I. Introduction
Acromegaly (hereafter referred to as “acromegaly”) is a chronic progressive endocrine disease with an insidious onset, which may last for several years or even 10 years at the time of diagnosis. The main cause of acromegaly is the excessive production of growth hormone (GH) in the body. 95% of patients with acromegaly are caused by GH-secreting pituitary adenomas. Long-term overproduction of GH can lead to excessive hyperplasia of soft tissues, bone and cartilage throughout the body, causing facial changes, hypertrophy of hands and feet, thick skin, enlarged internal organs, bone and joint lesions, and sleep apnea syndrome. In addition, the incidence of pituitary tumor compression symptoms, diabetes, hypertension, cardiovascular and cerebrovascular diseases, respiratory diseases, and malignant tumors such as colon cancer will also increase accordingly. These metabolic disorders and complications seriously affect patients’ health and quality of life, resulting in shortened life expectancy. Clinically, delays in diagnosis and treatment can significantly increase the incidence of these complications.
This diagnosis and treatment guideline aims to summarize and learn from the existing diagnosis and treatment experience of limbomegaly in China, combine the latest evidence-based evidence from home and abroad, improve the understanding of limbomegaly among Chinese physicians, and advocate a standardized diagnosis and treatment management model of limbomegaly.
II. Diagnosis
The diagnosis of acromegaly is usually made after the collection of relevant clinical information, through the determination of serum GH and insulin-like growth factor-1 (IGF-1), imaging examination and related complications. The final clarification was made by the examination of complications. Very few patients with limbomegaly are due to single gene defects, such as multiple endocrine adenoma type 1 (MEN-1), McCune-Albright syndrome and Carney syndrome, which require further screening and diagnosis of related co-morbidities.
2, clinical manifestations: acromegaly has characteristic appearance, such as ugly face, large nose and thick lips, enlarged hands and feet, thickened skin, excessive sweating and sebaceous gland secretion, and with the prolongation of the disease, there are longer head shape, prominent brow arch, long oblique forehead, protruding jaw, sparse teeth and backbite, enlarged posterior occipital bone, forehead and scalp folds, barrel-shaped chest and hunchback. Other clinical manifestations include: (1) headache, visual dysfunction, increased intracranial pressure, hypopituitarism and pituitary stroke due to pituitary adenoma compression and invasion of surrounding tissues; (2) insulin resistance, hypoglycemic tolerance, diabetes mellitus and its acute or chronic complications; (3) cardiovascular system involvement: hypertension, cardiomegaly, cardiac enlargement, arrhythmia, hypocardium, atherosclerosis, coronary artery disease, cerebral infarction and (iv) respiratory system involvement: tongue hypertrophy, low voice, ventilation disorders, wheezing, snoring and sleep apnea, respiratory infections; (v) bone and joint involvement: synovial tissue and articular cartilage hyperplasia, hypertrophic osteoarthropathy, impaired hip and knee joint function; (vi) amenorrhea, lactation, infertility in women and sexual dysfunction in men. (7) The incidence of colon polyps, colon cancer, thyroid cancer, and lung cancer may increase.
The possibility of limbomegaly needs to be considered and screened when patients do not have obvious characteristic manifestations of limbomegaly but present with 2 or more of the following symptoms, including: new onset diabetes, multiple joint pains, new or uncontrollable hypertension, cardiac disease such as ventricular hypertrophy or systolic and diastolic dysfunction, fatigue, headache, carpal tunnel syndrome, sleep apnea syndrome, excessive sweating, vision loss, colon polyps, and progressive Progressive jaw protrusion.
3.Laboratory tests
Measurement of serum GH levels Serum GH levels are consistently elevated in patients with active limbomegaly and are not suppressed by hyperglycemia. Therefore, the diagnosis of patients with limbomegaly is not only determined by fasting or random GH levels, but also by whether the serum GH level is suppressed to normal after glucose loading. A fasting or random serum GH level of <2.5ng/mL is considered normal; if it is ≥2.5ng/mL, an oral glucose tolerance test (OGTT) is required to determine the diagnosis. OGTT is usually performed with 75g of oral glucose, and blood is taken at 0min, 30min, 60min, 90min and 120min to determine blood glucose and GH levels. Patients with diagnosed diabetes can replace OGTT with 75g bun meal, and it is recommended to use GH test with sensitivity ≤0.05mg/L.
