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Signet-Ring Cell Carcinoma of Stomach

Last updated Nov. 29, 2018

Approved by: Krish Tangella MD, MBA, FCAP

Signet-Ring Cell Carcinoma (SRCC) of Stomach is a histological variant of gastric carcinoma, which is a type of common stomach cancer.


What are the other Names for this Condition? (Also known as/Synonyms)

  • Gastric Signet-Ring Cell Carcinoma
  • Gastric SRCC
  • SRCC of Stomach

What is Signet-Ring Cell Carcinoma of Stomach? (Definition/Background Information)

  • Signet-Ring Cell Carcinoma (SRCC) of Stomach is a histological variant of gastric carcinoma, which is a type of common stomach cancer. The tumor is diagnosed under a microscope, on examination of the cancer cells by a pathologist
  • SRCC is a subtype of poorly-cohesive carcinoma that is composed almost only of signet-ring cells. The carcinoma may be also described as a poorly-differentiated mucin-producing adenocarcinoma
  • The carcinoma develops under the influence of several genetic and environmental factors. However, the exact cause of Signet-Ring Cell Carcinoma of Stomach is generally unknown
  • Gastric carcinomas are believed to be strongly associated with untreated long-term Helicobacter pylori stomach infection, certain genetic defects, and food and lifestyle factors. Some cases may be associated with a variety of genetic syndromes too
  • The signs and symptoms of Signet-Ring Cell Carcinoma of Stomach may include abdominal pain, bleeding from the rectum, fatigue, and unexplained weight loss. Complications, such as tumor metastasis to lymph nodes and distant sites, are known to occur
  • The mainstay of treatment is surgical excision of the tumor, during the early stages. However, in many cases a combination of treatment measures that include surgery, chemotherapy, and radiation therapy may be necessitated
  • The prognosis of Signet-Ring Cell Carcinoma of Stomach is generally poor, since in many cases, these tumors are diagnosed at a later stage, when metastasis has already taken place. However, if the tumor is diagnosed early and treated accordingly, the prognosis can be improved

Who gets Signet-Ring Cell Carcinoma of Stomach? (Age and Sex Distribution)

  • Signet-Ring Cell Carcinoma of Stomach is a malignant tumor that is generally seen in adults over 30 years of age. Study reports indicate that between 9-14% (up to 30% in some regions/nations) of all gastric cancers belong to the SRCC type
  • Both males and females are affected. Many reports indicate that usually women of a younger age are affected by SRCC of Stomach
  • When children and young adults are affected, it is mostly seen in the background of a predisposing factor such as an inherited genetic disorder
  • All races and ethnic groups are at risk for the condition; although, a higher number of cases are reported among the Asian, African, Hispanic, Pacific Islander, and Native Alaskan populations
  • The geographical distribution of the malignancy varies widely from one region to another

The incidence of Gastric Signet-Ring Cell Carcinoma is increasing in certain geographical regions, such as parts of Asia, Europe, and United States of America, even as the overall stomach cancer incidence is decreasing. Research study informs that the increase was about 10-times between the years 1970 to 2000. However, this is somewhat believed to be due to a change in WHO classification of SRCC carcinoma.

What are the Risk Factors for Signet-Ring Cell Carcinoma of Stomach? (Predisposing Factors)

In general, the risk factors for Signet-Ring Cell Carcinoma of Stomach may include the following:

