Source: Chinese Journal of gastrointestinal surgeryPrinciples of pathological diagnosis(a) definition of GISTGIST is the most common gastroi
Source: Chinese Journal of gastrointestinal surgery
Principles of pathological diagnosis
(a) definition of GIST
GIST is the most common gastrointestinal mesenchymal tumors by c-kit or platelet-derived growth factor receptor a mutation (PDCFRA) gene driven; histology by spindle cells and epithelioid cells, or even pleomorphic cells arranged in fascicles or diffuse image, immunohistochemical detection is usually CD117 the positive expression of DOG-1 or.
(two) requirements for specimens
After the operation, the specimen must be fixed in time, and the specimen should be sent to the pathology department within 30 min, and it should be completely immersed and fixed with enough neutral formaldehyde solution (at least 3 times the volume of the sample). For tumors with a diameter greater than or equal to 2 cm, they should be cut every other 1 cm to achieve adequate fixation. The fixed time should be 12 ~ 48 h, in order to ensure the feasibility and accuracy of the subsequent immunohistochemistry and molecular biology. Conditional units, should take proper fresh tissue frozen for days after the molecular genetics of.
(three) the pathological diagnosis of GIST
1 basic diagnosis: histological basis, cell morphology of GIST can be divided into 3 categories: spindle cell type (70%), epithelioid cell type (20%) and spindle cell (or epithelioid cells) mixed type (10%). The positive rate of CD117 was 95% by immunohistochemistry, the positive rate of DOG-1 was 98%.CD34, the positive rate of -SMA was, the positive rate of S-100 protein was 5%, and the positive rate of Desmin was 2%. Diagnosis methods and standards: (1) for histology with GIST, and the CD117 positive cases, the diagnosis can be made of GIST; (2) for histology with GIST, but CD117 negative and DOG-1 positive tumors, the diagnosis can be made of GIST; (3) histological morphology with GIST, CD117 and DOG-1 were negative tumors, should be handed over to the specialized laboratory of molecular biology to detect the presence of mutations in the c-kit gene or PDGFRA, to assist in the diagnosis of GIST. If there is a mutation in this gene, the diagnosis may be made of GIST; (4) for histology with GIST, but CD117 and DOG-1 were negative and no c-kit or PDGFRA mutation cases can be excluded if the smooth muscle tumor, neurogenic tumors and other tumors, it can make GIST possible diagnosis.
2 genetic testing: should be in conformity with the laboratory for genetic testing, recommended the use of polymerase chain reaction (PCR) amplification of a direct sequencing method to ensure the accuracy and consistency of the test results. Gene mutation detection is very important, it is helpful for the diagnosis of some difficult cases, the prediction of the curative effect of molecular targeted drugs and the guidance of clinical treatment. The expert committee recommended the following conditions exist, should carry out genetic analysis: (1) all the initial diagnosis of recurrence and metastasis of GIST, the molecular targeted therapy; (2) primary resectable GIST after surgery, in a high risk of recurrence, undergoing imatinib adjuvant therapy; (3) of cases the c-kit or PDCFRA mutation analysis, to identify the diagnosis of GIST; (4) identification of NF1 type GIST, complete or incomplete Camey triad, familial GIST and children GIST; (5) identification and metachronous multiple primary GIST.
Detection of gene mutations should include at least twelfth of the PDCFRA gene and the exon and exon 18 of c-kit gene in eleventh, 9, 13 and 17 editions. Most of the GIST (65% ~ 85%) mutations in the c-kit gene exon ninth or eleventh. For patients with limited economic capacity, the two exons may be preferentially detected at the time of differential diagnosis. However, for patients with secondary drug resistance, the detection of, 14, 17 and exon 2 of the c-kit gene should be increased.
3 assessment of the risk of primary complete resection of GIST: the assessment of the risk of localized GIST should include the location of the primary tumor, the size of the tumor, the mitotic figure, and the presence of rupture. The previous 2002 edition of the National Institutes of health department (NIH) classification of risk, including the number of mitotic tumor size and each of the 50 under high magnification (Table 1 data for objective lens numerical aperture microscope lens: 0.65 stressed the need to count the number of mitotic figures rich 50 HPF). A number of retrospective studies have confirmed that these two indicators are significantly associated with the prognosis of GIST, but also found that only relying on these two indicators to predict the prognosis of patients with GIST is not sufficient. Therefore, in April 2008, NIH group of experts to discuss the primary GIST risk classification after resection, and reached a new consensus; in the 2008 edition of the new classification of risk, the primary tumor site (GIST prognosis Philippines primary gastric GIST compared with primary gastric tumor rupture and difference) as the basic evaluation the prognosis index.
