How to pathologically evaluate the efficacy of neoadjuvant therapy for lung cancer?

Lung cancer is the main cause of death from malignant tumors in China, of which non-small cell lung cancer (NSCLC) accounts for about 85%
.

Surgical resection after neoadjuvant therapy is an important treatment for patients with locally advanced NSCLC

Neoadjuvant therapy can reduce the tumor burden before surgery and remove tumor cells in the blood; at the same time, it can reduce postoperative recurrence and metastasis, and improve prognosis
.

However, currently, the imaging-based Response Evaluation Criteria for Solid Tumors (RECIST) scoring method is commonly used in clinical practice, and there is no relatively complete and feasible pathological evaluation method
.

In clinical practice, there is inconsistency between the RECIST score and the pathological assessment results

With the progress of neoadjuvant therapy for NSCLC, the assessment of pathological response, which is closely related to efficacy and prognosis, is widely used, but needs to be further standardized
.

To provide a reliable basis for further clinical treatment and prognosis prediction, pathologists and clinicians jointly formulated the "Expert Consensus on Pathological Evaluation of the Efficacy of Neoadjuvant Therapy for Non-Small Cell Lung Cancer (NSCLC) (2021 Edition)"

1.

1.

2.

Mainly manifested as different degrees of tumor cell regression, necrosis and interstitial changes (mainly including fibrosis and inflammatory lesions);

It has been shown to be effective in predicting patient survival

3.

In conclusion, pathological assessment after neoadjuvant therapy can more accurately and rapidly predict prognosis

2.

2.

Patient-related clinical information;

specimen collection;

Microscopic evaluation of pathological response (including original tumor bed and lymph node evaluation);

Pathological staging and standardized case report templates after neoadjuvant therapy;

Focus on histopathological features after neoadjuvant therapy

As a pathologist, we should not only pay attention to the pathological information, but also pay attention to the clinical information related to the patient

3.
Clinical information of lung cancer surgical specimens after neoadjuvant therapy

3.
Clinical information of lung cancer surgical specimens after neoadjuvant therapy 3.
Clinical information of lung cancer surgical specimens after neoadjuvant therapy

Clinicians are required to provide the following information on the pathology application form:

Whether the patient has received neoadjuvant therapy;

Neoadjuvant therapy regimen (including drug regimen, number of treatment cycles and date of last administration);

History of pneumonia, tuberculosis, pulmonary fibrosis, etc.
related to treatment;

Histological diagnosis before treatment, original tumor location, size and type of surgery;

Results of clinical and radiographic assessments of neoadjuvant therapy efficacy
.

Clinical and pathological cooperation can better serve patients! ! !

The following are the important contents of this consensus:

4.
Collection of surgical specimens for lung cancer after neoadjuvant therapy

4.
Collection of surgical specimens of lung cancer after neoadjuvant therapy 4.
Collection of surgical specimens of lung cancer after neoadjuvant therapy

1.
Identify the tumor bed

1.
Identify the tumor bed

Concept: "tumor bed" refers to the site where the original tumor was located before treatment;

The tumor bed can be searched by identifying the area of ​​pleural shrinkage and palpating the specimen;

After finding the tumor bed, it is necessary to make an incision along the largest section of the tumor bed, and it is recommended to measure the size of the tumor bed in a fresh state
.

However, in actual work, there are difficulties in identifying tumor beds, as follows:

The original tumor is small and difficult to identify by visual inspection or palpation when the treatment response is close to a significant pathological response (MPR) or complete pathological response (CPR);

After neoadjuvant therapy, the localized reactive lesions in the surrounding lung tissue were mistaken for the tumor bed;

Sometimes central squamous cell carcinoma can only present with limited endobronchial scar when CPR is achieved
.

Therefore, special emphasis is placed on:

Before sending the specimen for inspection, the clinician can mark the tumor location with sutures and inform the pathologist of the significance of the marking;

The pathologist can help correctly identify the tumor bed by comparing pre-treatment imaging
.