  • Longstanding, untreated stomach infection by bacterium Helicobacter pylori is the most important predisposing factor
  • Autoimmune gastritis: It is an immune-based, non-infectious inflammation of the stomach (gastritis), as a result of antibodies (auto- or self- antibodies) produced in the body, for unknown reason
  • Presence of precursor or premalignant lesions can be a significant risk factor: These are conditions that increase the risk of development of invasive carcinomas. Recognizing these conditions on a tissue biopsy is very helpful in early diagnosis of invasive carcinoma
  • Smoking: Studies have shown that the carcinogens in tobacco smoke and Helicobacter pylori infection may interact with each other to substantially increase the risk of development of stomach cancer
  • Diet: Consuming high amounts of salted and/or smoked foods; low vegetable/fruit intake, especially in the background of H. pylori infection. In some individuals, a high intake of all types of meat is a risk factor
  • Increase in bile reflux (bile backing-up from the liver) is noted 5-10 years after gastric surgery (Bilroth operation), which may increase the risk for stomach cancer
  • Certain genetic syndromes/disorders such as Li-Fraumeni syndrome, Juvenile polyposis syndrome, Peutz-Jeghers syndrome, Cronkhite-Canada syndrome, etc. may increase the risk

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Signet-Ring Cell Carcinoma of Stomach? (Etiology)

The exact cause and mechanism of Signet-Ring Cell Carcinoma of Stomach formation, in a majority of cases, is unknown. The malignancy exhibits changes at the genetic level that involves certain oncogenes and tumor-suppressor genes, including DNA repair system. Moreover, the influence of certain environmental factors towards formation of the carcinoma has been documented.

Infection due to Helicobacter pylori:

  • Helicobacter pylori infection, when present for long duration, usually several decades, is the most important factor responsible for the formation of gastric carcinoma (affecting the distal stomach)
  • Adequate treatment and cure of H. pylori infection through administration of antibiotics are known to significantly decrease the risk of formation of stomach cancer

Genetic abnormalities:

  • Damage to DNA is noted with Helicobacter pylori infection. It also interferes with the function of certain tumor-suppressing genes and oncogenes
  • Microsatellite instability (MSI): It occurs due to abnormalities in DNA mismatch repair (MMR) system. High levels of MSI (MSI-H) are seen in cases that involve the antral region of stomach (lower part, nearer to duodenum)
  • Germline mutations involving CDH1 gene has been specifically noted in Gastric SRCC

Gastric cancer risk is higher in the background of certain autosomal dominant (inherited) disorders including familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome (PJS), and Li-Fraumeni syndrome.

What are the Signs and Symptoms of Signet-Ring Cell Carcinoma of Stomach?

The signs and symptoms of Signet-Ring Cell Carcinoma of Stomach may include the following:

  • Small-sized tumors may not exhibit any signs and symptoms
  • Large tumors (size over 4 cm) can compress the surrounding structures or organs
  • Loss of appetite; feeling full after a light meal
  • Vomiting (sometimes with blood), nausea
  • Abdominal pain and discomfort
  • Gastrointestinal (GI) bleeding may occur
  • Blood in stool resulting in anemia
  • Presence of dark tarry stools
  • Irregular bowel movements; diarrhea or constipation
  • Abdominal distension/bloating/enlargement
  • Gastric obstruction may occur due to large-sized tumors
  • Ulceration of the tumor mass
  • Unintended loss of weight
  • Bleeding can occur within large tumors; hemorrhage within the tumors can lead to tissue death (or infarction)
  • Signs and symptoms of any underlying genetic disorder, if any present, may be noted

The following tumor characteristics may be observed (following its diagnosis):

  • Early gastric cancer affects the mucosal and/or submucosal layers of the stomach
  • Lymph node involvement may or may not be seen with early forms
  • The average tumor size is between 2-5 cm
  • They can progress within a few months or over many years (to advanced stages), in the absence of treatment
  • Most tumors belong to the superficial type - that may be described as flat, elevated, or depressed (constitute most of the cases)
  • The depressed superficial tumor types have a greater risk for lymph node metastasis and deep wall (submucosal) penetration
  • Tumors may be also described as fungating type or ulcerating type (many of the tumors)

How is Signet-Ring Cell Carcinoma of Stomach Diagnosed?

