Invasive carcinoma of no special type (invasive carcinoma NST), invasive breast carcinoma of no special type (IBC-NST), invasive ductal carcinoma (IDC), infiltrating ductal carcinoma (IDC) or invasive ductal carcinoma, not otherwise specified (NOS) is a disease. For international audiences this article will use "invasive carcinoma NST" because it is the preferred term of the World Health Organization (WHO).
Invasive carcinoma NST accounts for half of all breast cancer diagnoses in women and is the most common type of invasive breast cancer. It is also the most commonly diagnosed form of male breast cancer. Invasive carcinoma NST is classified by its microscopic, molecular, and genetic features. Microscopically it is a breast carcinoma of the adenocarcinoma type, originating from the breast ducts. It shows invasive features but lacks the "specific differentiating features" of other types of invasive breast cancers. Invasive carcinoma NST is a diagnosis of exclusion, which means that for the diagnosis to be made all the other specific types must be ruled out. There are several rare sub-types of invasive carcinoma NST including pleomorphic carcinoma, carcinoma with osteoclast-like stromal giant cells, carcinoma with choriocarcinomatous features, and carcinoma with melanotic features.[1]
Invasive breast carcinomas are most common in White women, followed by Black and Hispanic women. Black women tend to have greater severity of disease at diagnosis with worse overall survival. Breast cancer is often asymptomatic and diagnosis by screening, but may present with symptoms of pain, palpable mass, skin changes, or complications of metastasis.
Clinical disease or suspicious lesions on screening may evaluated further with tissue sampling. Diagnostic analysis will include histopathological typing, grading, and analysis for DNA markers and receptor-status. The prognosis for patients with invasive carcinoma NST is heterogenous and difficult to predict for every individual. However, general factors such as high tumor grade, stage, receptor negativity, BRCA1-positivity suggest higher risk of recurrence and lower overall survival. Treatment is individualized however most patients are offered some combination of neoadjuvant, surgical, radiation, and adjuvant systemic medical therapies.
Epidemiology
Invasive carcinoma NST is one of the most common types of all breast cancers, accounting for 55% of breast cancer incidence.[2] Of the invasive breast cancers, invasive carcinoma NST accounts for up to 75% of cases.[3][4] It is also the most common form of breast cancer occurring in men, accounting for 85% of cases.[5][6]
The incidence of ductal carcinomas as a whole is 86.3 cases per 100,000 women, with the incidence increasing sharply for women over 40 years of age and peaking at 285.6 cases per 100,000 for women between 70 and 79. This incidence has decreased slightly over time. Incidence of diagnosed cases is highest among White and non-Hispanic women, followed by Black and Hispanic women.[7]
Terminology
Invasive carcinoma NST is a type of breast cancer. It is one of the invasive breast cancers that originates from the breast ductal system, so that it is a type of ductal carcinoma. A defining feature of this ductal carcinoma is that it lacks the "specific differentiating features" of other types of ductal carcinomas. It is important to note that IDC, invasive ductal carcinoma NOS, and invasive carcinoma NST all refer to the same type of breast cancer. For consistency and to serve an international audience, this article will use invasive ductal NST.
The terminology of invasive carcinoma NST has undergone change since 2012. Differing opinions within the medical and public health communities have led to some variance in how this disease is referred in research and clinical settings.
In 2012 the International Agency for Research on Cancer (IARC), a sub-department of the WHO, published the 4th edition of the WHO Classification of Tumors of the Breast. Previously known as 'invasive ductal carcinoma, not otherwise specified', these most recent guidelines advocated for the use of 'invasive carcinoma of no special type'.[8][9]
There are, however, differing opinions and practices. The research literature continues to use IDC or invasive ductal carcinoma NOS,[10][11] and some medical textbooks have offered support for continued use of IDC or invasive ductal carcinoma NOS.[12][5]
Signs and symptoms
In most cases breast cancers are asymptomatic and are detected by routine clinical screening exams. In about 30% of cases a breast mass may be felt.[13][14] The mass will not fluctuate with the menstrual period.[15] Changes to the overlying skin including dimpling, pinching, orange peel-like texture, or nipple retraction may be seen.[16] Non-healing ulcers can form in advanced disease, and were more common historically prior to modern medical care.