Some experts think: in practice, only rely on these factors to assess GIST risk stratification may still exist deficiencies. Other pathological features, such as significant tumor cell atypia, tumor invasion, invasion of the surrounding organs (Note: the degree of involvement of surrounding organs do not belong to the limitations of the GIST, but in GIST), vascular and neural invasion and tumor thrombus formation, evaluation, for the biological behavior of GIST staging and grading also has important reference value.
The complete excision of localized GIST can be classified as benign, potentially malignant and malignant. Minimum standards for diagnosis of malignant GIST is one of the following characteristics: (1) markedly atypical tumor cells, tumor necrosis, muscle layer infiltration around blood vessels were ancient coins like growth, mitosis is greater than or equal to 10 /50 HPF; (2) mucosal invasion, perineural invasion, fatty infiltration, vascular invasion and lymph node metastasis: with these indications more, the higher the degree of malignancy. If there is no morphological characteristics, but the larger tumor, more abundant cells and a small number of mitotic figures, can be regarded as potentially malignant GIST. As for the tumor with small volume, sparse cells and no atypia of GIST, often combined with epithelial malignant tumors of the digestive tract, can be regarded as benign GIST. The relationship between morphology and biological behavior is helpful to guide the treatment and prognosis, but it is necessary to further support and combine the clinical evidence.
(four) specification GIST pathological diagnosis report
The pathological report should be standardized and meticulous, must accurately describe the primary site, tumor size, mitotic index and tumor rupture, but also records other indicators including the detection of malignancy, margin, risk assessment, immunohistochemistry and other pathological and prognostic reference indicators and other important information (biopsy excluded). Surgeons should pay attention to the description of the prognostic factors in the operation.
Two, surgical treatment principle
(I) biopsy principle
It is estimated that the operation can be completely removed without seriously affecting the function of the related organs. In recent years, the NCCN guidelines have made it clear that a biopsy is required for neoadjuvant therapy. It should be noted that inappropriate biopsy may lead to tumor rupture, bleeding, and increased risk of tumor spread: especially for deep sites, such as tumors located in the duodenum, biopsy should be cautious.
1 preoperative biopsy: (1) for most of the GIST that can be completely resected, preoperative biopsy or puncture is not recommended. (2) combined multiple organ resection, or surgery may affect the function of organs, can be considered a biopsy for pathological diagnosis before operation, and help determine whether direct surgery or surgery before drug treatment. (3) for patients who cannot be removed or estimated to be difficult to obtain R0 resection, a preoperative biopsy should be performed. (4) percutaneous puncture for patients who have been spread or relapsed. (5) primary and suspected GIST, preoperative for clear nature (such as the exclusion of lymphoma), preferred endoscopic ultrasound guided biopsy biopsy: EUS guided implantation, caused by the very small probability of sepsis. (6) biopsy of the anterior wall of the rectum is recommended for rectal and pelvic masses. (7) biopsy should be performed by experienced surgeons.
2 fine needle biopsy: ultrasound guided fine needle aspiration (EUS-FNA), and the immunohistochemical staining of the surgical specimens to achieve the consistency of 91%. diagnostic accuracy can reach 91%. For patients with high risk of EUS, no direct biopsy was performed.
3 endoscopic biopsy: rely on endoscopic guided biopsy pathological diagnosis is often difficult. Because only GIST involving the mucosa may not get cancer, and even can cause serious bleeding of tumor, need to be cautious.
4 intraoperative frozen biopsy: intraoperative frozen biopsy is not recommended, unless GIST is suspected to have lymph node metastasis or other malignancies may not be excluded.