Determination of serum IGF-1 level The effect of GH is mainly mediated by IGF-1, and the correlation between serum IGF-1 level and the disease activity of patients with limbomegaly is closer than that of serum GH. Serum IGF-1 levels are elevated in patients with active limbomegaly. Since the normal range of IGF-1 levels is significantly correlated with age and gender, the results of the assay should be compared to the age- and gender-matched normal range of values (normal mean ± 2 standard deviations). When the patient’s serum IGF-1 level is higher than the normal value range matched with gender and age, the serum IGF-1 level is judged to be elevated.
MRI is superior to CT in understanding the size of pituitary GH adenoma and the relationship between adenoma and adjacent tissues. These techniques can be used for large adenomas to understand whether the adenoma has aggressive growth and whether it is compressing and involving the optic crossing (paracentral or subsaddle).
Evaluation of other pituitary functions: Blood prolactin (PRL), follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) levels and their corresponding target gland functions should be measured. If the patient has significant polyuria, irritable thirst and excessive drinking, etc., the posterior pituitary function should be evaluated.
6.Visual acuity and visual field examination: observe the visual field changes before treatment, and also as one of the evaluation indicators of treatment effect.
7, the diagnosis of the complications of acromegaly: the qualitative diagnosis of patients with acromegaly should be followed by blood pressure, blood lipids, electrocardiogram, cardiac ultrasound, respiratory sleep function tests; according to the clinical manifestations can choose thyroid ultrasound, colonoscopy and other tests.
According to the patient’s clinical manifestations, laboratory tests and imaging examinations, the diagnosis of acromegaly should be made through comprehensive analysis, and a clear judgment should be made on the patient’s disease activity, acute and chronic complications of each system and the control of disease activity after treatment.
III. Treatment
Treatment goals for acromegaly ① Control serum GH levels to random GH <2.5ng/ml and OGTT GH trough <1ng/ml; ② Decrease serum IGF-1 levels to a normal range that matches age and sex; ③ Eliminate or shrink pituitary tumors and prevent their recurrence; ④ Eliminate or reduce clinical symptoms and comorbidities, especially cardiovascular, respiratory and metabolic (4) eliminate or reduce clinical symptoms and comorbidities, especially cardiovascular, respiratory and metabolic, and effectively monitor the comorbidities; (5) preserve pituitary endocrine function as much as possible, and patients with existing hypopituitarism should do the corresponding target gland hormone replacement therapy.
After treatment of acromegaly with random GH values <2.5ng/mL and OGTT GH trough values <1ng/mL, patient survival is similar to that of the normal population. Surgery, radiation therapy and pharmacotherapy are all options to achieve these treatment goals. However, to maximize the efficacy and preserve pituitary function at the same time, each of these 3 treatment methods has its own advantages and disadvantages; therefore, individualized treatment plans should be designed according to each patient's specific situation.
1.Treatment methods for acromegaly
Surgical treatment: Surgical removal of the tumor is the treatment of choice for patients with pituitary GH adenomas. Surgery is recommended as the first-line treatment option for patients with microadenomas, as well as for patients with focal growth of pituitary macroadenomas with potential surgical cure, because surgery can effectively control the tumor in the long term and normalize the associated biochemical indicators. Transnasal butterfly surgery to remove pituitary adenomas is safe and effective in patients with large limbs, with fewer complications and lower mortality than other surgical approaches (e.g., craniotomy).
Surgical approach: The main surgical approach for pituitary adenomas is transnasal pteropalatine adenomectomy, and craniotomy is used only in a few cases. The overall cure rate of conventional microsurgery is 57.3% for newly diagnosed patients with large limbs, 80% to 91% for microadenomas and 40% to 52% for macroadenomas. Endoscopic transsphenoidal surgery is a minimally invasive surgical approach that has been widely performed in recent years and is suitable for the removal of medium and small adenomas, as well as for some large adenomas, and can help improve the surgical cure rate. The surgery should be performed by an experienced neurosurgeon. Some patients can be treated with growth inhibitor analogues preoperatively to improve the surgical outcome. Neuronavigation and intraoperative MRI techniques can improve surgical resection rates.
