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The main molecular mechanism of melanoma and treatment suggestions
The main molecular mechanism of melanoma and treatment suggestions. The main molecular mechanism of melanoma.
The main molecular mechanism of melanoma
The development of melanoma is the result of the synergy of multiple signaling pathways, which affect the regulation of cell cycle, cell proliferation, differentiation, migration and survival, mainly including the following pathways:
- MAPK pathway: RAS/RAF/MEK/ERK pathway
- BRAF, NRAS mutations lead to continuous activation of the MAPK pathway
- Loss of CDKN2A (P16), loss of cell cycle regulation
- P53 pathway
Clark model: BRAF mutation is a melanoma driver mutation
Classification of BRAF mutations and signaling mechanism
The clinical significance of BRAF mutations
1. Metastatic melanoma: The prognosis of patients with BRAF mutations is worse than that of BRAF wild-type patients
2. BRAF mutation patients have an earlier onset, are more likely to develop ulcers, and the clinical pathological stage is late. The prognosis of BRAF mutation patients in Chinese melanoma is significantly worse than that of wild-type patients.
3. Resectable melanoma: cancers in patients with BRAF mutations are more aggressive
Molecular testing related to melanoma diagnosis
The role of molecular testing in the diagnosis of melanoma is limited. Histopathological diagnosis is the “gold standard” for melanoma diagnosis. Immunohistochemistry and molecular pathological testing are only used when tissue diagnosis is difficult.
When you have the following conditions, you can consider using molecular pathology testing to assist diagnosis:
• When it is difficult to distinguish acral melanoma from acral nevi
• It is difficult to determine whether the lesion in the lymph node is a melanoma or a mole
• When it is difficult to distinguish intraocular melanoma from melanoma
• Difficulty in distinguishing Spitz melanoma from atypical Spitz tumor
• When P16 negative cannot rule out melanoma (test for CDKN2A homozygous loss)
In addition, FISH detection of melanoma can assist in the diagnosis and is a relatively objective and reliable method to distinguish benign and malignant melanomas.
The sensitivity of FISH in the differential diagnosis of melanoma is 87%, and the specificity is 95.4%
Molecular testing related to melanoma treatment
BRAF mutations: metastases; BRAF and MEK inhibitors; preferential use in metastatic tissues;
c-KIT mutation: mainly occurs in mucosa and extremities, with high incidence in China, clinical application of effective drugs;
NRAS mutations: Unlike BRAF mutations, MEK inhibitors are effective for some melanomas with NRAS mutations.
BRAF-mutated melanoma patients can benefit significantly from BRAF targeted therapy
The dual-target combination therapy of dabrafenib and trametinib significantly prolongs the PFS and OS in patients with advanced/metastatic melanoma with BRAF mutations.
The NCCN, ESMO, and CSCO clinical guidelines recommend that all patients with advanced melanoma (stage III and IV that cannot be resected) undergo BRAF V600 mutation testing to guide the rational use of BRAF inhibitors.
BRAF molecular detection indications: (Clinical Practice Guidelines for Pathological Diagnosis of Melanoma (2021 Edition))
1. Tumors above clinical stage III (including);
2. For resectable stage I and II lesions, combined with the recommendations of some countries’s CSCO Melanoma Diagnosis and Treatment Guidelines (2020 Edition), it can also be detected;
3. In view of the good prognosis of melanoma in situ, testing is not recommended.
BRAF testing should be performed as soon as possible after the diagnosis of melanoma to provide reference for treatment decisions
Melanoma molecular detection technology
BRAF detection method clinical sampling
The NCCN Melanoma Guidelines recommend:
1. When suspicious stained lesions appear, the patient should undergo excisional biopsy, and the margin should be negative
2. When the lesions (such as face, fingertips, soles) are not suitable for excisional biopsy, full-thickness incision or drill biopsy can be used, and curettage biopsy can be used only when the suspicion is low
The CSCO Guidelines for Diagnosis and Treatment of Malignant Melanoma (2019 Edition) recommends:
1. For melanoma patients with no distant metastasis judged clinically, biopsy generally recommends complete resection, and needle biopsy or local resection is not recommended.
2. Sentinel lymph node biopsy is a pathological staging method to assess whether regional lymph nodes have metastasized. Sentinel lymph node biopsy is recommended for tumor thickness> 1mm. If the thickness of the lesion is 0.8-1.0mm, the sentinel lymph node biopsy can be combined with clinical considerations.
3. Processing of submitted specimens: The specimens need to be submitted for inspection completely, the surgical surgeon shall mark the margins, and fix the specimens with 10% formalin for 6-48 hours
It is recommended to use the ARMS-PCR method for BRAF detection first
Sample processing method (sample fixed)
Specimens from our hospital
• Timely fixation: fixation within 20 to 30 minutes after the body is separated (generally completed in the operating room)
• Fixative: 10% neutral buffered formalin solution, avoid using acidic and heavy metal ion-containing fixatives to process specimens
• Adequate fixation: the tissue should be completely immersed in the fixative, and the amount of fixative should be 10 times that of the tissue
• Fixed time: biopsy specimens: 6-12 hours, surgical specimens: 12-48 hours
Outer Court Specimen
• The wax block (≤3 years) stored in the outer hospital will try to test, and the results of specimens within 2 years are more guaranteed
• If the wax block in the outer hospital does not meet the requirements or mutations are not detected, it is recommended that the surgeon re-take the metastasis in this hospital for testing
It is recommended to keep a record of each time point during the inspection process
Requirement of material location
Due to the inconsistency of BRAF mutations between the primary tumor and metastases, molecular detection of BRAF should be carried out at the same time for 1 primary tumor + multiple metastases
• The occurrence and development of melanoma involves MAPK, TP53, CDKN2A, etc.
• When it is difficult to diagnose melanoma based on histology, consider using 5-probe or CDKN2A FISH test to assist in the diagnosis
• To guide the prognosis of treatment for melanoma molecular testing including BRAF, NRAS, CKIT mutation detection
• The guidelines recommend that all diagnosed non-in situ melanomas should be tested for BRAF mutations (it is recommended to be performed immediately after histological diagnosis)
• Strengthening multi-department cooperation can increase the detection rate of melanoma and the positive detection rate of BRAF
(source:internet, reference only)