Endocrinology: hormones, adenoma hypophysis, pituitary tumor

Grigoriev, A., Ivashchenko, OV Melnichenko GA, Marova EI, Vorontsov AV, Vladimirov, VP, Kolesnikova GS

Federal Endocrinology Research Center and Clinical

Itsenko-Kushing disease is a rare and severe neuroendocrine disease, caused by, in most cases, a pituitary adenoma, adrenocorticotropic cells from growing. This in turn leads to increased elaboration of adrenocorticotropic hormone (ACTH), with subsequent activation of the adrenal cortex and Cushing's development with the appropriate clinical and laboratory picture [5, 8, 11]. For the first time the disease was described in 1912 by the American neurosurgeon G. Cushing, and subsequently independently of him in 1924 by the Russian neurologist NM Itsenko.
Currently, there are two pathogenetic treatment BIC: Surgical (transnasal or transcranial removal of tumor) and radiation (proton therapy, "gammanozh" etc.). According to different authors [4, 9, 10] the effectiveness of these methods are comparable with each other, and reaches the order of 8090%. Each method has its advantages and disadvantages, indications and contraindications. For example, in the presence of pituitary adenoma preferred surgical treatment, and in its absence - radiotherapy [2, 3].
The present level of development of microsurgical techniques, in particular the development of endoscopy has greatly enhance the effectiveness of surgical intervention, almost reduced to zero the number of serious complications and deaths, as well as to minimize the incidence of complications such as diabetes insipidus, panhypopituitarism, nasal liquorrhea etc.
The aim of this work was to study the effectiveness of transsfenoidalnogo method using microscopic and endoscopic technique in FGU Rosmedtechnology "Endocrinology Research Center.

Materials and methods.

During the period from October 2004 to May 2007 in PG Entz RAMS (from April 2007 Federal Enz "Medical Technologies) was operated on 70 patients with the disease ItsenkoKushinga, of which women accounted for the overwhelming majority of 96% (67 obs.) Men 4 % (3 obs.).
Average duration of illness was about 4 years. Patient age ranged from 17 to 58 years (median was - 35). All patients underwent preoperative examination by the scheme adopted in the Department of Neuroendocrinology. This scheme includes the study of secretion of ACTH and cortisol (at 8.00 and 23.00) in serum, determination of their circadian rhythm, as well as study the level of free cortisol in the daily urine, holding the small and large deksametazonovyh samples.
All patients on MRI and / or CT of the brain was found pituitary adenoma. All patients were operated primarily under balanced Transnasal multicomponent anesthesia with artificial pulmonary ventilation. At the same time using the endoscopic technique was operated on 39 (55%) patients, using a microscope - 31 (45%) patients. All were produced total and subtotal removal of pituitary adenoma. In the vast majority of cases 69 (99%) tumors had a soft consistency. In 4 cases (6%) indicated the presence of cysts.
 
Table 1 shows the distribution of the number of pituitary adenomas by size, according to the classification, one based on classification, previously developed at the Institute of Inorganic Chemistry them. NN Burdenko [1].
Table № 1
Dimensions of kortikotropinomy%
Mikroadenomy (up to 10 mm in diameter) 48 69
Small (1125 mm in diameter) 19 27
Average (2635 mm in diameter) 3 4

In 63 observations (90%) tumors were located endosellyarno, in 7 (10%) patients had ekstrasellyarny growth in one or more directions. Since the invasion in the cavernous sinus was noted in 5 (7%) cases, infrasellyarny growth in 2 (3%), suprasellar tumor spread was noted in 2 (3%) cases.
Rate klinikogormonalnyh values were recorded for 57 days after surgery, as well as after 6, 12, 24 months of treatment. Determination of hormones in the blood serum and free cortisol in the daily urine was determined by radioimmunoassay in the laboratory hormone analysis.
Data processing was performed using the software package «Statistica» version 6.0.

Surgical technique.

Removing the tumor with the help of a microscope was performed in a patient half-sitting position, rotating the patient's head in the direction of the surgeon to 1520 degrees. Before the operation endolyumbalno injected 24 mL of air to verify the upper pole tumors and basal cisterns of the brain under the control of image converters (EOC).
At the stage surgical approach was performed crossing the nasal septum in the back of its departments, retiring 12 cm from the front wall of the sinus bone core, with a preliminary dissection of the mucosa of the medial wall of the nasal cavity at the same level. After dissection of the mucosa and the nasal septum, laterally offset, installing the port bow and the front wall trepan main sinus, with the leave remains of the nasal septum and rostrum, which are the basic guidelines in determining the middle line.

