operative medication, using α blockers, allowed a blood pressure control in the two patients for whom the diagnosis was strongly suspected.


Lomboscopic approach was attempted in the patients with peri-adrenal nodules. In one case, we converted to a lumbar incision as a sub-cutaneous emphysema occurred at the beginning of the procedure. In the other case, adrenalectomy and resection of the nodule were performed without incidents.


The patient with a renal pelvis tumor underwent a right nephro-ureterectomy (lumbotomy and Rutherford-Morrison incision).


Midline incision was preferred in patients with multiple-site tumors, to allow a better control of the dissection of the tumors in proximity to the aorta and the vena cava.


Only the patient with two nodules presented high blood pressure levels and sinus tachycardia during the operation, successfully controlled using anti-arrhythmic agents and calcium channel inhibitor. The resection was complete in the two cases; there were no hemorrhagic incidents during the procedures. (Figure 4).


Figure 4
Figure 4. 

Operative exploration: An encapsulated tumor, anterior to the aorta, measuring 40mm.




Post-operative course was uneventful for the five patients. Average post-operative hospital stay was 5.6days (4-7days). Histological examination of the surgical specimen concluded to a paraganglioma without signs of malignancy or aggressiveness. The average follow-up period was 22.8months (6-29months). There were no signs of clinical or radiological signs of recurrence. Blood pressure level was normal and catecholamine-excess signs disappeared in the patients with multiple-site tumors.


Discussion


Paraganglioma is a rare entity, sharing the same clinical presentation as pheochromocytomas.


Symptoms usually include the classical association of cephalalgia, increased sweating and palpitation. Blood pressure is commonly high and poorly controlled [4]. Diffuse abdominal pain, anxiety and tremor less often described [5]. Catecholamine-related cardiomyopathy has also been reported [6].


Positive diagnosis of chromaffin cell tumors is based on hormonal assays. Measurement of the plasma free or the urine fractionated metanephrines identifies most of the cases of paragangliomas. A recent German laboratory evaluation suggests that the first-morning spot urines offers an accurate measurement and can be considered as a more convenient option than the 24hours collection of urines [7]. Urinary normetanephrines and plasmatic Chromogranin A correlates well with the tumor mass and the risk of progression [8].


Imagery remains essential to locate the tumor and to predict the most appropriate surgical attitude. Abdominal CT-scan is indicated in first intention. As it precisely describes the tumors, its measurements and composition, it can be sufficient in localized forms. MRI is useful in metastatic paragangliomas, affording a better resolution than CT-scan. It's also indicated when the risk of irradiation should be limited in some patients. Metastatic, extra adrenal and multiple site tumors are better explored by a MIBG-scintigraphy; even small and not obvious locations show a pathological fixation [2].


In our cases, symptoms were found in two patients, urinary hormonal dosage was in a pathological level. The indication for the MIBG scintigraphy before surgery was the presence of multiple retro-peritoneal tumors.


Paragangliomas are known to be more aggressive than pheochromocytomas. Malignancy; defined by the presence of metastasis; concern 10 to 15% of the forms. Metastatic lesions are usually observed in the lungs, the liver, the spleen and the skeleton [9]. It's mainly suspected when the tumor weights more than 80gr, or when it's described in imagery as a heterogeneous mass with irregular margins [10].


For the symptomatic patients, abdominal and thoracic CT-scan didn't reveal any metastatic lesion.


The curative treatment of paragangliomas is surgical. The surgical management of a hormonally functional paraganglioma must be preceded by a 7days preoperative medication, by α blockers, to prevent peri-operative cardiovascular events [11]. β-blockers and calcium channel blockers can also be prescribed, only in association with α-blockers [2]. Prescribing β Blockers alone may expose to per-operative troubles as it increases the catecholamine's-induced vasoconstriction by blocking vasodilatation. Some protocols have been proposed, using a 3days-infusion of Urapidil and Magnesium sulfate, offering better treatment compliance [12]. Preoperative medication is justified by the fact that a high level of catecholamines and their derivatives is associated with a higher incidence of per and post operative cardio-vascular incidents [13].


The challenge of the anesthesia is to control blood pressure and volume and to prevent cardiac rhythm disorders. Therefore, an invasive monitoring is necessary. Even if there are no recommendations for the induction agents, propofol remains the most indicated. Ketamine and phenothiazines should be avoided, as they indirectly increase catecholamine secretion. Etomidate has a beneficial effect in patients with hemodynamic instability [14].


The major risk after tumor resection is circulatory collapse explained by vasomotor paralysis. It can be anticipated by decreasing progressively the vasodilating agents, optimizing volume status and the careful use of catechoamines after the tumor's vessels ligation [14].


In the cases we report, 7days α Blocker premedication allowed an acceptable control of blood pressure levels for patients with hypertension. Per-operative hemodynamic and rhythmic troubles were observed in one patient, successfully managed by the anesthesiologists. The surgery duration was longer, as the manipulation of the tumor increased the troubles.


Due to the low incidence of paragangliomas, there are no prospective studies comparing the superiority end the efficiency between the open surgery and the coelioscopic approaches.


As paraganglioma are more frequently malignant than pheochrocytomas, open surgery remains the recommended attitude, affording a better control while handing and resecting the mass [2]. Coelioscopic approach can be performed by experienced surgeons, in small paragangliomas, in accessible locations, with no radiological signs of invasiveness [3]. An exploration of the entire abdominal cavity is possible once the trans-peritoneal approach is performed. As a Japanese retrospective study of 49patients, comparing coeliosocpy in pheochromocytoma and single-site-paraganglioma concluded that the operation is longer and post-operative cardio-vascular incidents are more frequent, it's reasonable and more secure to treat paranganliomas by open surgery [15]. The indication of coelioscopy needs further studies on a larger series of patients to be strengthened.


