I. Overview
Breast cancer is one of the common malignant tumors in women, and the incidence rate ranks the first among female malignant tumors, which seriously endangers women’s physical and mental health. At present, through comprehensive treatment, breast cancer has become one of the most effective solid tumors.
In order to further standardize the diagnosis and treatment behavior of breast cancer in China, improve the level of breast cancer treatment in medical institutions, improve the prognosis of breast cancer patients, and guarantee medical quality and medical safety, this specification is formulated.
Diagnosis
The diagnosis and differential diagnosis of breast cancer should be made by combining the clinical manifestations, physical examination, imaging examination and histopathology of patients.
(A) Clinical manifestations. Early stage breast cancer does not have typical symptoms and signs, so it is not easy to attract patients’ attention. The following are the typical signs and symptoms of breast cancer, which mostly appear in the middle and late stages of cancer.
Breast lumps: 80% of breast cancer patients are first diagnosed with breast lumps. The lump is often found unintentionally and is mostly solitary, hard, with irregular edges and a poorly smooth surface. Most of the breast cancer lumps are painless, only a few of them are accompanied by varying degrees of hidden pain or stabbing pain.
2. Nipple overflow. If there is blood, plasma, milk or pus flowing from the nipple during the non-pregnancy period, or if there is still milk flowing after stopping breastfeeding for more than half a year, it is called nipple overflow. There are many causes of nipple overflow, and common diseases include intraductal papilloma, breast hyperplasia, ductal dilatation of the breast and breast cancer. Unilateral single-hole bloody overflow should be further examined, and more attention should be paid if accompanied by breast lumps.
3.Skin changes. The most common one is that the tumor invades Cooper’s ligament and then adheres to the skin, resulting in the “dimple sign”. If the cancer cells block the lymphatic vessels, orange peel-like changes may occur. In advanced stage of breast cancer, the cancer cells infiltrate into the skin along the lymphatic ducts, glandular ducts or fibrous tissues and grow into the skin, forming “skin satellite nodules”.
4. Abnormal nipple and areola. If the tumor is located in or close to the deep part of the nipple, it may cause nipple retraction. If the tumor is far away from the nipple and the large duct in the breast is invaded and shortened, it may also cause nipple retraction or elevation. Eczema-like carcinoma of the nipple, i.e. Paget’s disease of the nipple, is characterized by itching, erosion, rupture, crusting, flaking, burning pain, and nipple retraction.
5. Enlarged lymph nodes in the axilla. The first symptom of occult breast cancer is swollen lymph nodes in the axilla, which cannot be felt on physical examination. More than 1/3 of breast cancer patients admitted to hospitals have axillary lymph node metastasis. At the initial stage, the lymph nodes in the axilla on the same side may be enlarged, and the enlarged lymph nodes are hard, scattered and pushable. As the disease progresses, the lymph nodes will gradually fuse and adhere to the skin and surrounding tissues. In advanced stages, metastatic lymph nodes may be felt in the supraclavicular and contralateral axillae.
(B) Breast palpation. Before performing breast palpation, a detailed history of breast disease, menstrual history of marriage, and family history of previous tumors (breast cancer, ovarian cancer) should be asked. Premenopausal women should preferably undergo breast palpation after menstruation.
The examinee is usually in the sitting or standing position, or in combination with the supine position for ptotic or large breasts. The breast physical examination should follow the principle of visualization before palpation and the healthy side before the affected side.
Most of the breast cancers can be diagnosed easily by palpation. Some early breast cancers are negative to palpation. During physical examination, attention should be paid to localized glandular thickening and hardening, nipple erosion, nipple overflow, as well as mild nipple retraction, mild indentation of breast skin, mild edema of the areola, and breast pain after menopause, etc., which should be alerted. Diagnosis should be made by combining imaging and histopathological findings and, if necessary, biopsy for cytological diagnosis.
(C) Imaging examinations.
1. Mammography.
Conventional positions include bilateral medial-lateral oblique position (MLO) and cephalic foot position (CC). For those who do not show well in conventional positions or do not have the whole breast parenchyma, supplementary positions can be chosen according to the location of the lesion. In order to make the lesion display better, some special photographic techniques such as local compression photography, magnification photography or local compression magnification photography can be carried out if necessary.
(1) Indications.
1) Breast mass, sclerosis, nipple overflow, abnormal breast skin, local pain or swelling.
2)Abnormal changes found by screening.
3)Short-term follow-up of benign lesions.
4)After breast repair and reconstruction surgery.
5)During breast tumor treatment.
6)Other cases that require radiological examination or consultation with radiologists.
Mammography is not recommended for women under 35 years of age with no clear risk factors for breast cancer or no abnormalities on clinical examination.
(2) See Annex 1 for the basic norms of diagnostic report.
2.Breast ultrasound.
For all people with suspected breast lesions. Examination of the breast and axillary lymph nodes can be performed simultaneously. Breast ultrasound scan is performed in the supine position, from the top of the axilla to the lower border of both breasts, including the whole breast and the axilla.
(1) Indications.
1) The imaging examination of choice for breast lesions in young, pregnant and lactating women.