A diagnosis of Signet-Ring Cell Carcinoma of Stomach may involve the following tests and procedures:

  • Complete physical exam with evaluation of medical history
  • Ultrasound scan of the stomach/abdomen: It is a non-invasive procedure that uses high frequency sound waves to produce real-time images
  • Abdominal CT scan: It is a noninvasive procedure that provides more details of soft tissues, blood vessels, and internal organs
  • Stool sample analysis
  • Upper GI endoscopy: An endoscopic procedure is performed using an instrument called an endoscope, which consists of a thin tube and a camera. Using this technique, the radiologist can have a thorough examination of the insides of the gastrointestinal tract
  • Chromoendoscopy can help detect small-sized tumors; small tumors can also be detected using narrow band imaging technique
  • Esophagogastroduodenoscopy (EGD): It is a procedure to check the linings of the esophagus, stomach, and duodenum. Through this procedure, biopsies may be performed at the same time. It is generally preferred for evaluating individuals with suspected stomach cancer
  • Vascular angiographic studies of the tumor
  • Exploratory laparoscopy (diagnostic laparoscopy) may be required, if gastrointestinal symptoms are present. In this procedure, the abdomen is examined using a minimally-invasive technique, and a tissue biopsy and tissue for culture obtained

Although the above modalities can be used to make an initial diagnosis, a tissue biopsy of the tumor is necessary to make a definitive diagnosis to begin treatment. The tissue for diagnosis can be procured in multiple different ways which include:

  • Endoscopic fine needle aspiration (FNA) biopsy of the tumor: An endoscopic FNA biopsy may not be helpful, because one may not be able to visualize the different morphological areas of the tumor. Hence, a FNA biopsy as a diagnostic tool has certain limitations, and an open surgical biopsy is preferred
  • Core biopsy of the tumor
  • Open biopsy of the tumor

Tissue biopsy:

  • A tissue biopsy of the tumor is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
  • Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
  • The tumors may have varying proportions of blood vessels, smooth muscle, and fat cells, when examined by a pathologist under a microscope
  • Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, molecular testing, and very rarely, electron microscopic studies to assist in the diagnosis

Note: A differential diagnosis, to eliminate other tumor types is considered, before arriving at a definitive diagnosis.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Signet-Ring Cell Carcinoma of Stomach?

The complications of Signet-Ring Cell Carcinoma of Stomach are dependent upon the size of the tumor and may include:

  • Large tumor masses may get secondarily infected with bacteria or fungus
  • Stress and anxiety due to fear of stomach cancer
  • Perforation of the stomach due to presence of infiltrative tumors
  • Involvement of local and distant lymph nodes is noted in many cases
  • Metastasis: Spread of the cancer can occur to the peritoneal cavity (termed peritoneal dissemination); or, to organs nearby such as lungs and liver (and the ovary and uterine cervix in women). The tumor spreads via the vascular system (blood)
  • Complications due to an underlying genetic disorder, if any present
  • Side effects of chemotherapy (such as toxicity) and radiation
  • Recurrence of the tumor following treatment
  • Damage to the muscles, vital nerves, and blood vessels, during surgery
  • Post-surgical infection at the wound site is a potential complication

How is Signet-Ring Cell Carcinoma of Stomach Treated?

The staging system most often used for stomach cancer is the American Joint Committee on Cancer (AJCC) TNM system, which is based on 3 key pieces of information:

  • The extent (size) of the tumor (T): How far has the cancer grown into the 5 layers of the stomach wall? Has the cancer reached nearby structures or organs?
  • The spread to nearby lymph nodes (N): Has the cancer spread to nearby lymph nodes?
  • The spread (metastasis) to distant sites (M): Has the cancer spread to distant lymph nodes or distant organs such as the liver or lungs?

Numbers or letters after T, N, and M provide more details about each of these factors. Higher numbers mean the cancer is more advanced. Once a person’s T, N, and M categories have been determined, this information is combined in a process called stage grouping to assign an overall stage.