Pathological features: Pituitary overproduction of GH is predominantly adenoma. pathological types include dense granular or sparse granular GH cell adenoma or hyperplasia, mixed GH and PRL cell adenoma, eosinophilic stem cell adenoma and multihormone-secreting cell adenoma. immunohistochemical staining such as Ki67 helps to understand the proliferative capacity of adenoma cells.
Advantages of surgical treatment: In principle, all diagnosed patients are suitable for surgical treatment. Patients with severe acute tumor compression (e.g., progressive loss of visual function or diplopia) and hypopituitarism should receive early surgical treatment. Most cases can be cured in a single operation by an experienced surgeon. For patients with microadenoma, surgery is recommended as the first choice of treatment. Surgery is recommended as the primary treatment for patients with large adenomas that have a high chance of cure (e.g., not invading the cavernous sinus). For patients with surgically incurable macroadenomas with local compression symptoms, partial excision may be performed to improve their response to subsequent drug therapy or radiotherapy. Successful surgery can immediately reduce serum GH levels and relieve tumor compression. Another advantage of surgical treatment is the availability of tissue specimens for pathological diagnosis and scientific study. The main factors affecting the outcome of surgery are: (i) tumor volume, texture and aggressiveness; (ii) preoperative GH and IGF-1 levels (a large number of studies have shown that preoperative GH and IGF-1 levels are negatively correlated with surgical outcome). Microadenomas that do not invade the cavernous sinus and have preoperative GH and IGF-1 levels only slightly higher than normal can be cured by surgery in more than 80% of cases, while tumors that invade the cavernous sinus or have preoperative GH >200 ng/ml are very unlikely to be cured.
Complications of surgical treatment: Although great progress has been made in surgical treatment of acromegaly, there are still certain risks and problems, such as the possibility of causing anterior and posterior pituitary hypoplasia, damage to important intracranial nerves, blood vessels and brain tissue, causing optic nerve dysfunction, cerebrospinal fluid nasal leakage or meningitis. Patients with pituitary GH adenomas are at significantly higher risk of receiving general anesthesia than other types of pituitary tumors. It is well documented that the operator’s surgical experience is associated with surgical cure rates, complication rates, and mortality, with complication rates ranging from approximately 3% to 10% among experienced neurosurgeons. Therefore, surgery for pituitary adenomas should be done in a treatment center with a team of specialists in the appropriate discipline to achieve the most optimal surgical outcome. This team should include specialists in endocrinology, neurosurgery, radiosurgery, neuropathology and radiological imaging.
2. Preoperative growth inhibitor analogue (SSA) therapy
The use of preoperative growth inhibitor analogs (SSA) can improve surgical outcomes There has been considerable debate about the role of preoperative pharmacotherapy, particularly the use of SSA, and several national and international studies have shown that preoperative use of SSA for 3-6 months can improve postoperative remission rates, especially for patients with macroadenomas. However, further high-quality, multicenter, prospective studies are needed to confirm the efficacy of preoperative SSA and to determine the types of patients who may benefit from preoperative SSA use. and IGF-1 are significantly elevated.
Preoperative use of growth inhibitor analogs (SSA) may reduce cardiopulmonary comorbidities and anesthesia-related risks Patients with acromegaly may have comorbidities such as cardiovascular disease, pulmonary insufficiency, and metabolic disorders, which place patients at high risk for anesthesia and surgery. Therefore, controlling these comorbidities may reduce the risk of surgery and improve surgical outcomes. Studies have reported that up to 30% of patients with acromegaly have difficulty with intubation during anesthesia, and 20%-80% of patients have sleep apnea syndrome due to oropharyngeal swelling and macrophagia. SSA treatment in such patients significantly reduces soft tissue swelling after a few days and some studies have shown that sleep apnea disappears after 6 months of octreotide treatment. Therefore, it is predicted that preoperative SSA treatment may lead to a reduction in intubation-related complications. However, this still needs to be supported by further trials to obtain higher quality evidence.
Patients with acromegaly are also at risk for comorbid cardiac disorders, including left ventricular hypertrophy, increased output per beat and cardiac index, cardiomyopathy, reduced ejection fraction or heart failure in advanced patients. Domestic and international studies have found that SSA treatment can significantly improve cardiovascular function, including lowering heart rate, systolic and diastolic blood pressure, reducing posterior left ventricular wall thickness and septal thickness, increasing ejection fraction, and prolonging activity tolerance time.