2)To confirm clinically palpable masses and suspicious abnormalities and to further evaluate clinical and imaging findings.
3)Evaluation of breast lesions after implantation of prosthesis.
4)Guiding interventional operations.
(2) See Annex 1 for the basic specifications of the diagnostic report.
3) Breast magnetic resonance imaging (MRI) examination.
MRI is not used as a routine examination item for breast cancer diagnosis. It can be used for breast cancer staging assessment, determining the extent of ipsilateral breast tumor, and determining whether there are multifocal or multicentric tumors. It can be used to screen for contralateral breast tumors at the time of initial diagnosis. It is also helpful to assess the tumor extent before and after neoadjuvant therapy, treatment remission status, and whether breast-conserving therapy can be performed.
(iv) Histopathologic diagnosis.
Histopathological diagnosis is the basis for confirming the diagnosis and treatment of breast cancer, and is the final diagnosis derived from the comprehensive analysis of various clinical information and pathological patterns. To perform histopathological diagnosis, clinicians need to provide complete and exact clinical situation and timely and sufficient amount of tissue specimens.
1.Tissue specimen fixation standard.
Fixation solution: 10% neutral formalin solution.
Amount of fixative: fixative should be more than double the specimen. If the specimen is too thick and too large, it is recommended to update the fixing solution once in the middle.
Fixation temperature: room temperature.
Fixation time: depending on the specimen.
2, tissue specimen sampling requirements and processing.
(1) Intraoperative rapid freezing of specimens for examination.
1) Check the specimen and the application form.
2) Observe the specimen, measure 3 diameter lines (length × width × height) and record in centimeters, describe the nature. When available, take a general image or trace the sketch of the specimen.
3) Take a quick freeze film of the typical lesion area, and if it is largely suggestive of malignant tumor another 1 or 2 pieces of tumor tissue should be taken and fixed immediately for immunohistochemical detection.
4) Immediately after the report is issued, the remaining specimens are taken and fixed for 12 to 24 hours.
(2) Needle-piercing specimens (including fine and coarse needle-piercing specimens).
Check specimens and application forms. Observe and describe the number and size of specimens sent for examination, stained with eosin and wrapped in thin paper. The specimens sent for examination must all be taken (if the clinical labeled serial number, then take the number according to the serial number), taking care not to squeeze and break the specimens, placed in parallel and fixed for 6 to 12 hours.
(3) Lumpectomy specimens.
Check the specimen and the application form. Take all the specimens in the order of delivery, number them, place them in parallel and fix them for 6 to 12 hours.
(4) Cut specimens.
Check the specimen and the application form. Observe the specimen, measure the 3 diameter lines (length × width × height) and record in centimeters, describe the nature, and take a general image or sketch the specimen if available. The abnormal parts were taken as much as possible and fixed for 12 to 24 hours. All parts of the tumor should be taken. If the tumor is too large, all parts of the tumor should be taken, at least the largest section of the tumor should be taken, including the junction between the tumor and normal tissue.
(5) Breast-conserving surgical specimens.
1) Intraoperative perioperative cutting edge specimen. Check the specimen and application form. Observe the specimen, measure 3 diameter lines (length × width × height) and record in centimeters, describe the nature, take a large body image or trace the sketch of the specimen if available. The specimens were taken according to clinical markers (recommended for specimens with full circumference if available), and the orientation of the corresponding tissue block was recorded. The remaining specimens were fixed for 12 to 24 hours for postoperative retrieval. If the submitted cutting edge is clinically selected, the specimen will be taken and filmed for observation according to the cut-off surface of the clinically selected specimen, and noted in the report.
2) Postoperative specimens for breast conservation. Check the specimens and application forms. Specimens without intraoperative peri-incisional margin pathological examination are subject to macroscopic specimen photography or tracing sketch if available to determine the tumor location and nipple end. A section was made every 5 mm in the vertical direction of the line connecting the tumor and the nipple end, and each section was taken sequentially one by one in succession in order to record the corresponding orientation of the tissue block.
(6) Mastectomy specimens.
1) Fresh specimens. Check specimens and application forms. Observe, measure, and describe the gross specimen, and videotape or trace sketches when available. The surgeon sends the lymph nodes in groups according to the local anatomical signs and intraoperative views to locate the lymph node drainage area. Or the lymph nodes in the specimen (at least 10) are dissected by the pathologist and all the lymph nodes are detected for sampling. Cut the specimen with a line connecting the papilla to the center of the tumor/incision/scar and make the bottom of the specimen connected (to maintain the anatomical position), if the specimen is too large, several sections can be made parallel to the previous section. Rinse the specimen of blood and dry it and then fix it for 24-48 hours for retrieval.
2) Fix the specimen. Make several sections parallel to the first day’s incision to dissect, observe and record. The main sampling sites include the papilla and a piece of tissue in the largest section of the tumor all taken; tumor tissue all taken. The abnormal parts of the tumor were taken for general observation.
3.judge the histological classification and pTNM stage of breast cancer (see Annex 2 and 4).
4.Other.
