In recent years, with the improvement of socio-economic level and people’s health awareness, the detection rate of pituitary adenoma has been increasing year by year. Since pituitary adenomas not only have various characteristics of tumors, but also can cause abnormal endocrine functions (including infertility and sterility), they bring great adverse effects to patients, families and society. Pituitary adenomas are benign tumors, and their detection rate has been increasing year by year in recent years. Due to the varying medical standards and differences in medical personnel’s understanding and management of the disease, the prognosis of patients with pituitary adenomas is seriously affected.
In order to improve the level of surgical treatment of pituitary adenoma, the China Pituitary Adenoma Collaborative Group organized experts and scholars related to pituitary adenoma to write the Expert Consensus on Surgical Treatment of Pituitary Adenoma in China.
I. Introduction of pituitary adenoma
The incidence of pituitary adenoma ranks the second among intracranial tumors, accounting for about 15% of intracranial tumors, with a population incidence of 8.2%-14.7% and an autopsy detection rate of 20%-30%.
1. Classification.
(1) According to the type of hormone secretion: functional pituitary adenoma (including prolactin adenoma, growth hormone adenoma, thyrotropin adenoma, adrenocorticotropic hormone adenoma, gonadotropin adenoma and mixed pituitary adenoma) and non-functional pituitary adenoma.
(2) According to the size of the tumor, there are microadenoma (<1cm in diameter), macroadenoma (1-3cm in diameter) and giant adenoma (>3cm in diameter).
(3) The tumors are classified into invasive pituitary adenomas and non-invasive pituitary adenomas by combining imaging classification, intraoperative findings and pathology. Atypical pituitary adenoma: Ki-67>3%, P53 staining is widely positive, and nuclear heterogeneity, and atypical pituitary adenoma can be diagnosed if two of the above three points are met clinically.
2. Main clinical manifestations.
(1) headache; (2) visual field disorder; (3) other corresponding symptoms caused by tumor compression of adjacent tissues; (4) corresponding symptoms and signs of functional pituitary adenoma.
3. Diagnosis.
(1) Corresponding clinical manifestations.
(2) Endocrinological examination: prolactin adenoma: prolactin > 150 μg/L and exclude other specific causes of hyperprolactinemia. Serum prolactin < 150 μg/L must be diagnosed with caution in context. Growth hormone adenoma: Diagnosis by random growth hormone levels alone is not recommended and a glucose growth hormone suppression test should be performed. Pituitary growth hormone adenoma can be excluded if the post-load serum growth hormone trough value is < 1.0 μg/L.
Serum insulin-like factor (IGF)-1 also needs to be measured. an abnormality is judged when the patient’s serum IGF-1 level is higher than the age- and sex-appropriate range of normal values. Cushing’s disease: loss of circadian rhythm of blood cortisol, normal or mildly elevated ACTH, and elevated 24-h urinary free cortisol (UFC). In patients with Cushing’s disease, the classic low-dose dexamethasone suppression test (LDDST) is not suppressed and the high-dose dexamethasone suppression test (HDDST) is suppressed.
The differential diagnosis of Cushing’s disease and ectopic ACTH syndrome can be improved by measuring ACTH levels in subclavian sinus veins in hospitals where available. (b) Thyrotropin adenoma: plasma thyroxine levels are elevated and TSH levels are mostly elevated, with a few in the normal range.
(3) Enhanced MRI or dynamic MRI scan of the saddle area: definite adenoma found in the saddle area. MRI may be negative in some patients with Cushing’s disease.
Indications for surgical treatment of pituitary adenoma
The purpose of surgical treatment of pituitary adenoma includes removing the tumor to relieve the clinical symptoms caused by long-term pressure on the surrounding structures such as vision loss; correcting the endocrine dysfunction; preserving the normal pituitary function; and clarifying the tumor histology.
1.Surgical indications.
(1) Transnasal butterfly approach surgery: ① Symptomatic pituitary adenoma stroke exists. (2) The occupying effect of pituitary adenoma causes compression symptoms. The symptoms may include compression of the optic nerve, actinic nerve and other adjacent cerebral nerves as well as hypopituitarism caused by pituitary gland compression, and surgery should be preferred after excluding prolactin adenoma. Prolactin adenomas and other hypersecretory pituitary adenomas (mainly ACTH tumors and CH tumors) that have difficulty tolerating adverse drug reactions or are resistant to drug therapy.