Pharmacological treatment: Pharmacological treatment for large limb includes growth inhibitor receptor ligands (SRL), i.e. growth inhibitor analogs (SSA), dopamine receptor agonists (DA), and GH receptor antagonists, which are mainly used as adjuvant therapy for patients with unremitting disease after surgery. Drug therapy is also preferred for patients with large adenomas that are not expected to be completely removed by surgery and do not have symptoms of tumor compression, patients who are not suitable for surgery (including: patients with poor systemic conditions that make it difficult to tolerate the risks of surgery; patients with high risk of anesthesia due to airway problems; patients with severe systemic manifestations of large limbs such as cardiomyopathy, severe hypertension, and uncontrolled diabetes), or patients who do not want to undergo surgery . Growth inhibitor analogs are the first choice in drug therapy.
Growth inhibitor analogs: Growth inhibitor (SST) is processed by precursors into two biologically active forms, growth inhibitor-14 and growth inhibitor-28. natural SST has a plasma half-life of less than 3 min, and synthetic growth inhibitor analogs (octreotide, octreotide long-acting extended-release agent LAR, lanreotide) can mimic the physiological effects of SST and inhibit GH overproduction.
Growth inhibitory analogs have a role in the treatment of limbomegaly in five phases: 1) First-line treatment: for patients with macroadenomas that are not expected to be completely resected by surgery and do not have symptoms of tumor compression, patients who are reluctant to undergo surgery, and patients who are not suitable for surgery, including: patients with poor general condition who are difficult to tolerate the risk of surgery; patients with high risk of anesthesia due to airway problems; patients with severe systemic manifestations of limbomegaly (including cardiomyopathy, severe hypertension and uncontrolled diabetes mellitus, etc.). ② Pre-surgical treatment: For patients with serious complications and poor basic conditions, such as obvious respiratory dysfunction, cardiac insufficiency and patients with severe metabolic disorders, pre-surgical drug treatment can reduce serum GH and IGF-1 levels, and combined with related medical treatment can improve cardiopulmonary function to reduce the risk of anesthesia and surgery, as well as reduce tumor volume, so it is possible to improve the surgical outcome. As mentioned above, preoperative use of SSA can improve the postoperative remission rate in patients with macroadenoma. (iii) Adjuvant therapy for residual tumor after tumor resection: Studies have shown that approximately 10% of patients with microadenoma and 55% of patients with macroadenoma require adjuvant therapy after surgery if the OGTT GH trough value of << span="">1.0ng/ml is used as the goal of cure. Therefore, it is recommended that 1) patients with postoperative OGTT GH trough values <1.0ng/ml and IGF-1 within normal range should be followed up regularly; 2) patients with postoperative OGTT GH trough values >1.0ng/ml, or elevated IGF-1, or still have significant symptoms of limb enlargement such as headache, should receive SSA therapy for at least 3 to 6 months, and depending on the changes in GH and IGF-1, decide whether to long-term treatment or combined with radiation therapy. ④Transition treatment after radiotherapy: Since serum GH and IGF-1 levels drop slowly after radiotherapy, SSA can be used for the transition period during the waiting period before radiotherapy takes full effect. ⑤ Treatment of complications: SSA treatment can improve the complications related to limb size such as hypertension, cardiac insufficiency and respiratory dysfunction.
Efficacy of growth inhibitor analogues: ①Reducing tumor volume: tumor growth was controlled in more than 97% of patients treated with SSA; ②Controlling serum GH and IGF-1 levels: SSA can normalize GH and IGF-1 levels in about 55% of patients, and drug efficacy was negatively correlated with tumor volume and the level of GH hypersecretion. ③Improve clinical symptoms: SSA can reduce the tumor volume by effectively controlling GH and IGF-1, thus comprehensively controlling the symptoms of limbomegaly. For example, SSA can significantly improve five common symptoms of limbomegaly: headache, fatigue, excessive sweating, joint pain and abnormal sensation. ④Control of complications: As mentioned before SSA can bring significant cardiovascular benefits and improve respiratory dysfunction, even left ventricular hypertrophy and sleep apnea syndrome will disappear after receiving SSA treatment.