(two) surgical indication of GIST
(1) for the maximum diameter of the tumor line for more than 2 of the limitations of CM GIST, on the principle of surgical removal and unresectable GIST limitations, or critical resection. However the removal of risk or seriously affect the function of organs, should advance preoperative medication, to reduce tumor after surgery. (2) for patients with a tumor with a maximum diameter of less than or equal to a suspected cm of 2 GIST, symptomatic patients should undergo surgery. Asymptomatic GIST located in the stomach, once diagnosed, should be based on their performance to determine the risk of endoscopic classification (adverse factors for the boundary is irregular, ulcers, strong echo and heterogeneity). Such as the combination of adverse factors, should consider resection; if there is no adverse factors, regular review of endoscopic ultrasonography. Because of the high degree of malignancy and the enlargement of the tumor, the operation difficulty of preserving the anal function is increased, which is more likely to be resected early in GIST. (3) recurrent or metastatic GIST, divided into the following distinction: without molecular targeted therapy, but the estimated complete excision surgery and little risk, can recommend medication or consider the total resection of lesions. Molecular targeted drugs are effective in the treatment of tumor recurrence and metastasis of GIST, and it is suggested that all lesions should be resected in the case of all recurrent and metastatic lesions. The limitations of the progression of recurrence and metastasis of GIST, in view of molecular targeted drug therapy after satisfactory overall control, often only a single or a few lesions progress, can consider to choose carefully good general condition of patients underwent surgical resection. Surgical resection of the lesion was performed, and more metastases were removed as far as possible. The molecular targeted therapy is widely in metastatic GIST, in principle does not consider surgery. The palliative cytoreductive surgery patients can only surgery and is expected to surgery can improve the quality of life in patients with the situation. (4) indications of emergency surgery: emergency surgery should be performed in patients with GIST who cause complete intestinal obstruction, digestive tract perforation, massive hemorrhage of digestive tract, and spontaneous rupture of the tumor.
(three) operative principles of GIST
1 surgical principles: (1) the surgical goal is to try to achieve R0 resection. If the initial surgery is only R1 resection, the operation is expected to be difficult and the risk can be controlled, will not cause major functional organ damage, you can consider the two operation. In the case of complete resection of the tumor, tumor rupture and dissemination should be avoided. Lymph node metastasis is rarely seen in GIST, and there is no need for routine cleaning unless there is a clear indication of lymph node metastasis. (2) one of the causes of tumor rupture bleeding is less spontaneous bleeding, in addition to the operation of the touch of the tumor caused by improper bleeding, so the intraoperative exploration should be careful and gentle. (3) at present, domestic and foreign scholars tend to use molecular targeted drug therapy.
2 laparoscopic surgery: laparoscopic surgery is likely to cause tumor rupture and lead to abdominal implantation, it is not recommended for routine use. If the diameter of the tumor is less than or equal to 5 cm, laparoscopic resection can be considered in an experienced center. Recommend the use of "bag", with particular attention to avoid the spread of tumor rupture. For tumors larger than 5 cm, laparoscopic surgery is not recommended, in addition to clinical research.
3 stomach GIST operation: generally take local resection, wedge resection, subtotal gastrectomy or total gastrectomy, cut margin of 1 to 2 cm, to meet the requirements of R0 resection can be. Application of proximal gastrectomy in GIST after surgery may cause cardia stricture. Multifocal, huge GIST or concomitant with gastric cancer, can take the total gastrectomy or total gastrectomy should be avoided. Single focal lesions, the estimated total gastrectomy can be pre surgical treatment: combined organ resection should be in ensuring the safety of surgery and fully consider the premise of organ function, to achieve R0 resection. Lymph node metastasis is rarely seen in gastric GIST and lymph node dissection is not recommended.
4 small bowel GIST surgery: for the diameter of 2 to 3 cm in the small intestine of the GIST, such as the integrity of the capsule, no bleeding bad dead may be appropriate to reduce the cutting edge distance. Small intestinal stromal tumor is relatively small, small bowel resection anastomosis can, sometimes tumor and mesenteric vessels become one, in the jejunum was more common in unresectable patients, drug treatment can consider surgery two times. 10% ~ 15% of cases of lymph node metastasis, to grasp the appropriate area of lymph node dissection. Small bowel GIST may have lymph node metastasis, should be appropriate to clean the surrounding lymph nodes.
5 of the duodenum and rectum GIST surgery: operation of duodenal and rectal GIST should be considered according to the degree of adhesion of the size of primary tumor, location, tumor and surrounding organs and have no tumor rupture, operation method. The GIST of the duodenum was feasible for pancreaticoduodenectomy, local excision and repair of the intestinal wall, third, 4 and proximal partial resection of the duodenum, subtotal gastrectomy, and so on. Rectal GIST, surgical methods are generally divided into local resection, anterior resection of the rectum and the combination of abdominal and perineal resection. In recent years, due to the molecular targeted drug use, decreasing abdominal perineal resection, recommended indications for: (1) no shrinking tumors after drug treatment; (2) tumors located in the anus, below 5 cm, and the rectal wall can not be separated; (3) recurrent cases, after second-line drugs first, after treatment, no significant improvement of defecation function.