(iv) Partial pituitary gland resection and/or biopsy of the lesion. For lesions of pituitary origin with severe endocrine function (especially pituitary ACTH), pituitary exploration or partial resection is feasible; for lesions of pituitary origin that cannot be determined preoperatively but require treatment, biopsy is feasible to clarify their nature. (5) The selection of transsphenoidal surgery should also take into account the following factors: the height of the tumor; the shape of the lesion; the texture and blood supply of the tumor; whether the saddle septal surface is smooth and intact; the extent of intracranial and cavernous sinus invasion; sinus development and nasal pathology; the patient’s general condition and willingness to operate.
(2) Open pituitary adenoma resection: patients who cannot undergo transsphenoidal sinus approach; patients with nasal cavity infection.
(3) Combined approach surgery: the main body of the tumor is located in the saddle, supra-saddle and parasternal development, in the shape of “dumbbell”.
2. Contraindications
(1) Transnasal butterfly approach surgery: the surgery is relatively contraindicated due to pathological hypersecretion of pituitary hormone which leads to severe systemic dysfunction or low pituitary function which leads to poor general condition of the patient. ①Active intracranial or nasal cavity or pterygoid sinus infections can be operated after the infection is controlled. ②Patients with poor general condition cannot tolerate surgery. The lesion is mainly located in the suprasellar area or in the shape of “dumbbell”. (3) Residual or recurrent tumor without obvious symptoms and difficult to be removed by surgery.
(2) Craniotomy for pituitary adenoma: ①Pituitary microadenoma; ②If there is obvious hypopituitary gland function, it should be corrected before surgery.
Assessment and management of perioperative conditions
The evaluation and treatment of perioperative patients include: (1) indications for surgery, timing of surgery and selection of surgical methods; (2) treatment of preoperative and postoperative pituitary hormone abnormalities resulting in comorbidities or pre-existing medical diseases; (3) evaluation of preoperative and postoperative pituitary function and adjustment of hormone levels and treatment; (4) adjustment of water and electrolyte balance before and after surgery; (5) publicity and education of perioperative conditions. (5) publicity and education on perioperative conditions. It is recommended that multidisciplinary teams or groups experienced in the treatment of pituitary adenomas should be involved in the development of treatment plans in tertiary hospitals or above.
Perioperative management should focus on the following areas.
(1) Complicated cardiovascular lesions, including acromegaly cardiomyopathy, cardiac insufficiency, arrhythmia, etc., need to be treated with cardiovascular medicine consultation before and after surgery, such as cardiac diuresis, angiotensin-converting enzyme inhibitors and B-blocker therapy. In patients with pituitary growth hormone adenoma, even if their heart function can tolerate surgery, they can first use medium- and long-acting growth inhibitors to improve their heart disease before surgery.
For patients with combined hypertension and diabetes mellitus, symptomatic treatment should be given before and after surgery to actively control blood pressure and blood glucose. Patients with pituitary adenoma, especially growth hormone adenoma combined with OSAS, are at high risk of anesthesia, so anesthesiologists and cardiovascular doctors should be consulted before surgery.
(2) Management of postoperative water-electrolytes and uremia: Patients with postoperative pituitary adenoma should routinely record 24-h fluid intake and output, and monitor blood electrolytes and urine specific gravity. If symptoms of uremia appear immediately after surgery, antidiuretic hormone treatment should be given if necessary according to the volume and electrolyte condition.
(3) Perioperative hormone replacement therapy: Patients with pituitary adenoma should undergo preoperative evaluation of adenopituitary function, including measurement of hormone levels of thyroid axis, adrenal axis, gonadal axis, growth hormone, IGF-I, etc. In the presence of secondary hypothyroidism and secondary hypoadrenocorticism, physiological replacement volume therapy is required. Patients with pituitary adenoma are given a stress dose of glucocorticoids on the day of surgery (except for Cushing’s disease), and the dose of glucocorticoids is adjusted postoperatively to maintain normal vital signs and water-electrolyte balance, and the dose of glucocorticoids is gradually reduced to a physiological replacement dose. Patients with pituitary adenoma should be followed up clinically and evaluated for pituitary function to adjust the dose of hormone replacement therapy, and some patients need lifelong adenopituitary hormone replacement therapy.