The surgery related-risks must be considered by surgeons. The most important difficulty is the frequently observed proximity of paragangliomas to the large vessels, increasing the risk of bleeding. A meticulous dissection is required to avoid hemorrhagic accidents while liberating the tumor mass. The capsule rupture is a dread complication that occurs mainly in voluminous tumors, firmly adhering to adjacent organs and structures. It causes an intra and retro peritoneal dissemination of the tumor cells. Recurrence has been described after capsule rupture, even years after remission [16].


Disappearance of clinical troubles, normalization of blood pressure levels and hormonal assays are credible criteria to judge the efficiency of the surgical treatment.


We performed open surgery in the two patients presenting multiple-site paraganglioma. The location of the tumors, firmly adhering to the abdominal aorta and the inferior vena cava, led us to opt for a midline incision, affording a better control of the tumor dissection to minimize the risk of bleeding. Lomboscopic exploration was attempted in two patients, presenting a single paraganglioma, described as a suspect adrenal adenoma in imagery. Sub-cutaneous emphysema and hypercapnia compelled us to convert to dorsal lumbotomy in one case.


Data regarding outcome and survival rates regarding chromaffin cells tumors is limited and mainly concern pheochromocytomas, few cases of paragangliomas are included. The Mayo Clinic experience of a 66paragangliomas study group reported by O'Riordian, risk factors for persistent or recurrent disease are the tumor size, the local invasion and distant metastasis. A complete surgical tumor resection clearly improves outcome [17]. Surgical removal and debulking remains the recommended attitude for recurrent or metastatic disease. Once surgery isn't conceivable, palliation medical treatment is discussed. Chemotherapy and high dose I-MIBG radionuclide therapy have been attempted. Larger studies are required for a better evaluation of the efficiency and the disease's control [18, 19].


According to The Task Force recommendations (2014), all patients presenting a paraganglioma should be engaged in a genetic study. Identified mutations are found in 30% of the cases [20]. The most common is the Succinate-Deshydrogenase (SDH) mutation; the sub-unit B mutation (SDH-B) is found in 40% of the metastatic paragangliomas [21]. Other less frequent mutations have been mentioned, like the HIF-2A mutation, observed in the association of polycythemia to paraganglioma [22].


The five patients didn't show any clinical signs suggesting recurrence or distant metastasis. A longer follow-up is required to make recovery certain and to detect precociously a possible recurrence or distant metastasis. Genetic study should be included in the medical management of our patients, to identify possible mutations and to prevent further syndromic manifestations. The HIF-2A is particularly worthy of attention in the patient presenting polycythemia, geneticist must be informed of the patient's medical history.


Conclusion


An awareness of clinical symptoms is required to evoke the diagnosis of chromaffin cell tumors. Hormonal assays ensure positive diagnosis and recent studies conclude to interesting results concerning more specific methods and biomarkers. Physicians have to keep in mind the possibility of extra-adrenal sites, better identified by MIBG scintigraphy. The particular difficulty of the retro-peritoneal location is the proximity to large blood vessels, thus open surgery looks more secure. Further studies in larger patient's groups are needed to strengthen the indication of coelioscopy.


Disclosure of interest


The authors have not supplied their declaration of competing interest.




Table 1 - Clinical, pre-operative and surgical findings.
Age
medical history 
Symptoms  Hormonal dosage  Explorations  Surgery 
25years old female patient  Cephalalgia, sweating, palpitation
Resistant hypertension 
Elevated urinary metanephrines, in 6times the normal rate  Abdominal CT-scan
MIBG scintigraphy 
Midline incision
Resection of 2 paragangliomas, adhering to the aorta and the vena cava
Hypertensive crisis and sinus tachycardia 
40years old male patient
Sickle-cell anemia 
Asymptomatic
Abdominal ultra-sound
(vaso-occlusive crisis) 
Plasmatic and urinary hormonal assay in the normal rate.  Abdominal CT-scan
Adrenal MRI 
Lomboscopic exploration
Conversion: lumbar incision, left adrenalectomy
Hemodynamic and cardio-vascular stability 
40years old male patient
Diabetes
Dyslipemia
Polycythemia 
Cephalagia, sweating, palpitation
Hypertension
Loss of weight 
Elevated urinary methoxyated derivates level  Abdominal angioscan
MIBG scintigraphy
Adrenal MRI 
Midline incision
4paragangliomas between the aorta and the vena cava
3paragangliomas in the left side of the aorta
Hemodynamic and cardio-vascular stability 
62years old female patient
Diabetes, asthma 
Right lumbalgia,
Painful urination
Normal blood pressure 
Urinary hormonal assay in the normal rate.  Abdominal CT-scan  Lomboscopic exploration
Normal macroscopic aspect of the adrenal gland
Suspect nodule adhering to the posterior wall of the renal vein
Resection of the nodule, right adrenalectomy
Hemodynamic and cardiovascular stability 
45years old female patient
Mitral valve stenosis 
Right lumbalgia
Mictional disorders
Normal blood pressure 
Urinary hormonal assay in the normal rate.  Abdominal US
Abdomianl CT-scan 
Dorsal lumbotomy, Rutherford Morrison incision
Nephro-ureterectomy
Hemodynamic and cardiovascular stability 




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