Metastatic lesions from breast cancer may produce symptoms according to that organ system. The most common sites for metastasis are the bone, lung, liver, and brain.[17] Skin metastases most commonly extend to the skin overlying the mass, but may spread to the axilla or more distant areas.[18] Metastasis to adjacent lympatics may produce palpable masses in the axilla or an orange peel-like texture of the skin of the effected breast.[18][19]
Non-specific skin changes that may be signs of breast cancer.
The process of diagnosing invasive carcinoma NST is similar to that of other breast cancers. The process may be prompted by a patient presenting with a palpable mass or by evidence of a suspicious lesion on routine screening tests.[20] Tissue sampling is required for complete classification which will help determine prognosis and treatment plan. Tissue samples will be looked at under the microscope for histopathological type, grade, and stage(TNM). Immunohistochemical staining is used to establish receptor status, and the presence or absence of pertinent genes is determined by DNA testing.
Histopathology of invasive carcinoma of no special type, H&E stain, intermediate magnification. It shows typical plump tumor nests (rather than the single-file linear pattern of invasive lobular carcinoma). The presence of tumor nests in adipose tissue at right in image strongly favors invasiveness.High magnification of invasive carcinoma of no special type shows non-specific adenocarcinoma features.
On microscopic evaluation carcinomatous cells are seen below the basement membrane of lactiferous ducts and invade into the surrounding breast stroma. Otherwise, there are no specific histologic characteristics, essentially making it a diagnosis of exclusion.[21] The histopathologic characteristics seen in these lesions are heterogenous. The cells of a lesion of invasive carcinoma NST may retain >70% ductal differentiation or appear completely undifferentiated. The tumor cells may be arranged in sheets, nests, cords, or singly distributed. They are pleomorphic (i.e., vary in size and shape). They usually have prominent nucleoli and multiple mitotic cells per magnified field of view, which are features generally consistent with cancerous cells. The surrounding non-ductal tissue, known as stroma, can range from none to abundant.[22][23]
Small inclusions of special features may be present within an invasive carcinoma NST tissue sample, but will be 'limited' (i.e. <10%). Carcinomas of mixed type will have a specialized pattern or lobular carcinoma in the majority (i.e. at least 50%) of the tumor and a non-specialized pattern in between 10 and 49% of the sample. Thus, such tumors will be called mixed invasive NST and special type or mixed invasive carcinoma NST and lobular carcinoma.[24]
Mastectomy specimen containing a very large invasive ductal carcinoma of the breast. To the right, the nipple can be seen on the pink skin, while in the center of the picture a large blue and pink swelling or tumor can be seen. Blood stained fat tissue is seen at the cut margins.
Typical macroscopic (gross) appearance of the cut surface of a mastectomy specimen containing an invasive ductal carcinoma of the breast (pale area at the center).
Invasive ductal carcinoma of the breast assayed with anti Mucin 1 antibody.
Invasive ductal carcinoma, with occasional entrapped normal ducts (arrow)
Histopathology of invasive ductal carcinoma of the breast representing a scirrhous growth. Core needle biopsy. Hematoxylin and eosin stain.
Invasive ductal carcinoma of the breast. H&E stain.
Staging
Cancers in general will be staged according their degree of tumor size, lymph node involvement, and evidence of metastasis. There are two types, clinical staging and pathologic staging. Clinical staging uses information derived from physical examination, clinical imaging, and biopsy. Pathologic staging takes place after the tumor is removed surgically, when a pathologist is able to make more direct measurements of the tumor characteristics. Pathologic staging is considered more accurate, but clinical staging can give useful information to determine treatment plans prior to surgical efforts. Both clinical and pathologic staging use the TNM staging system, which take into account the tumor size (T), lymph node involvement (N), and evidence of metastasis (M). The TNM staging system designed for breast cancer is shown in the table below.[25]
Tumor size
In clinical staging, tumor size is determined by clinical imaging. A more accurate measurement of tumor size and observation of extension into adjacent structures can be determined via pathological staging following surgery.