IV. Operating room conditions and personnel training
1. Microscope, endoscope and instruments: We have a neurosurgical microscope or endoscopic system and a variety of microscopic instruments for transsphenoidal or open surgery of pituitary adenoma.
2. Monitoring system: intraoperative C-arm or neuronavigation equipment.
3.Personnel training: have the foundation of skull base microscopic operation training and participate in the pituitary adenoma microscopic operation training course, and have done more than 50 cases of similar operations under the guidance of superior doctors. Endoscopic surgery operators should have the anatomical training of neuroendoscopic operation and hold the associate certificate, and have done more than 50 cases of endoscopic operation under the guidance of the superior doctor.
V. Surgical treatment
1. Transnasal pteridian approach surgery.
(1) Surgical principles: adequate preoperative preparation. (1) The principles of surgery: adequate preoperative preparation, intraoperative positioning, resection of tumor and better protection of pituitary function. (3) Good repair of the saddle base and cerebrospinal fluid leak. Anatomical and physiological reset.
The tumor cavity is moderately filled with hemostatic materials, such as gelatin sponge, fluid gelatin, regenerated oxidized cellulose (quick i.e. yarn), small bone fragments, fibrin adhesive, etc. to reconstruct the saddle base (if necessary, white body fascia, muscle or fat are used for repair), the nasal septum and mucosa are repositioned, and the nasal cavity is moderately filled.
②Neuroendoscopic transsphenoidal approach: a. Endoscopic access to the selected nostril (routinely via the right side), with the inferior turbinate visible on the lateral side of the nasal septum. After filling the inferior nasal tract (between inferior turbinate and nasal septum), middle nasal tract and superior nasal tract with a cotton pad soaked with epinephrine dilution (1 mg epinephrine/10 ml physiological saline), the gap between the nasal tract is significantly enlarged and the endoscope is passed along the nasal tract to the pterygoid septal fossa where the opening of the pterygoid sinus can be found. The opening of the pterygoid sinus can be determined based on the upper edge of the posterior nostril, 0.8-1.5 cm anteriorly along the nasal septum toward the pterygoid septal fossa; b. 1 cm upward at the lower edge of the root of the middle turbinate
c. A curved incision is made medially along the anterior edge of the opening of the pterygoid sinus on the anterior wall of the pterygoid sinus and the vertical plate of the septum, and the mucosal flap is turned toward the posterior nostril (there is a branch of the pterygopalatine artery near the root of the middle turbinate) to reveal the anterior wall of the pterygoid sinus. d. The bone of the anterior wall of the pterygoid sinus and the intracavity of the pterygoid sinus are removed with a high-speed grinding drill to fully expose the saddle base. The OCR (internal carotid artery-optic nerve crypt), optic canal bulge, internal carotid artery bulge, slope crypt, and pterygoid plateau can be seen. The saddle base bone is fully opened. After puncture, the dura of the saddle base is incised and the tumor can be removed either by separation along the tumor pseudopapillary or by spatula and suction. After removal of the tumor, a reliable method is used to reconstruct the saddle base. e. Post-operative treatment: The other procedures are the same as transnasal microsurgery.
2. Craniotomy.
(1) Trans-frontal approach: ① Scalp incision: mostly coronal incision in the hairline. (2) Cranial bone flap: Generally do the right frontal bone flap, the front is as close to the front skull base as possible. ③Tumor exposure: stellate incision of the dura mater, with the anterior side flush with the supraorbital area. The arachnoid is sharply incised along the lateral fissure of the pterygoid crest to release the cerebrospinal fluid and reduce the intracranial pressure. The ipsilateral optic nerve and internal carotid artery were explored to reveal the tumor anterior to the optic cross. ④Tumor resection: electrocoagulate and puncture the tumor, incise the pseudo-envelope of the tumor, and first perform intracapsular resection of the tumor in blocks. The periphery of the tumor is freed and the tumor is removed gradually. For recurrent tumor, take care not to damage the penetrating artery and pituitary stalk around the tumor during the operation.