(1) Histological classification of breast cancer. Mainly for the infiltrating ductal carcinoma part of invasive carcinoma, grading is performed according to the following indicators
Glandular duct formation: In the tumor section, glandular duct structure is greater than 75% for 1 point, 10% to 75% for 2 points, and less than 10% for 3 points.
Nuclear pleomorphism: 1 point for consistent cell size, shape and chromatin, 2 points for moderate irregularity, 3 points for obvious pleomorphism.
Nuclear division count: 10 high-powered fields of view with 0 to 5 nuclear division images were scored as 1, 6 to 10 as 2, and 11 or more as 3.
When the scores determined by the above three indicators are added together, 3-5 are classified as grade I (highly differentiated), 6-7 as grade II (moderately differentiated), and 8-9 as grade III (poorly differentiated).
(2) Cancer tissue invasion and lymph node metastasis.
Lymphovascular invasion: no lymphovascular invasion in tumor section is (-); suspicious lymphovascular invasion is (±); one lymphovascular invasion is (+); two lymphovascular invasions are (++); three or more lymphovascular invasions are (+++); the whole tumor cannot be observed due to incomplete filming or tumor delivery is (cannot be evaluated).
Vascular invasion: the same criteria as above, classified as (-), (±), (+), (++), (+++), (++++) and (unable to assess).
Nerve invasion: same criteria as above, classified as (-), (±), (+), (++), (+++), (++++) and (unable to assess).
Invasion of other tissues: Involvement of nipples, skin, fat, pectoral muscle, chest wall and other tissues, including gross and microscopic findings.
Tumor extent: The breast was divided into 6 parts: nipple areola area (E), superior internal (A), inferior internal (B), superior external (C), inferior external (D) and caudal lobe of the breast (C’), according to the depiction of the position occupied by the tumor. Includes gross (M) and microscopic (m) views.
Lymph node metastasis: the number of microscopically confirmed metastatic lymph nodes and soft tissue invasion outside the lymph nodes.
(3) Histopathological assessment of treatment effect.
The pathomorphological changes seen after radiation therapy, chemotherapy, endocrine therapy, and molecular targeted therapy for breast cancer can be used as a histopathological basis for evaluating its therapeutic efficacy. Since such pathomorphological changes are similar, the histopathological assessment criteria for their efficacy are basically the same. They are judged as grade 0 (ineffective), grade I (partially effective), grade II (efficacious), and grade III (effective).
(4) Detection and determination of molecular biological markers and genes.
1) Immunohistochemical method to detect steroid hormone receptors (ER and PR). Each batch of staining should have positive controls (internal and external controls) and negative controls, and the same batch of stained sections in which all control sections appear to have the expected results can be used for the determination of the results of immunohistochemical staining. The percentage of positive cells and the intensity of staining (strong, moderate and weak) were assessed by microscopic observation. Cancer cells with brownish-yellow granular staining of the nucleus were considered ER(PR) positive cells.
2) Immunohistochemical method to detect HER2/neu protein. Each batch of staining should have positive control (external control) and negative control (internal and external control), and the results of immunohistochemical staining should be determined only when the same batch of stained sections show the expected results, and the cell membrane staining of infiltrating cancer cells should be determined. The results were classified as (-), (+), (++) and (++++).
3) Fluorescence in situ hybridization (FISH) for HER2/neu gene detection: Select cancer cells with consistent nuclear size, intact nuclear border, no overlap and clear green signal in the infiltrating cancer region, and randomly count the number of red and green signals in the nuclei of at least 20 cancer cells. The ratio (total number of red signals in 20 nuclei/total number of green signals in 20 nuclei) was calculated, and the results were classified as negative, positive, critical, or undetermined (see Annex 6).
Due to the heterogeneity of breast cancer itself and the influence of detection system, antibody and detection method, the test results may have some inconsistency. Therefore, the re-test should provide the detection system used for the initial test, the detection method (fully automatic, semi-automatic, manual detection), the name and concentration of antibody, and the name of probe, etc.
(5) Pathology report.
The contents and format of the pathology report of breast cancer are shown in Annex 5.
Differential diagnosis
Breast cancer needs to be differentially diagnosed from benign diseases such as breast hyperplasia, fibroadenoma, cyst, intraductal papilloma, ductal dilation (plasmacytoid mastitis), breast tuberculosis, malignant lymphoma of the breast, and secondary malignant tumors of the breast metastasized to the breast from other primary tumors. The differential diagnosis requires a detailed history and careful physical examination, combined with imaging (breast ultrasound, mammography and breast MRI) and finally cytology and/or pathological histology to clarify the diagnosis.
About 80% of breast cancers with palpable lumps on clinical examination can be diagnosed by surgical biopsy and pathological histology, and in hospitals with the ability to do so, the diagnosis can be made by puncture as soon as possible. However, breast cancer that is negative to clinical palpation increases the difficulty of differential diagnosis and requires imaging to locate the lesion for puncture or to place a metal locator wire under the guidance of mammography technology, followed by surgical excisional biopsy for clear diagnosis.
A small number of breast cancer patients with nipple overflow need to be differentiated from breast hyperplasia, ductal dilatation, milk retention, intraductal papilloma and papillomatosis. If necessary, biopsy can be performed to clarify the diagnosis.