The next stage, depending on the thickness and looseness of the main sinus mucosa, produced total or partial removal, and then performed trepanation bottom of the sella turcica. The boundaries of the trephine windows were: cavernous sinus on the side, bottom - the horizontal platform base of the sella turcica, top - the place of the diaphragm with the tubercle of the sella turcica. After puncture and dissection of the dura mater and capsules adenoma, if any, was carried out to remove the tumor with pituitary spoons and kyuretok different sizes, mikrokusachek and aspirator. After removal of the tumor and the implementation of the landmark hemostasis was performed tamponade floor of the sella turcica hemostatic materials, carried plastic Turkish saddle bone fragments from the nasal septum, and if liquorrhea made by sealing the adhesive components autozhira, ballonakatetera etc.
At the final stage after the removal nosorasshiritelya, nasal septum was returning to its original place and its mucous membrane clinging to both sides of thin films of carcasses to improve the increment of the mucosa to the partition. Then through the nasal passages into the nasopharynx installed air ducts, with subsequent tamponade of the nasal cavity with gauze turundae soaked sintomitsinovoy emulsion. Tampons, air ducts and frame of the film were removed at 35 days postoperatively.
The desire for total selective removal of adenoma and reduce the frequency of intraoperative damage to the contents of the cavernous sinuses, optic nerves and the diaphragm of the sella turcica caused the recent use of endoscopic techniques.
The principal difference between endoscopic technique is that the visual control during the operation via an endoscope with breeding the image on the monitor. This requires in addition to the availability of special equipment (endoscopic rack, etc.), additional surgical skills than the skills used in operations under a microscope.
The advantages of using an endoscope during surgery on the pituitary gland are: reducing the trauma of the mucous nasal cavity, a panoramic view of sphenoid sinus cavity and sella turcica, a clear differentiation of the tumor and normal pituitary tissues, early diagnosis and removal of CSF. In contrast to the limited review of the tubular microscope, the optical system of endoscope with lateral and retrograde review 0o 120o allows you to inspect the structure, located supra and retrosellyarno, ekstrasellyarnye identify areas of the tumor, and radical removal of an adenoma with maximum preservation of intact tissue adenohypophysis.
No need for nasal tamponade with a corresponding decrease in the frequency of postoperative complications and pain, leading to more rapid recovery and vocational rehabilitation patients.
Endoscopic removal of pituitary adenomas was conducted in the position of a patient lying on his back. Carried out laying jackets, moistened with a solution of vasoconstrictive drugs (0,1% pp adrenaline hydrochloride, 0.05% pp naftizina) between the mean nasal turbinate and nasal septum to reduce the "thickness" of the mucous membrane, thus increasing the "useful" for the surgeon operating the canal lumen . After exposure for 1015 minutes quilted removed, and carried the standard procedure of processing of the nasal cavity with antiseptic solutions ("Octenisept"). Further increase in lumen was achieved by nasal turbinate lateralization performed after the panoramic view of the nasal cavity. It should be noted that successful implementation of laterality increases the possible manipulation of freedom for the surgeon and to reduce mucosal trauma throughout surgery. If necessary (curvature of the nasal septum, narrow lumen nasal passages) can be set nosorasshiritel.
Following the discovery of the natural sinus fistulas core, is located at the lower boundary of the upper bow of the shell and medial to it (in some cases it may be covered with the lower part of supraturbinal) performed partial removal of the mucosa of the nasal cavity from the front wall of the main sinus by coagulation and / or by a miniature electric shavers (Shaver, debrider). At this stage, be careful when dealing with mucosal projections in the bottom of the main sinus, to avoid traumatizing klinovidnonebnoy artery (A. sphenopalatina), a member of the nasal cavity through klinovidnonebnoe hole (foramen sphenopalatinum), is located at the rear of the middle nasal sinks, and namely its medial branch - incisive artery (A. nasopalatina), passing over the choanal and a member of the nasal septum. This branch often has a fairly large gap, and the development of bleeding from it may bring some unpleasant moments for the surgeon when accessed.
After removing the mucosa, depending on the intended access (transseptalny, universities, bilateral transostialny) trepanize front wall of the main sinus by increasing its mouth with an offset rear sections septum laterally. Then removed the mucous membrane of the main sinus and the sella turcica was performed trepanation with subsequent removal of the tumor. Final stages of the operation in general similar to those described above, a microscopic approach to removal of the tumor, but after the plastic bottom of the sella turcica nasal tamponade were performed. Carried out only reposition nasal turbinate and septum. However, it is possible to reduce bleeding in the middle setting nasal passage "insert" of the hemostatic sponge.

Results and discussion.