(2) Surgical methods of trans-pterygoid approach: ① Skin flap and bone flap: The skin incision of the pterygoid approach is as far as possible within the hairline. The bone flap is close to the skull base, and the pterygoid crest is ground away as much as possible in order to reduce the strain on the frontal lobe. ②Tumor disclosure: Sharp incision of the lateral fissure pool to release cerebrospinal fluid. The frontal lobe is retracted to reveal the optic nerve and internal carotid artery. The main body of the tumor is exposed by exploring the anterior and posterior optic cross, the optic nerve and the internal carotid artery and the external space of the internal carotid artery. (3) Tumor resection method is the same as above.
3.Surgical method of combined approach.
The above approaches are combined with endoscopic or microscopic transnasal butterfly surgery.
Intraoperative special conditions treatment
1.Intraoperative bleeding.
(1) Intercavernous sinus bleeding: Intraoperative encounter with intercavernous sinus bleeding, hemostatic materials can be used to stop bleeding. If the bleeding is difficult to control, consider using a special gun-shaped titanium clamp for transsphenoidal sinus surgery to close the hemostasis.
(2) Spongy sinus hemorrhage: after suctioning sufficiently to keep the operative field clear and removing the tumor as soon as possible, local filling with appropriate amount of hemostatic material and cotton pad to stop the hemorrhage, but need to avoid damaging the sinus nerve and thrombosis.
(3) Suprasellar hemorrhage: If the pituitary macroadenoma invades into the suprasellar area and adheres to the Willis artery ring, intraoperative traction and scraping of the tumor may cause hemorrhage.
(4) Bleeding from internal carotid artery and its branches: due to the anatomical variation of internal carotid artery or the growth of tumor encircling internal carotid artery, the internal carotid artery may be damaged during surgery, causing intraoperative hemorrhage and even endangering the patient’s life. In this case, the coarse suction device should be replaced immediately to keep the operation field clear and find the bleeding point quickly. Postoperative angiography is required to rule out pseudoaneurysm in these patients.
(5) Intracerebral hematoma: Intracerebral hematoma can occur during craniotomy due to overstretching of the brain pressure plate and injury to the frontal lobe; when a giant pituitary adenoma can only be partially removed, it is easy to have a residual stroke. In addition, craniotomy is advocated to carry out surgical treatment without cerebral pressure plate.
Intraoperative hemostasis method and material selection. For pituitary adenoma surgery, intraoperative hemostasis is very critical, and incomplete hemostasis can affect the patient’s function and even life. In case of intraoperative venous bleeding, hemostasis can be achieved by cotton pad compression and bipolar electrocoagulation and electrocautery. If the bleeding from the intercavernous sinus or cavernous sinus is difficult to stop completely, hemostatic materials can be used to stop the bleeding, such as gelatin sponge, fluid gelatin, and regenerated oxidized cellulose (quick i.e. yarn). In case of intra-arterial hemorrhage, in addition to compression to stop the bleeding, digital subtraction cerebral angiography (DSA) should be performed at the same time to clarify the bleeding artery and site, and if necessary, to stop the bleeding by interventional treatment.
2. Intraoperative cerebrospinal fluid leak.
After septal collapse, the area is prone to leakage of cerebrospinal fluid or too high dural incision at the base of the saddle, and the septum is directly cut open when incising the saddle base; ⑤ Patients with pituitary adenoma with empty pterygoid saddle sometimes have a thin or even absent septum.
(2) Points to note to reduce the occurrence of cerebrospinal fluid leakage during surgery: (1) the position of the saddle base incision should not be too high, and the upper edge of the saddle base dural incision should be at a certain distance from the septal attachment edge; (2) the tumor should be scraped as gently as possible, especially when scraping the residual tumor in the suprasellar and septal folds; (3) the suprasellar arachnoid and its deep gray-blue suprasellar pool should be found during surgery.
(3) Cerebrospinal fluid leak repair method: ① For small rupture and intraoperative cerebrospinal fluid leakage only, fill the saddle with gelatin sponge, and then close the saddle dura with dry artificial dura or gelatin sponge plus fibrin adhesive; ② For large rupture, fill the leak with white body fascia or muscle, and then close the saddle dura with dry artificial dura plus fibrin adhesive, and routinely drain the lumbar pool after surgery. The success of intraoperative cerebrospinal fluid leak repair is judged by the criterion that no clear cerebrospinal fluid leakage is found under high magnification microscopy or endoscopy before the saddle base is closed with fibrin adhesive.
