I. The content of pathological diagnosis is revised greatly
1. Definition: The origin and biological characteristics of GIST were clarified, and the confusion in some previous diagnostic names was unified.
GIST is the most common mesenchymal-derived tumor of the gastrointestinal tract, which can range from benign to malignant in terms of biological behavior and clinical manifestations. Immunohistochemical detection usually expresses CD117, shows Cajal cell (Cajal cell) differentiation, and most cases have c-kit or PDGFRA activating mutations.
According to the current diagnostic criteria, most of the smooth muscle tumors (including smooth muscleoblastoma) diagnosed in the past are actually GIST; and the tumors once defined as gastrointestinal autonomic neuroma (GANT) are the same as GIST in terms of clinical manifestations, histological morphology, immunophenotype and molecular pathology, and should be classified as GIST, and are no longer treated as an independent lesion type.
2. Basic diagnosis: In addition to the original histomorphological classification, the expression of immunohistochemical examination in different parts of GIST and the differential diagnostic significance are elaborated to facilitate accurate diagnosis and differentiation by clinicians.
The positive rate of CD117 and DOG1 by immunohistochemistry was 94%-98% and 94%-96%, respectively. Among them, CD117 and DOG1 are highly concordant. Most spindle cell GISTs (especially gastric GISTs) express CD34, but expression is inconsistent in epithelioid GISTs, and CD34 can be negative in small intestinal GISTs. In routine workup, the combination of these 3 markers is recommended. It should be noted that a few non-GIST tumors may also express CD11 and/or DOG1, such as pancreatic smooth muscle tumors, retroperitoneal smooth muscle tumors, intrapelvic smooth muscle tumor disease, malignant melanoma of the rectum and anus, and uterine smooth muscle sarcoma. Other markers (e.g. desmin and HMB45) should be used in combination to differentiate them.
In addition, immunohistochemical detection of succinate dehydrogenase B (SDHB) can help identify succinate dehydrogenase-deficient GIST (SDH-deficientGIST). This type of GIST does not express SDHB and is often clinically associated with the Carney triad (GIST, paraganglioma and pulmonary chondrosarcoma) or Carney-Stratakis syndrome (familial GIST and paraganglioma) [10]. c-kit or PDGFRA gene mutation detection shows wild type.
3. Genetic testing: Recommendations were given for when genetic testing should be performed and what it should include.
Genetic analysis should be performed when the following conditions exist.
(1) c-kit or PDGFRA mutation analysis should be performed in difficult cases to clarify the diagnosis of GIST;
(2) Those with preoperative proposed molecular targeting therapy;
(3) All first diagnosed recurrent and metastatic GIST, proposed to be treated with molecular targeted therapy;
(4) Those at moderate to high risk of recurrence after primary resectable GIST surgery, to be treated with imatinib adjuvant therapy;
(5) Identify NF1 type GIST, complete or incomplete Carney triad, familial GIST and pediatric GIST;
(6) Identify concurrent and diachronic multiple primary GISTs;
(7) Secondary resistance requires retesting and additional testing of exons 14 and 18 of the c-kit gene is appropriate.
4. The concept of micro GIST (less than or equal to 25 px in diameter) and the risk assessment of primary completely resected GIST are supplemented and updated, which are of great help to clinically refine the classification of people at high risk of postoperative recurrent metastasis and to develop treatment follow-up plans and protocols.
The biological behavior of GIST varies from patient to patient, and the 2013 edition of the WHO Soft Tissue Tumor Classification classifies it into benign, undetermined malignant potential, and malignant types.
Both the 2010 edition of the WHO Classification of Tumors of the Gastrointestinal Tract and the 2013 edition of the WHO Classification of Soft Tissue Tumors adopt the 6-category, 8-level criteria proposed by Miettinen and classify GIST into benign, undetermined malignant potential, and malignant based on prognostic grouping.
It should be noted that some parameters in Tables 1, 2 and 3 are not consistent. If group 3a is defined as benign, it can be assessed as intermediate (gastric) and high risk (small intestine), respectively, if the risk is assessed according to Table 1. According to the current situation in China, the expert committee recommends that the risk assessment for primary completely resected GIST should be based on Table 1, with Table 2 and Table 3 as references. In addition, unlike the common type GIST, nuclear split image cannot assess the risk of SDH-deficient GIST.
Liver metastases can occur in those with few nuclear schizograms, but not in those with many nuclear schizograms. Another characteristic is that the interval between metastases is long, so long-term follow-up is required. Many patients with metastatic general type GIST usually die within 1-2 years, while patients with SDH-deficient type GIST often survive for 5 years or more after treatment with TKI inhibitors.