All patients had active stage of the disease, 3 (4%) disease was mild, in 60 (86%) - moderate and in 7 (10%) disease was of a heavy character. The criteria for evaluating the severity of the disease were the presence of lesions of the cardiovascular system, as well as the severity of osteoporosis, disorders of carbohydrate and mineral metabolism.
In 38 patients (54%) of neurosurgical operations was the primary method of treatment. 32 patients (46%) in the preoperative period to use other methods of treatment, which only led to temporary or partial remission of the disease or were not effective at all. Preceding operation radiation (proton therapy) therapy were 7 (10%) patients, in 6 (91%) of them it was combined with medication. Unilateral adrenalectomy was carried out 9 (13%) patients, of whom 2 patients (3%) in combination with radiation therapy and in 1 (1%) combination therapy (a combination of radiation, medical and surgical methods of treatment). Previous drug therapy was carried out 17 patients, or 24%.
Adrenal hyperplasia was observed in 38 (54%) patients, of whom unilateral hyperplasia was noted in 16 (23%), two-sided in 18 (31%) and 2 (3%) cases revealed the formation of adrenal gland volume. Correlations between tumor size, degree of infestation and the severity of manifestations of the disease were observed.
The frequency of clinical manifestations of Cushing's is presented in table number 2.

Table № 2
The frequency of clinical manifestations of Cushing's
Clinical manifestations of%
matronizm 43 61
nervnopsihicheskie violations 43 61
hirsutism 39 56
striae 31 44
tissue swelling podkozhnozhirovoy 25 36
trophic disorders of the skin 23 33
hyperemia of the facial skin 20 29
Acne 16 23
sweating October 1914
laktoreya May 7

Overweight or obese varying severity was noted in 60 patients, accounting for 86%. Body mass index was calculated 64 patients, of them 28 (44%) was recorded overweight, obesity I grade in 19 (30%), obesity II level in 5 (8%), obesity degree III in 2 (3%) .
Osteopenia was observed in 39 patients (56%), osteoporosis in 14 (20%), of these, 10 (14%) was revealed severe osteoporosis with fractures of the bones (ribs, vertebral compression fracture).
In 19 patients (27%) had concomitant thyroid involvement, most often represented nodular. Concomitant hypothyroidism was observed in 5 patients (7%) (mild in 3 (4%), moderate in 1, decompensated at 1).
Hypogonadism was noted in 55 (79%) patients.
Artralgichesky syndrome was noted in 21 (30%) patients.
Diabetes mellitus was diagnosed in 24 (34%) patients, and in 10 (14%) - mild, 13 (19%) - moderate and in 1 (1%) case - heavy.
Preoperative none of the cases are not noted the presence of diabetes insipidus.
Cardiovascular changes in the form of ischemic heart disease, arterial hypertension of varying severity, steroid cardiopathy, circulatory failure verified in 62 patients (89%), of whom 26 patients (37%) violations were moderate in the remaining cases had lung disorders.
The defeat of the gastrointestinal tract in the form of concomitant esophagitis, gastritis, cholecystitis, pancreatitis was observed in 57 patients (81%).
Diseases of the urinary tract were detected in 24 (34%) patients and in 13 patients (4%) patients violations of the respiratory system.
In 9 patients (13%) patients before surgery were noted lungs visual impairment in the form of incomplete bitemporal hemianopsia and / or reduction of visual acuity to 0.6.
Cephalgic syndrome was diagnosed in 45 (64%) patients, of them 4 (6%) of moderate severity. Myo neuropathy were noted in 37 (53%) patients. Astenonevroticheskoe state - 43 (61%) patients.
Reduced cortisol levels after adenomectomy developed in 69 patients (98%), and in 48 (68%) noted the development of adrenal insufficiency, and in 11 (16%) of its normalization.
There was no korelyatsii between disease duration and frequency of postoperative normalization of cortisol levels or the development of adrenal insufficiency.
It is noted that in the group of patients was carried out only where neurosurgical treatment, the incidence of adrenal insufficiency in a short time after surgery was higher than 3 times.
There were no relationships between severity of Cushing's source and the frequency of adrenal insufficiency or normal levels of cortisol.
The presence of the invasive growth of adenomas affect the radical operation and the incidence of adrenal insufficiency - 73% against 29% for invasive growth (p = 0,027). This apparent difference in the frequency of normalization of hormonal levels, depending on the size of adenomas had been received. The incidence of adrenal insufficiency after removal makroadenom was about 65%, and after mikroadenomektomii - about 70%.
Efficacy of treatment with transnasal interventions using a microscope was comparable to that of using an endoscope - 87% and 82% respectively. No differences in the volume of blood loss is also not revealed, but at the time of the endoscopic surgical intervention was slightly shorter, at an average of 2,530 minutes.
Intraoperative complications.
While access is preferable to make partial removal of the main sinus mucosa, because sometimes its total removal may be accompanied by marked venous bleeding from the main sinus, leading to an increase in the time of surgical intervention. In our sample of such a hemorrhage developed in 6 patients.
The vast majority of patients, given poretichnost bone, trepanation not be highly technical. Only in 2 cases because of marked thickness and density of bone tissue had to use special tools.
In 2 patients with access, due to anatomical features in the form of unexpressed Turkish saddle, were rastrepanirovany posterior portions ethmoid labyrinth.
In 5 patients during surgical access during endoscopic removal developed bleeding of varying severity from klinovidnonebnoy artery, left bipolar coagulation.
During the removal of the tumor in 15 patients (21%) were severe bleeding of tumor tissue. 5 (7%) patients was performed to remove the tumor from the cavernous sinus. The average volume of blood loss was 250 ml.
Intraoperative liquorrhea was noted in 30 observations (43%), which was the reason for events to seal the bottom of the sella turcica: using adhesive wafer "Tachocomb" in 34 (49%), bone autograft in 15 patients (21%), autozhirom in 3 ( 4%), glue "Tissukol" in 1.
7 patients (10%) had been stitched to the dura mater. Prophylactic external lumbar drainage for up to 7 days in the postoperative period was set 3 (4%) patients.
In one case the patient is 23 years old at the stage of initial anesthesia developed bradycardia with episodes of 4045 to 25, with normal levels of BP. With the introduction of atropine increased frequency of the rhythm was not observed, with the introduction of adrenaline surge of blood pressure and the development of ventricular tachycardia with triplets. Given the existence of pathology of the conduction (preexcitation syndrome type CLC) operation was postponed. The patient had established a temporary pacing electrode
During the operation the bleeding varying degrees of severity of upper and / or lower hypertrophic mezhkavernoznyh sinuses was noted in 12 (17%) patients. As a rule, such as bleeding were wordless in nature and could stop by pressing the hemostatic sponge. In two cases, with the development of pronounced bleeding last stop made by a tight two-sided tamponade Turkish saddle hemostatic sponge.
Of the 5 patients who had tumor ingrowth in the cavernous sinus, the other three observed bleeding from the cavernous sinus, sinus stopped tight tamponade hemostatic gauze and sponge in the defect area. In 6 patients noted marked venous bleeding during trepanation of the spongy substance of bone or major divisions lowback sinus after removal of the mucosa. These bleeding was stopped or pressing of a tight tamponade hemostatic sponge.