6 parenteral GIST surgery: Currently, parenteral GIST are not sensitive to conventional radiotherapy and chemotherapy, surgery is the preferred treatment, radical surgical treatment and the prognosis of the disease is closely related to the whole complete resection of the lesion is recommended for. In some patients, the tumor may be extensively adherent or disseminated to the surrounding tissue, and sometimes biopsy or palliative surgery may be used to achieve a definite diagnosis or reduction of the tumor.
7.GIST endoscopic treatment principle: because GIST originated in the submucosal growth modes, radical resection under endoscopy for converting, and complications, is not routinely recommended.
Three, the principle of molecular targeted drug therapy
(a) GIST preoperative treatment
1 the significance of preoperative treatment: at present, most of the clinical trials of preoperative GIST therapy are mostly small-scale retrospective studies or case reports. In the 2010 second edition of NCCN clinical practice guidelines for soft tissue sarcoma, the group recommends "neoadjuvant therapy" was renamed "preoperative treatment", the 2011 NCCN guidelines to be followed, after discussion, agreed to adopt the term after expert consensus. The main significance of preoperative treatment: reduce tumor volume, reduce the clinical stage: reducing the scope of operation, to avoid unnecessary combined organ resection, reduce the risk of surgery, while increasing the chance of radical resection; for the special parts of the tumor, can protect the structure and function of important organs for huge tumor, intraoperative rupture and bleeding risk the larger, can reduce the risk of iatrogenic dissemination.
2 preoperative indication: (1) preoperative estimation is difficult to achieve R resection; (2) large tumors (greater than 10 cm), intraoperative bleeding, easy rupture, may cause iatrogenic dissemination; (3) the special parts of the tumor (such as gastroesophageal junction, duodenal and rectal etc.), the operation is easy to damage the function of important organs; (4) although the tumor can be removed, but the estimated operation risk, high recurrence rate after operation; (5) to estimate the need for multiple organ resection.
3 preoperative treatment time, treatment dose and timing of operation: during drug treatment, should be regularly (every 3 months) to evaluate the therapeutic effect, recommend the use of Choi standard or reference RECIST (Response Evaluation Criteria in Solid Tumors) standard. For preoperative treatment time, the expert committee has not yet reached a consensus. It is generally believed that it is more appropriate to give imatinib before surgery for about 6 months. Excessive lengthening before treatment time may lead to secondary resistance.
The initial dose of imatinib was 400 mg/d before surgery. For patients with tumor progression, evaluate the condition, can surgery (possibly complete excision of the lesion), should promptly stop drugs, early surgical intervention; not surgery, according to recurrence and metastasis in patients with second-line treatment.
4 preoperative stopping time and postoperative treatment time: it is recommended to stop the drug for about 1 weeks before the patient's basic condition is met. After surgery, as long as the patient's gastrointestinal function and can tolerate drug treatment, drug treatment should be carried out as soon as possible. For R0 resection, postoperative adjuvant therapy can maintain the drug reference standard time: for palliative resection, recurrence or metastasis (whether or not to R0, resection) postoperative treatment and recurrence and metastasis without operation similar to that of the GIST patients.
(two) adjuvant therapy after GIST
1 indications for adjuvant therapy: we recommend that patients with moderate and high risk of recurrence as a suitable treatment for the crowd. The American Society of Surgeons (ASOCOG) Z9001 study showed that, with the risk factors of recurrence after complete resection of GIST, the use of imatinib adjuvant therapy for 1 years can significantly improve the patient's recurrence free survival rate. Two studies of domestic scholars have confirmed that imatinib adjuvant therapy in patients with moderate to high risk GIST benefit. ASOCOG Z9001 subgroup analysis suggests that different types of gene mutation in patients benefit from adjuvant treatment differences, c-kit mutations in exon 11 of PDGFRA and non D842V patients with adjuvant therapy can benefit; at the same time, there is no evidence that c-kit mutations in exon 9 of GIST can benefit from adjuvant therapy: PDGFRA mutation and D842V wild type GIST adjuvant therapy failed to benefit. The results of SSGX VIII /AIO study also repeatedly confirmed this conclusion.