2.
Specimen fixation

2.
Specimen fixation

After confirming the tumor bed, fix the specimen;

Incision and fixation are recommended;

Parallel to the largest surface of the tumor bed, incision is made every 0.
5 cm (the largest diameter of the tumor bed is ≤ 3 cm);

Cut parallel to the largest surface of the tumor bed every 1 cm (the largest diameter of the tumor bed is >3 cm);

The fixation time should be at least 6 h and not more than 72 h
.

3.
Collection of specimens

3.
Collection of specimens

The necrosis of the entire tumor bed and the percentage of residual tumor were first evaluated before sampling, followed by microscopic correction;

All tumor beds with the largest diameter ≤ 3 cm were taken;

>3 cm, select all representative slices (usually the largest slice), and take at least one slice from each slice for other slices, and take normal lung tissue around the tumor bed to define the boundary of the tumor bed (Figure 2);

Before taking materials, it is recommended to print and take pictures, and draw pictures on the pictures to mark the tissue blocks
.

Note: Since the specimens after neoadjuvant therapy not only have clear guiding significance for clinical prognosis, but also have high scientific research value, it is recommended that qualified laboratories collect as many materials as possible! ! !

V.
Pathological evaluation of lung cancer surgical specimens after neoadjuvant therapy

V.
Pathological evaluation of lung cancer surgical specimens after neoadjuvant therapy V.
Pathological evaluation of lung cancer surgical specimens after neoadjuvant therapy

1.
After reading all sections with tumor beds, semi-quantitative evaluation methods were used to comprehensively evaluate the percentage of main components in the tumor beds:

residual tumor cells;

necrosis;

Interstitial (mainly fibrous tissue and inflammatory lesions)
.

2.
The sum of the three components is 100%, each component is recorded in 10% increments, and any component less than 10% is recorded as a specific percentage value
.

Here are some specific concepts:

1.
Tumor bed boundary

1.
Tumor bed boundary

Further correction of the tumor bed boundary under the microscope;

Fibrosis, inflammatory lesions, or lymph nodes directly involved by the tumor around the tumor bed were not counted within the borders
.

2.
Surviving tumor cells

2.
Surviving tumor cells

It refers to the well-preserved tumor cells in the tumor bed after neoadjuvant therapy, and the cytoplasm is clearly visible;

Nuclear "ghost" outlines, nuclear debris, or apoptotic tumor cells remaining in necrosis are inactive tumor cells
.

3.
CPR and MPR

3.
CPR and MPR

CPR refers to the absence of residual tumor cells in the tumor bed and lymph nodes after neoadjuvant therapy (Figure 3);

MPR refers to the percentage of remaining viable tumor cells in the tumor bed after neoadjuvant therapy ≤10%, regardless of whether there are viable tumor cells remaining in the lymph nodes (Figure 4);

When the treatment response was not obvious, a large number of tumor cells remained in the tumor bed, and only a few changes such as necrosis or fibrous tissue proliferation were seen (Figure 5)
.

have to be aware of is:

If the percentage of residual tumor cells is close to MPR or reaches CPR, the gross specimen needs to be re-examined and supplemented as appropriate;

When CPR is achieved, it is necessary to verify whether the tumor bed is accurately located in combination with pre-treatment imaging;

For colloid carcinoma, it is recommended to treat the residual tumor cells together with the mucus lake as the residual tumor cells.
If only the mucus lake exists, it is regarded as the stroma;

Squamous cell carcinoma in situ, atypical adenomatous hyperplasia, adenocarcinoma in situ, or minimally invasive adenocarcinoma independently existing outside the tumor bed did not affect the assessment of MPR or CPR
.