Lymph node involvement
Absence of cancer cells in the lymph nodes is a good indication that the cancer has not spread systemically. Presence of cancer in the lymph nodes indicates the cancer may have spread. In studies, some women have had presence of cancer in the lymph nodes, were not treated with chemotherapy, and still did not have a systemic spread. Therefore, lymph node involvement is not an absolute predictor of spread.[26]
Description
Primary tumor (T)
T1=tumor size ≤20mm
T2=>20mm but ≤50mm T3=>50mm T4=tumor of any size with direct extension to the chest wall and/or skin
Regional lymph nodes (N)
N0=no regional lymph node metastases
N1mi=micrometastases N1=metastases to moveable ipsilateral axillary lymph nodes N2=metastases in ipsilateral axillary lymph nodes that are clinically fixed N3=metastases that are more extensive
Distant metastasis (M)
M0=no evidence of distant metastases
M1=distant detectable metastases as determined by clinical and radiographic means
Stage
0
DCIS
I
IA=T1, N0, M0
IB=T0, N1mi, M0 or T1, N1mi, M0
II
IIA=T0, N1, M0 or T1, N1, M0 or T2, N0, M0
IIB=T2, N1, M0 or T3, N0, M0
III
Larger size tumors with various combinations of lymph node involvement that are more extensive than stage II, but no distant metastases
The appearance of cancer cells under a microscope is another predictor of systemic spread. The more different the cancer cells look compared to normal duct cells, the greater the risk of systemic spread. There are three characteristics that differentiate cancer cells from normal cells.
Tendency to form tubular structures
Nuclear size, shape, and staining intensity
Mitotic rate - Rate of cell division
The histologic appearance of cancer cells can be scored on these three parameters on a scale from one to three. The sum of these grades is a number between 3 and 9. The score is called a Bloom Richardson Grade (BR) and is expressed [sum of the grades]/9. For example, cells that were graded 2 on all three parameters would result in a BR score of 6/9.
A score of 5 and under is considered low. 6 to 7 is considered intermediate. 8 to 9 is considered high.[26]
Histopathology of lymphatic invasion by carcinoma, H&E stain
Lymphovascular invasion is the presence of cancer cells in lymph channels and/or blood vessels. The presence of lymphovascular invasion increases the probability of systemic spread.[26]
DNA analysis
DNA analysis indicates the amount of DNA in cancer cells and how fast the cancer is growing.
Cells with the normal amount of DNA are called diploid. Cells with too much or too little DNA are called aneuploid. Aneuploid cells are more likely to spread than diploid cells.
DNA testing indicates the rate of growth by determining the number of cells in the synthetic phase (S phase). An S phase > 10% means a higher chance of spreading.
The results of DNA testing are considered less reliable predictors of spread than size, histology, and lymph node involvement.[26]
While prognosis in invasive carcinoma NST is difficult to predict, there are some prognostic factors that help estimate survival. The factors included here tend to be generalizable to most breast cancers, and further information can be found in the main articles on breast cancer and breast cancer screening.
The prognosis of ductal carcinomas in general depend, in part, on its histological subtype. Mucinous, papillary, cribriform, and tubular carcinomas have longer survival, and lower recurrence rates. The prognosis of the most common form of invasive carcinoma NST is intermediate. Regardless of the histological subtype, the prognosis of IDC depends also on tumor size, presence of cancer in the lymph nodes, histological grade, presence of cancer in small vessels (vascular invasion), expression of hormone receptors and of oncogenes like HER2/neu.