Adverse effects of growth inhibitor analogues: The adverse effects of SSA are mainly injection site reactions and gastrointestinal symptoms, which are usually mild to moderate. 10% to 20% of patients have local discomfort, erythema or swelling, pain and pruritus from injection. 5% to 15% of patients have gastrointestinal symptoms, diarrhea, abdominal pain, bloating, steatorrhea, nausea and vomiting, but they are usually a The symptoms are usually transient. Long-term use of SSA can increase the incidence of gallbladder sludge or gallstones, which are usually asymptomatic, not clinically significant, and generally do not require surgical intervention and can be detected by periodic ultrasound. Rare adverse effects also include alopecia, bradycardia, and constipation.
Dopamine agonists: Dopamine agonists can inhibit GH release through dopamine receptors in the hypothalamus. The most commonly used dopamine agonists include the ergot derivatives bromocriptine and carbergoline, which have the advantage of being orally available and relatively inexpensive. 10% to 20% of patients with mild to moderately elevated GH levels have satisfactory GH and IGF-1 levels with these drugs at doses two to four times higher than those used to treat PRL tumors. Side effects of dopamine receptor agonists include gastrointestinal discomfort, upright hypotension, headache, nasal congestion and constipation. Only the first-generation dopamine agonist bromocriptine is currently available in China. This drug is suitable for patients with mildly elevated GH levels who have failed to use SSA for other reasons.
Drug combination therapy: Combining drugs with different mechanisms of action may have a synergistic effect. In patients with partial response to SSA therapy, combination therapy with dopamine agonists may further reduce GH or IGF-I levels.
3. Radiation and radiosurgery
Status of radiotherapy: Considering the complications such as slow decrease in serum GH levels and hypopituitarism, radiotherapy is usually not the first choice treatment option for pituitary GH adenomas, but is most often used as an adjuvant treatment for incomplete remission after surgery and for residual and recurrent tumors. Patients with GH hypersecretion status after surgery may be treated with radiotherapy. Radiotherapy may also be the treatment of choice for patients who cannot undergo surgery.
Radiosurgery: Traditional fractionated radiotherapy usually takes 6 months to 2 years to be effective, with some taking 5 to 15 years to be fully effective, and has been used in the past to control tumor growth and achieve biochemical remission. Recently, studies have looked at the effectiveness of high-dose targeted radiotherapy (single or multiple doses) for residual pituitary tumor foci. These methods include stereotactic radiosurgery (gamma knife and x-ray knife) and proton beam therapy.
Studies on outcomes and complications have shown that stereotactic radiotherapy and stereotactic radiosurgery (e.g., Gamma Knife) provide more rapid relief than conventional radiotherapy. Some studies have shown that 40% of patients with normal GH levels at 12 months are treated, but not all patients are candidates for radiosurgery because of its effect on vision. In general, stereotactic radiosurgery is used for small to medium diameter residual or recurrent tumors and for patients who cannot tolerate or refuse surgical treatment. The distance between the tumor and the optic cross or optic nerve should preferably be greater than 2-5 mm to avoid visual impairment. Secondly radiosurgery requires special attention to the impact on fertility.
Limb size recurrence rates of 2% to 14% have been reported in the literature. Prophylactic radiotherapy is not recommended for patients who have undergone successful surgery and have normal serum GH levels. However, each patient should be routinely evaluated by follow-up every 6-12 months for at least 5 years to detect any signs of recurrence in a timely manner and to give immediate treatment if necessary.
Complications of radiotherapy and radiosurgery The most common complication is impaired anterior pituitary function, which occurs in about 30% of cases and usually requires hormone replacement therapy. Long-term follow-up studies have shown a high incidence of impaired pituitary function with conventional radiotherapy. Less common complications include impaired vision, radiation brain necrosis, and malignancy secondary to radiation field. The potential neuropsychiatric effects of radiotherapy and the incidence of secondary tumors, especially in patients with cerebrovascular disease and organic encephalopathy, need to be further investigated. Disadvantages of conventional radiotherapy also include the slow decline in GH levels.
Treatment process: The most important part of the treatment process for limb size is the need to develop an individualized treatment plan that takes into account the local pituitary tumor treatment center and the patient’s actual condition. Factors to be considered are: ① the availability of a local treatment team consisting of endocrinologists, neurosurgeons, radiologists, and imaging specialists. ②The patient’s degree of endocrine activity of the tumor and the degree of visual impairment. ③The patient’s status of complications related to limb size at the time of consultation. ④The patient’s treatment claims. ⑤ Whether the patient can afford the cost of examination and long-term treatment, etc. Treatment options should be selected on a region-by-region, person-by-person basis.