Postoperative complications.

Postoperative mortality and severe complications in our cases were not recorded. In the early postoperative period minor complications developed in 24 (34%) patients and 2 patients (3%) - moderate complications [2].
Of these, 3 (4%) patients noted the increase or the appearance of headache, one patient developed diplopia, in one case, noted the development of psychotic disorder with symptoms of psychomotor agitation (moderately complication). In one case, decreased sense of smell.
Diabetes insipidus developed in 11 (16%) patients, and with the same frequency as after endoscopic adenomectomy, and after surgery using a microscope.
In 10 (14%) cases in the early postoperative period developed systemic complications. Of these, 2 (3%) developed pneumonia, one patient worsened trophic crural ulcers, in two cases there was exacerbation of chronic pyelonephritis in one case developed an abscess gluteal area (moderately complication), one patient developed collaptoid state. In 3 (4%) cases developed inflammatory changes in paranasal sinuses.
Conclusion
1. Transsfenoidalnaya adenomectomy - a highly effective and fairly safe method of treatment of patients with BIC. According to our data, its efficiency was over 84%. Moreover, the apparent differences in the effectiveness of treatment and frequency of postoperative complications between the micro and endoscopic techniques in the treatment of this nozoologii not received. Endoscopic adenomectomy is less invasive technique, which has a great overview of the wound, increasing the possibility of manipulative ("four hands") in the surgical wound. Because of this less traumatic access it more easily tolerated, reduced the period of postoperative rehabilitation, which ultimately leads to a decrease in the number koykodney and the period of disability. Shortens the duration of preoperative preparation and the period of the surgery.
The disadvantages of this method is an absence of space vision of operational field. Perhaps the improvement of endoscopic equipment (serial production of endoscopes with the presence of volumetric images) can neutralize this disadvantage.
2. The effectiveness of treatment depends on the BIC of the disease, as well as the degree of invasion kortikotropinomy. Thus, the earlier diagnosis of disease and the early holding of pathogenetic treatment promoted the effectiveness of therapy.
References:
1. Kadashan BA "Indications for various methods of treatment of pituitary adenomas, diss.na competition of art. Dr. med. Sciences, Moscow, 1992.
2. Kadashan BA, Rosenfeld BI, Shifrin MA "Information card patient pituitary adenoma", preprint, Moscow, 1985.
3. Marova E.I, Arapova SD, Trunin JK, Kolesnikova G.S, "Early and late results of neurosurgical treatment of FT," Problems of Endocrinology, 2006, T.52, № 4, 1,3, 610.
4. Marova EI "Advances in the treatment of FT, Russian Medical Journal, 2005 Volume 13, № 6.
5. Marova EI Arapova SD, Belchenko LV