Histologic factors associated with worse prognosis include high histologic grade, hormone receptor negativity, and HER2 negativity. Regarding genetic risk factors, BRCA1-associated breast cancers may have higher rates of lung and brain metastases but a lower rate of bone metastases. Cases detected by screening have favorable survival compared to cases that present clinically.[12]
White women have the highest rate of breast carcinoma, followed by Black, Asian/Pacific Islander, and Hispanic women. However, Black women are most likely to have greater severity of disease and triple-receptor negativity at time of diagnosis. Compared to other populations, they tend to have reduced chance of cure and a shorter survival after diagnosis if unable to be cured.[27][28][12]
In 2003, one study found the five-year survival rate of invasive carcinoma NST was approximately 85%.[29] In general, greater tumor size and presence of lymph node metastasis predicts higher risk of recurrence after initial diagnosis and treatment. In one study, the lifetime risk of recurrence was 20% for smaller (<2cm) tumors without lymph node metastasis. Larger tumors without lymph nodes had 38% risk of recurrence. Presence of lymph nodes in tumors of any size showed 62% and 86% risk of recurrence in patients with 1-3 and >4 positive lymph nodes, respectively. Another study showed “90% of recurrences occurred within 9, 7, and 5 years for patients with grades 1, 2, and 3 tumors, respectively. The rate of death due to breast carcinoma was also influenced by grade, with 90% occurring in 40, 13, and 8 years among patients with grades 1, 2, and 3 tumors, respectively.”[12][30]
Immunohistochemistry of breast cancer (Infiltrating ductal carcinoma of the breast) assayed with anti HER-2 (ErbB2) antibody.
Immunohistochemistry of invasive ductal carcinoma of the breast representing a scirrhous growth. Core needle biopsy. HER-2/neu oncoprotein expression by Ventana immunostaining system.
Immunohistochemistry of estrogen receptor in invasive breast cancer, showing nuclear staining.
Treatment
The treatment of invasive carcinoma NST is often similar to management plans for other invasive breast carcinomas. The treatment options offered to an individual patient are determined by the form, stage and location of the cancer, and also by the age, history of prior disease and general health of the patient. Not all patients are treated the same way.
Management options for patients with invasive breast carcinomas include surgery, radiotherapy, and systemic adjuvant medical therapy. Surgical treatment ranges from radical mastectomy to breast conserving procedures such as lumpectomy. Patients at risk for local recurrence of disease may be offered radiotherapy. Patients at risk for systemic disease may be offered chemotherapy, and those whose tumors test positive for certain hormone receptor or genetic markers may be offered specific adjuvant medical therapies. Selective estrogen receptor modifying drugs (e.g., tamoxifen) or aromatase inhibitors (e.g., anastrozole) may be offered to those with estrogen or progesterone receptor positive tumors. HER2-positive tumors may be treated with the targeted medical therapy (e.g., trastuzumab).
Treatment of non-metastatic invasive breast cancer can vary based on staging, usually early stage (stages I and II) versus locally advanced (stage III). Patients with early stage disease may be offered surgery, including breast conserving therapy. This may be followed by radiotherapy for those at risk of local recurrence or systemic adjuvant medical therapy for those at risk of distant metastasis. Patient with locally advanced invasive breast cancer may be offered neoadjuvant systemic therapy and evaluated for tumor response prior to surgery, radiation, and adjuvant therapy.[31]
Prophylactic treatment may be an option for those with genetic predisposition to breast cancer. The National Comprehensive Cancer Network (NCCN) guidelines recommend bilateral prophylactic mastectomy and bilateral salpingo-oophorectomy for women who are carriers of germline BRCA1/2 mutation. At the age of 35 to 40 years, or once childbearing is completed, the procedure is recommended for risk reduction purposes. The NCCN states such management has led to reduced risk of breast carcinoma by 90% in this group.[32]
Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin. In those with distant spread of the disease, there may be bone pain, swollen lymph nodes, shortness of breath, or yellow skin.
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.
Lumpectomy is a surgical removal of a discrete portion or "lump" of breast tissue, usually in the treatment of a malignant tumor or breast cancer. It is considered a viable breast conservation therapy, as the amount of tissue removed is limited compared to a full-breast mastectomy, and thus may have physical and emotional advantages over more disfiguring treatment. Sometimes a lumpectomy may be used to either confirm or rule out that cancer has actually been detected. A lumpectomy is usually recommended to patients whose cancer has been detected early and who do not have enlarged tumors. Although a lumpectomy is used to allow for most of the breast to remain intact, the procedure may result in adverse affects that can include sensitivity and result in scar tissue, pain, and possible disfiguration of the breast if the lump taken out is significant. According to National Comprehensive Cancer Network guidelines, lumpectomy may be performed for ductal carcinoma in situ (DCIS), invasive ductal carcinoma, or other conditions.
Papillary thyroid cancer is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases. It occurs more frequently in women and presents in the 20–55 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck. It is often well-differentiated, slow-growing, and localized, although it can metastasize.