The 2 auxiliary therapeutic dose and time: according to ASOCOG Z9001 and SSGX VIII /AIO results, the currently recommended adjuvant treatment with imatinib dose was 400 mg/d; the treatment time: for patients, should be given at least 1 years of adjuvant treatment with imatinib: high-risk patients, adjuvant therapy for 3 years. ASCOGZ9000 and Z9001 study, patients receiving imatinib adjuvant therapy for 1 years after treatment, the recurrence rate of GIST increased significantly and SSGX results: VIII /AIO study showed that the high risk of recurrence of GIST treated with imatinib adjuvant therapy for 3 years and 1 years. Can further improve relapse free survival and overall survival period. Domestic studies suggest that patients with moderate or high risk of GIST who have been treated with imatinib for 3 years may improve their relapse free survival and overall survival compared with patients who underwent surgery alone for a period of 3 years.
(three) treatment of metastatic recurrence or non resectable GIST
1 first-line treatment with imatinib: imatinib is a first-line treatment for metastatic recurrence or non resectable GIST, with an initial recommended dose of 400 mg/d. The results of B2222 test showed that imatinib was an effective treatment for patients with metastasis and recurrence of GIST, and could significantly improve the median overall survival.
In the EORTC62005 study, the initial treatment of patients with c-kit exon 9 mutations, compared with imatinib 800 mg/d with a 400 mg/d, resulted in a longer progression free survival. High dose imatinib is recommended for initial treatment. In view of the majority of patients in clinical practice can not tolerate imatinib 800 mg/d treatment, therefore, for the c-kit exon 9 mutation in Chinese patients with GIST, the initial treatment can be given imatinib mg/d.
For the treatment of metastatic recurrence or non resectable GIST, such as imatinib, should continue to use until the disease progression or intolerable toxicity. The results of the BFR14 study, which is based on the French Sarcoma collaboration group, suggest that treatment with imatinib will lead to repeated disease and rapid tumor progression.
The common side effects of imatinib were edema, gastrointestinal reactions, white blood cells, anemia, skin rash, muscle cramps, and diarrhea. The majority of adverse reactions were mild to moderate, mostly in the first 8 weeks of treatment, showed a transient and self limiting, symptomatic support treatment can improve.
2, the standard dose of imatinib treatment after failure of choice: if in the imatinib treatment during tumor progression, should first confirm whether patients complied with the doctor's advice, which adhere to the medication in the correct dosage: except in compliance with factors, should refer to the following principles. (1) limitations: during the course of imatinib therapy, some lesions developed, while others remained stable or even partially relieved. Limitations of the GIST, in the case of a surgical resection of a focal lesion, may be recommended for surgical treatment, which may be followed by the addition of a primary dose of imatinib or an increased dose of therapy. A small sample of clinical studies has shown that patients with localized progression who continue to receive imatinib after complete resection of the tumor may benefit from better progression free and overall survival. GIST is not recommended for surgery when extensive progress is made: failure to obtain complete resection should follow the principle of treatment of GIST's generalized progression. The part can not be implemented surgery GIST patients with liver metastasis, arterial embolization and radiofrequency ablation can also be considered as adjuvant therapy: advances in focal and should not accept the local treatment of patients, can increase the imatinib dose or given sunitinib treatment. (2) the development of a wide range of applications: recommendations for increasing the dose of imatinib or the use of sunitinib in the treatment of patients with extensive progression after standard dose imatinib therapy. The imatinib dose: EORTC62005 and S0033 research shows that for the extensive progression of GIST patients, imatinib dose increased to 800 mg, 1/3 of patients can be of clinical benefit: 2010 NCCN Guide Second edition that can use imatinib 400 mg bid. With increasing doses of imatinib, adverse effects will increase accordingly. In our country, GIST patients have a better tolerance to 600 mg/d imatinib, which is similar to that reported in foreign countries with a dose of 800 mg/d. Therefore recommended for patients with GIST priority increment of 600 mg/d. Sunitinib treatment: the A6181004 study shows that, in patients with imatinib therapy progression or intolerance, the use of sunitinib second-line therapy is still effective, can improve the time of disease progression and overall survival. There is no evidence of randomized controlled studies of the dosage and method of sunitinib. 37.5 mg/d continuous dosing and a 50 mg/d (4/2) option. The major adverse effects of sunitinib include anemia, thrombocytopenia, thrombocytopenia, and hand foot syndrome,