6.
Evaluation of lymph node pathological response

6.
Assessment of lymph node pathological response 6.
Assessment of lymph node pathological response

1.
As far as possible, take all the lymph nodes to be examined.
For larger lymph nodes, cut them along the largest plane.
If the tumor bed is clearly visible on the cut surface, the size of the tumor needs to be measured, and the samples are the same as the original tumor bed;

2.
Detailed records of pathological changes in lymph nodes, including the presence or absence of tumor cells and treatment response
.

For macroscopically measurable tumor beds in lymph nodes, it is recommended to evaluate the original tumor bed microscopically;

After neoadjuvant therapy, changes such as necrosis, granuloma, and fibrosis may also occur in lymph nodes without tumor cells.
At present, there is no good method to identify whether it is a response to treatment.
Descriptive prompts can be made, but they are ignored.
residual tumor
.

However, the clinical significance of the assessment of lymph node pathological response is still unclear, and further data accumulation and exploration are needed
.

7.
Pathological staging after neoadjuvant therapy

7.
Pathological staging after neoadjuvant therapy 7.
Pathological staging after neoadjuvant therapy

The TNM staging system, 8th edition of the American Joint Cancer Society (AJCC) was used
.

1.
T stage (size of residual tumor)

If the residual tumor is measurable at the time of gross assessment, directly measure the tumor size;

If the residual tumor is scattered and multifocal in the tumor bed, surrounded by necrotic and fibrotic stroma, the size of the residual tumor (ypT) = the percentage of residual tumor cells × the largest diameter of the tumor bed;

It is necessary to remove the adherent growth components in the tumor;

Pleural invasion: If only necrosis and fibrosis and other treatment responses are seen in the invasion site without the existence of viable tumor cells, it should be regarded as PL0
.

2.
N staging (with or without tumor cells in the lymph nodes)

There may be cases where no tumor cells remain in the original tumor bed, but tumor cells are seen in the lymph nodes, that is, ypT0N1~3;

The clinical staging method recommended by the International Association for the Study of Lung Cancer ypN0 is stage 0, ypN1 is stage IIB, and ypN2 is stage IIIA
.

Note: The clinical significance of this staging method is unclear
.

8.
Pathological diagnosis report after neoadjuvant therapy for NSCLC

8.
Pathological diagnosis report after neoadjuvant therapy for NSCLC 8.
Pathological diagnosis report after neoadjuvant therapy for NSCLC

This consensus recommends that pathology reports include the following:

General patient information;

Types of specimens submitted for inspection and types of neoadjuvant therapy;

General description and pathological diagnosis;

Treatment response assessment and neoadjuvant immunotherapy-related treatment response assessment;

Lymph nodes and staging
.

A standardized pathology report is helpful for the diagnosis, treatment and prognosis of patients.
Therefore, it is recommended that pathologists use this format
.

9.
Remaining problems and suggestions

9.
Remaining problems and suggestions 9.
Remaining problems and suggestions

1.
The consistency of pathological response assessments made by different pathologists needs to be further verified.
It is recommended that at least two pathologists conduct the assessment and obtain consistent results;

2.
In order to conduct accurate assessment, it is recommended to obtain as much material as possible, but the conditions of each unit are different.
If sufficient material cannot be obtained, there may be differences in the assessment of MPR and CPR;

3.
In the future work, multi-center research is still needed to further verify and continuously update;

4.
With the continuous updating of the treatment plan, further clinical and pathological cooperation is needed for pathological evaluation
.

references

references

[1] Expert Committee on Lung Cancer Quality Control of National Cancer Center for Quality Control.
Expert consensus on pathological evaluation of the efficacy of neoadjuvant therapy for non-small cell lung cancer [J].
Chinese Journal of Pathology, 2021, 50(9):6.

[1] Expert Committee on Lung Cancer Quality Control of National Cancer Center for Quality Control.
Expert consensus on pathological evaluation of the efficacy of neoadjuvant therapy for non-small cell lung cancer [J].
Chinese Journal of Pathology, 2021, 50(9):6.
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