Vulvar cancer is a cancer of the vulva, the outer portion of the female genitals. It most commonly affects the labia majora. Less often, the labia minora, clitoris, or Bartholin's glands are affected. Symptoms include a lump, itchiness, changes in the skin, or bleeding from the vulva.
Breast cancer management takes different approaches depending on physical and biological characteristics of the disease, as well as the age, over-all health and personal preferences of the patient. Treatment types can be classified into local therapy and systemic treatment. Local therapy is most efficacious in early stage breast cancer, while systemic therapy is generally justified in advanced and metastatic disease, or in diseases with specific phenotypes.
Cancer of unknown primary origin (CUP) is a cancer that is determined to be at the metastatic stage at the time of diagnosis, but a primary tumor cannot be identified. A diagnosis of CUP requires a clinical picture consistent with metastatic disease and one or more biopsy results inconsistent with a tumor cancer
Thymic carcinoma, or type C thymoma, is a malignancy of the thymus. It is a rare cancer that is often diagnosed at advanced stages. Recurrence following treatment is common, and thymic carcinoma is associated with a poor prognosis.
Medullary breast carcinoma is a rare type of breast cancer that is characterized as a relatively circumscribed tumor with pushing, rather than infiltrating, margins. It is histologically characterized as poorly differentiated cells with abundant cytoplasm and pleomorphic high grade vesicular nuclei. It involves lymphocytic infiltration in and around the tumor and can appear to be brown in appearance with necrosis and hemorrhage. Prognosis is measured through staging but can often be treated successfully and has a better prognosis than other infiltrating breast carcinomas.
Metaplastic carcinoma, otherwise known as metaplastic breast cancer (MBC), is a heterogeneous group of cancers that exhibit varied patterns of metaplasia and differentiation along multiple cell lines. This rare and aggressive form of breast cancer is characterized as being composed of a mixed group of neoplasms containing both glandular and non-glandular patterns with epithelial and/or mesenchymal components. It accounts for fewer than 1% of all breast cancer diagnoses. It is most closely associated with invasive ductal carcinoma of no special type (IDC), and shares similar treatment approaches. Relative to IDC, MBC generally has higher histological grade and larger tumor size at time of diagnosis, with a lower incidence of axillary lymph node involvement. MBC tumors are typically estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER-2) negative, meaning hormone therapy is generally not an effective treatment option, which correlates to a relatively poor prognosis. MBC was first recognized as a distinct pathological entity in 2000 by the World Health Organization.
Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells, which produce the hormone calcitonin. Medullary tumors are the third most common of all thyroid cancers and together make up about 3% of all thyroid cancer cases. MTC was first characterized in 1959.
Lung cancer staging is the assessment of the extent to which a lung cancer has spread from its original source. As with most cancers, staging is an important determinant of treatment and prognosis. In general, more advanced stages of cancer are less amenable to treatment and have a worse prognosis.
Lobular carcinoma in situ (LCIS) is an incidental microscopic finding with characteristic cellular morphology and multifocal tissue patterns. The condition is a laboratory diagnosis and refers to unusual cells in the lobules of the breast. The lobules and acini of the terminal duct-lobular unit (TDLU), the basic functional unit of the breast, may become distorted and undergo expansion due to the abnormal proliferation of cells comprising the structure. These changes represent a spectrum of atypical epithelial lesions that are broadly referred to as lobular neoplasia (LN).
Breast cancer classification divides breast cancer into categories according to different schemes criteria and serving a different purpose. The major categories are the histopathological type, the grade of the tumor, the stage of the tumor, and the expression of proteins and genes. As knowledge of cancer cell biology develops these classifications are updated.
Uterine clear-cell carcinoma (CC) is a rare form of endometrial cancer with distinct morphological features on pathology; it is aggressive and has high recurrence rate. Like uterine papillary serous carcinoma CC does not develop from endometrial hyperplasia and is not hormone sensitive, rather it arises from an atrophic endometrium. Such lesions belong to the type II endometrial cancers.