All treatment regimens should aim at striving to control GH secretion at normal levels as the ultimate goal. While aiming to obtain biochemical control and relief of tumor pressure, the treatment team should weigh the risks and benefits, contraindications to treatment and side effects for each patient. Factors to be considered include severity of disease, tumor compression of surrounding structures, potential long-term pituitary damage, and, especially in young, fertile patients, preservation of pituitary function.
Most patients in the flow chart have surgery as the first line of treatment, and if surgery fails to cure, they may receive pharmacologic therapy. If maximum doses of SSA or dopamine agonists do not adequately control the disease, radiotherapy, or surgery again should be considered, depending on the clinical activity of the disease and biochemical indicators. In some patients who opt for surgery, SSA treatment may be advanced for 12-24 weeks to create the conditions for surgery if tumor volume reduction is needed to reduce the difficulty of surgery, improve the chances of total surgical resection, or ameliorate major limb complications, especially severe cardiac and respiratory comorbidities. Some patients may also prefer SSA drug therapy, and if the serum GH and IGF-1 biochemical indicators are still abnormal, the combination of DA therapy may be used.
IV. Diagnosis and treatment standard
1.Diagnosis and treatment process
When patients are first diagnosed, firstly, qualitative diagnosis (serum random GH, OGTT GH and IGF-1 test) should be done, and local diagnosis (MRI or CT of saddle area) should be done at the same time. A comprehensive evaluation of pituitary function [blood PRL, FSH, LH, epinephrine (E2), ACTH, cortisol (F), TSH, triiodothyronine (T3), thyroxine (T4), etc.] should also be performed, along with an evaluation of complications.
2. An individualized treatment plan (surgery, medication or radiotherapy) was adopted after comprehensive evaluation.
After treatment, regular follow-up should be performed every 3-6 months to re-evaluate pituitary function and to do imaging of the saddle area if necessary. Lifelong follow-up should be done regardless of whether the disease is well controlled or not. Routine annual checkups are recommended to adjust the treatment plan and management of related complications when appropriate. Complications of pituitary GH adenoma can be caused by local compression of the tumor, high serum GH and IGF-1 levels, and decreased secretion of other pituitary hormones. In order to reduce the morbidity and mortality caused by cardiovascular diseases, respiratory diseases and malignant tumors, risk factors should be actively controlled and early screening should be performed to standardize the management of complications of limb size.
3. Postoperative monitoring and long-term follow-up ① Blood GH will be measured 1 d after surgery and at discharge. ② When patients are discharged from the hospital, health education will be emphasized and the importance of long-term follow-up will be instructed for their disease control and improvement of survival quality, and follow-up cards will be given to inform the follow-up process. Patients will receive annual follow-up questionnaires, and the follow-up physician will be informed of any change in address or telephone number. ③Pituitary hormone testing will be performed from week 6 to 12 postoperatively to assess pituitary function and the need for hormone replacement therapy, and patients with complications will be followed up with the appropriate tests. ④OGTT GH levels and IGF-1 levels were reviewed at 3 months postoperatively, and pituitary enhancement MRI was reviewed. ⑤ OGTT GH, IGF-1 and pituitary MRI were selectively reviewed at 6 months postoperatively based on the 3-month postoperative follow-up results. ⑥For well-controlled patients, OGTT GH level and IGF-1 level should be reviewed once a year after surgery, and saddle MRI should be reviewed annually after surgery according to the degree of patient’s disease control; for patients with complications, evaluation of complications should be performed once a year.
Since acromegaly is a relatively rare and chronic disease involving multiple disciplines and fields, it is easy to delay the diagnosis and treatment, thus causing a corresponding increase in complications and morbidity and mortality in patients. Therefore the treatment plan for acromegaly should ideally be developed by a panel of experts who will weigh the pros and cons of each case and develop an individualized treatment plan to achieve the most optimal outcome. This treatment team should include experts in endocrinology, neurosurgery, radiotherapy, diagnostic radiology and pathology. To standardize and improve the diagnosis and treatment of limbomegaly as much as possible, taking into account the actual situation in China. Improving the cure rate and reducing complications and mortality is a very important task that requires the collaboration of multidisciplinary specialists.