5. The pathological changes of GIST after targeted drug therapy are also described in detail.
GIST lesions treated with targeted drugs can undergo necrosis and/or cystic degeneration; in some cases, cell density is significantly reduced, tumor cell composition is sparse, and the interstitium is accompanied by extensive collagenization, which may be accompanied by more or less inflammatory cell infiltration and histiocytic reaction [13]. In a few cases, rhabdomyosarcoma-like differentiation or dedifferentiation may occur.
Second, GIST surgical treatment emphasizes the principle of deletion of many detailed restrictions
With the improved understanding and clinical practice of GIST in recent years, and also through the promotion of the first two editions of the guidelines and surgeons’ increasing understanding of GIST, domestic surgical treatment has become more and more standardized, and the restrictions on surgical pathways and details can no longer meet clinical needs. Moreover, the details of which method is the best for surgical operation of GIST at different sites cannot be established from the existing clinical studies.
Therefore, the surgical treatment section simplifies the limitations on surgical treatment pathways and methods for specific tumor sites, and places more emphasis on the principles of surgical treatment, recommendations, and the problems and controversies that exist. In addition, with the development of laparoscopic surgery, the guidelines for GIST are based on general principles and are recommended for relevant clinical trials and exploration.
Third, the part of molecular targeted drug therapy is less modified
This part mainly emphasizes individualized drug and dose selection based on molecular typing guidance, and still encourages patients who have failed imatinib or sunitinib treatment to participate in clinical studies, etc.
For preoperative treatment, it is recommended to first perform genetic testing and determine the initial dose of imatinib based on the test results. For patients with tumor progression, a comprehensive assessment of the disease should be performed, and those who are still operable (with the possibility of complete resection of the lesion) should be treated with timely discontinuation of the drug and early surgical intervention.
The recommended dose of imatinib adjuvant therapy is 400 mg/d. Treatment time frame: for intermediate risk patients, imatinib should be given adjuvant therapy for at least 1 year; for high risk patients, the duration of adjuvant therapy should be at least 3 years; for patients with tumor rupture, extended adjuvant therapy should be considered.
It is generally believed that the type of mutation in c-kit and PDGFRA can predict the efficacy of imatinib, with the best efficacy in those with c-kit exon 11 mutation; while PDGFRA D842V and D846V mutations may be primary resistant to imatinib and sunitinib therapy. The survival benefit of sunitinib in second-line treatment of patients with primary c-kit exon 9 mutations and wild-type GIST is better than that of patients with c-kit exon 11 mutations; the efficacy of treating patients with secondary c-kit exon 13 and 14 mutations is better than that of secondary c-kit exon 17 and 18 mutations.
IV. Comparison of the differences between NCCN guidelines and Chinese expert consensus
1. In the part of biopsy principles, in 2011, both domestic and foreign experts recommended the use of ultrasound endoscopic fine needle aspiration (EUS-FNA), and in 2013, NCCN still recommended EUS-FNA, while the Chinese expert consensus changed to recommend hollow needle aspiration (CNB) (the amount of tissue obtained is different). This can obtain enough tissue for clinical confirmation and genotyping.
Although not mentioned in the NCCN guidelines, the domestic expert consensus always believes that when GIST involves the mucosa and forms an ulcer (usually umbilical-like), endoscopic forceps biopsy can often obtain tumor tissue for a definitive diagnosis.
For the time of preoperative application of Imatinib, NCCN suggested that when two consecutive CT examinations found that the tumor no longer regressed, it means that the treatment reached its maximum effect, which is the best time for surgery, and the domestic expert consensus suggested that Imatinib preoperative treatment for about 6 months is the best time for surgery; for the issue of preoperative discontinuation time, NCCN suggested that preoperative discontinuation is sufficient, and the domestic consensus suggested that preoperative discontinuation is 1 week based on safety considerations. For the preoperative application of imatinib and the time frame for continuing imatinib application after complete resection, domestic and foreign experts are inconclusive; for the increase of imatinib dose after progression, NCCN recommends an increase to 800 mg, and due to the tolerability of Chinese patients and clinical study results, the domestic recommendation is to increase the dose to 600 mg.
Summary The Chinese Consensus on Diagnosis and Treatment of Gastrointestinal Mesenchymal Tumors (2013 edition) has been greatly improved from the 2011 edition, and many recommendations are based on domestic clinical research evidence and experts’ clinical practice experience. However, there are still many clinical issues that could not be solved during the development of the specification, and it is difficult to reach consensus on treatment choices, such as the indication population and advantages and disadvantages of laparoscopic surgery, the choice of drug treatment for rare genotypes, the pattern of organismal changes and tumor biological alterations in patients after drug resistance, and the choice of individualized treatment.
However, there is a consensus on the research direction and development prospect of GIST, and we all hope that there will be more evidence based on individualized treatment based on the rich clinical resources of GIST in China, especially clinical research in multidisciplinary collaboration.