Stage 0: Tis, N0, M0

  • There is high grade dysplasia (very abnormal looking cells) in the stomach lining
  • OR, there are cancer cells only in the top layer of cells of the mucosa (innermost layer of the stomach) and have not grown into deeper layers of tissue such as the lamina propria (Tis). This stage is also known as carcinoma in situ (Tis)
  • It has not spread to nearby lymph nodes (N0) or distant sites (M0)

Stage IA: T1, N0, M0

  • The tumor has grown from the top layer of cells of the mucosa into the next layers below such as the lamina propria, the muscularis mucosa, or submucosa (T1)
  • It has not spread to nearby lymph nodes (N0) or to distant sites (M0)

Stage IB:

T1, N1, M0

  • The cancer has grown from the top layer of cells of the mucosa into the next layers below such as the lamina propria, the muscularis mucosa, or submucosa (T1), AND it has spread to 1 to 2 nearby lymph nodes (N1)
  • It has not spread to distant sites (M0)

OR

T2, N0, M0

  • The cancer is growing into the muscularis propria layer (T2)
  • It has not spread to nearby lymph nodes (N0) or to distant sites (M0)

Stage IIA:

T1, N2, M0

  • The cancer has grown from the top layer of cells of the mucosa into the next layers below such as the lamina propria, the muscularis mucosa, or submucosa (T1), AND it has spread to 3 to 6 nearby lymph nodes (N2)
  • It has not spread to distant sites (M0)

T2, N1, M0

  • The cancer is growing into the muscularis propria layer (T2), AND it has spread to 1 to 2 nearby lymph nodes (N1), but not to distant sites (M0)

T3, N0, M0

  • The cancer is growing into the subserosa layer (T3)
  • It has not spread to nearby lymph nodes (N0) or to distant sites (M0)

Stage IIB:

T1, N3a, M0

  • The cancer has grown from the top layer of cells of the mucosa into the next layers below such as the lamina propria, the muscularis mucosa, or submucosa (T1), AND it has spread to 7 to 15 nearby lymph nodes (N3a)
  • It has not spread to distant sites (M0)

OR

T2, N2, M0

  • The cancer is growing into the muscularis propria layer (T2), AND it has spread to 3 to 6 nearby lymph nodes (N2)
  • It has not spread to distant sites (M0)

T3, N1, M0

  • The cancer is growing into the subserosa layer (T3), AND it has spread to 1 to 2 nearby lymph nodes (N1), but not to distant sites (M0)

OR

T4a, N0, M0

  • The tumor has grown through the stomach wall into the serosa, but the cancer has not grown into any of the nearby organs or structures (T4a)
  • It has not spread to nearby lymph nodes (N0) or to distant sites (M0)

Stage IIIA:

T2, N3a, M0

  • The cancer is growing into the muscularis propria layer (T2), AND it has spread to 7 to 15 nearby lymph nodes (N3a)
  • It has not spread to distant sites (M0)

OR

T3, N2, M0

  • The cancer is growing into the subserosa layer (T3), AND it has spread to 3 to 6 nearby lymph nodes (N2)
  • It has not spread to distant sites (M0)

OR

T4a, N1, M0

  • The cancer has grown through the stomach wall into the serosa, but it has not grown into any of the nearby organs or structures (T4a)
  • It has spread to 1 to 2 nearby lymph nodes (N1) but not to distant sites (M0)

OR

T4a, N2, M0

  • The cancer has grown through the stomach wall into the serosa, but it has not grown into any of the nearby organs or structures (T4a)
  • It has spread to 3 to 6 nearby lymph nodes (N1), but not to distant sites (M0)

OR

T4b, N0, M0

  • The cancer has grown through the stomach wall and into nearby organs or structures (T4b)
  • It has not spread to nearby lymph nodes (N0) or to distant sites (M0)

Stage IIIB:

T1, N3b, M0

  • The cancer has grown from the top layer of cells of the mucosa into the next layers below such as the lamina propria, the muscularis mucosa, or submucosa (T1), AND it has spread to 16 or more nearby lymph nodes (N3b)
  • It has not spread to distant sites (M0)