3.Frontal lobe contusion: it often occurs in craniotomy with inferior frontal approach, due to excessive pulling of frontal base by cerebral pressure plate. Postoperatively, patients should be observed for changes in the patient’s mental pupil, and CT examination should be performed immediately once the condition deteriorates, so that hematoma and contusion foci can be found in time for timely treatment and craniotomy to remove hematoma and decompression if necessary.
4, optic nerve and internal carotid artery injury: craniotomy to remove tumor in optic cross and optic nerve interval, transsphenoidal sinus access surgery to chisel out the saddle base to damage the optic nerve canal or remove part of the tumor on the saddle with scraper and suction device may damage the optic nerve, especially for patients with weak vision before surgery, vision loss or even blindness may occur after surgery. Prevention can only be achieved by skillful microscopic techniques and gentle surgical operations. Treatment does not require reoperation and can be treated with neurotrophic drugs, vasodilators and hyperbaric oxygen. See above for treatment of internal carotid artery injury.
VII. Treatment of postoperative complications
1. Postoperative hemorrhage: It is manifested as headache with rapid loss of vision, or even hypothalamic disorders such as impaired consciousness, hyperthermia, and uremia within a few hours after surgery. CT should be reviewed immediately. If bleeding in the saddle area or in the brain is found, an aggressive approach should be taken, and if necessary, the hematoma should be removed by transsphenoidal or craniotomy again.
2, postoperative vision loss: common causes are bleeding in the operative area; too tight intra-saddle filling; acute vacuolated butterfly saddle; acute optic nerve ischemia due to optic nerve vasospasm and other causes can also cause vision loss. After the operation, observe the condition closely, once the visual dysfunction appears, CT should be reviewed as soon as possible, and the bleeding should be treated by surgery as soon as possible.
3, postoperative infection: mostly secondary to cerebrospinal fluid leakage. Common clinical manifestations include: body temperature over 38℃ or below 36℃. There are clear signs of meningeal irritation, associated symptoms of increased intracranial pressure, or clinical imaging evidence. Lumbar puncture cerebrospinal fluid examination reveals total leukocyte count >500 x 106/L or even 1,000 x 106/L, multinucleation >0.80, sugar <2.8 -4.5 mol/L (or <2>0.45 g/L, positive bacterial smear findings, and positive cerebrospinal fluid bacteriology culture.
Also add fungal, tumor, tuberculosis, and viral tests for differential diagnosis as appropriate. Empirical medication is used to select antibiotics that can cross the blood-brain barrier. Adjust the treatment plan in a timely manner according to the pathogenic and drug sensitivity results. The intravenous route should be used whenever possible, and intrathecal administration by lumbar puncture is generally not recommended, but the intracerebroventricular route can be added if necessary. Combination of multiple bacterial infections or multisystemic infections may be used. The maximum drug dose in the tolerated drug profile and a long course of treatment (2-8 weeks or longer) are generally recommended.
4. Central uremia: If uremia has not occurred as of discharge, blood sodium levels should be rechecked on postoperative day 7. If the uremia is not resolved at discharge, appropriate medication may be used until the symptoms disappear.
5. Hypopituitarism: endocrinological evaluation should be performed at week 12 postoperatively, and endocrine replacement therapy should be given if any pituitary-target gland insufficiency is found.
VIII. Pathology and molecular marker testing
Clinicopathologic classification of pituitary adenomas based on hormonal phenotype and transcription factor expression using immunohistochemistry (Table 1) is feasible in China and should be promoted.
The majority of pituitary adenomas are benign tumors with a single ovoid cell morphology, round or ovoid nuclei, slender chromatin, rare nuclear schistosomes, moderate cytoplasm, and a Ki-67 marker index usually <3%; if the cell morphology is heterogeneous, the nucleus is clear, nuclear schistosomes are easily seen, ki-67 >3%, and p53 protein is positively expressed, the diagnosis is “atypical” pituitary adenoma. “If the pituitary adenoma cells have evidence of invasion of submucosal tissue of the nasal cavity, soft tissue of the skull base or bone tissue, “invasive” pituitary adenoma can be diagnosed; if metastasis occurs (brain, spinal cord or other parts of the body), pituitary cancer can be diagnosed.