Sebaceous carcinoma, also known as sebaceous gland carcinoma (SGc), sebaceous cell carcinoma, and meibomian gland carcinoma, is an uncommon malignant cutaneous (skin) tumor. Most are typically about 1.4 cm at presentation. SGc originates from sebaceous glands in the skin and, therefore, may originate anywhere in the body where these glands are found. SGc can be divided into 2 types: periocular and extraocular. The periocular region is rich in sebaceous glands making it a common site of origin. The cause of these lesions in the vast majority of cases is unknown. Occasional cases may be associated with Muir-Torre syndrome. SGc accounts for approximately 0.7% of all skin cancers, and the incidence of SGc is highest in Caucasian, Asian, and Indian populations. Due to the rarity of this tumor and variability in clinical and histological presentation, SGc is often misdiagnosed as an inflammatory condition or a more common neoplasm. SGc is commonly treated with wide local excision or Mohs micrographic surgery, and the relative survival rates at 5 and 10 years are 92.72 and 86.98%, respectively.
Lymphovascular invasion is the invasion of a cancer to the blood vessels and/or lymphatics.
Carcinoma of the tonsil is a type of squamous cell carcinoma. The tonsil is the most common site of squamous cell carcinoma in the oropharynx. It comprises 23.1% of all malignancies of the oropharynx. The tumors frequently present at advanced stages, and around 70% of patients present with metastasis to the cervical lymph nodes. . The most reported complaints include sore throat, otalgia or dysphagia. Some patients may complain of feeling the presence of a lump in the throat. Approximately 20% patients present with a node in the neck as the only symptom.
Invasive cribriform carcinoma of the breast (ICCB), also termed invasive cribriform carcinoma, is a rare type of breast cancer that accounts for 0.3% to 0.6% of all carcinomas in the breast. It originates in a lactiferous duct as opposed to the lobules that form the alveoli in the breasts' mammary glands. ICCB was first described by Dixon and colleagues in 1983 as a tumor that on microscopic histopathological inspection had a cribriform pattern, i.e. a tissue pattern consisting of numerous "Swiss cheese"-like open spaces and/or sieve-like small holes. The latest edition (2019) of the World Health Organization (2019) termed these lesions invasive cribriform carcinomas indicating that by definition they must have a component that invades out of their ducts of origin into adjacent tissues. In situ ductal cancers that have a cribriform histopathology are regarded as belonging to the group of ductal carcinoma in situ tumors.
Pure apocrine carcinoma of the breast (PACB) is a rare carcinoma derived from the epithelial cells in the lactiferous ducts of the mammary gland. The mammary gland is an apocrine gland. Its lactiferous ducts have two layers of epithelial cells, a luminal layer which faces the duct's lumen and a basal layer which lies beneath the luminal layer. There are at least four subtypes of epithelial cells in these ducts: luminal progenitor cells and luminal mature cells which reside in the luminal layer and mammary stem cells and basal cells which reside in the basal layer. Examination of the genes expressed in PACB cancer cells indicate that most of these tumors consist of cells derived from luminal cells but a minority of these tumors consist of cells derived from basal cells.
1 2 Milam EC, Rangel LK, Pomeranz MK (April 2021). "Dermatologic sequelae of breast cancer: From disease, surgery, and radiation". International Journal of Dermatology. 60 (4): 394–406. doi:10.1111/ijd.15303. PMID33226140. S2CID227134680.
↑ Mathis KL, Hoskin TL, Boughey JC, Crownhart BS, Brandt KR, Vachon CM, etal. (March 2010). "Palpable presentation of breast cancer persists in the era of screening mammography". Journal of the American College of Surgeons. 210 (3): 314–318. doi:10.1016/j.jamcollsurg.2009.12.003. PMID20193894.
↑ Yedjou, Clement G.; Sims, Jennifer N.; Miele, Lucio; Noubissi, Felicite; Lowe, Leroy; Fonseca, Duber D.; Alo, Richard A.; Payton, Marinelle; Tchounwou, Paul B. (2019). "Health and Racial Disparity in Breast Cancer". Breast Cancer Metastasis and Drug Resistance. Advances in Experimental Medicine and Biology. Vol.1152. pp.31–49. doi:10.1007/978-3-030-20301-6_3. ISBN978-3-030-20300-9. ISSN0065-2598. PMC6941147. PMID31456178.
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