OR

T2, N3b, M0

  • The cancer is growing into the muscularis propria layer (T2), AND it has spread to 16 or more nearby lymph nodes (N3b)
  • It has not spread to distant sites (M0)

OR

T3, N3a, M0

  • The cancer is growing into the subserosa layer (T3), AND it has spread to 7 to 15 nearby lymph nodes (N3a)
  • It has not spread to distant sites (M0)

OR

T4a, N3a, M0

  • The cancer has grown through the stomach wall into the serosa, but it has not grown into any of the nearby organs or structures (T4a), AND it has spread to 7 to 15 nearby lymph nodes (N3a)
  • It has not spread to distant sites (M0)

OR

T4b, N1, M0

  • The cancer has grown through the stomach wall and into nearby organs or structures (T4b)
  • It has spread to 1 to 2 nearby lymph nodes (N1), but not to distant sites (M0)

OR

T4b, N2, M0

  • The cancer has grown through the stomach wall and into nearby organs or structures (T4b)
  • It has spread to 3 to 6 nearby lymph nodes (N1), but not to distant sites (M0)

Stage IIIC:

T3, N3b, M0

  • The cancer is growing into the subserosa layer (T3), AND it has spread to 16 or more nearby lymph nodes (N3b)
  • It has not spread to distant sites (M0)

OR

T4a, N3b, M0

  • The cancer has grown through the stomach wall into the serosa, but it has not grown into any of the nearby organs or structures (T4a), AND it has spread to 16 or more nearby lymph nodes (N3b)
  • It has not spread to distant sites (M0)

OR

T4b, N3a, M0

  • The cancer has grown through the stomach wall and into nearby organs or structures (T4b), AND it has spread to 7 to 15 nearby lymph nodes (N3a)
  • It has not spread to distant sites (M0)

OR

T4b, N3b, M0

  • The cancer has grown through the stomach wall and into nearby organs or structures (T4b), AND it has spread to 16 or more nearby lymph nodes (N3b)
  • It has not spread to distant sites (M0)

Stage IV:

Any T, Any N, M1

  • The cancer can grow into any layers (Any T) and might or might not have spread to nearby lymph nodes (Any N).
  • It has spread to distant organs such as the liver, lungs, brain, or the peritoneum (the lining of the space around the digestive organs) (M1)

The staging system described above uses the pathologic stage, which is determined by examining tissue removed during an operation. This is also known as surgical staging. This is likely to be more accurate than clinical staging, which takes into account the results of a physical exam, biopsies, and imaging tests, done before surgery. The clinical stage will be used to help plan treatment.

(Source: Stomach Cancer Stages, December 2017, provided by the National Cancer Institute at the National Institutes of Health; U.S. Department of Health and Human Services)

The treatment measures for Signet-Ring Cell Carcinoma of Stomach may include the following:

  • Endoscopy:
    • When the tumor is confined to the surface, then endoscopic mucosal/submucosal resection (or surgical removal via endoscopy) is undertaken
    • Individuals with tumors less than 2 cm in size affecting the submucosa, and showing no involvement of the lymph/vascular system, are candidates for endoscopic resection
  • Gastrectomy or surgery to remove part (or all) of the stomach, termed subtotal (partial) gastrectomy or total gastrectomy respectively
  • Aggressive lymphadenectomy, or surgery to remove lymph nodes, is proposed when several lymph nodes are affected
  • Feeding tube placement into the intestine, called jejunostomy (or J tube placement)

If the tumor has metastasized, then a combination of chemotherapy, radiation therapy, and invasive procedures may be used to treat the tumor.

  • Chemotherapy: This approach uses a combination of drugs to kill the cancerous cells and can be used in patients, for all stages of the tumor
    • There can be severe side effects including fatigue, nausea, hair loss, anemia, high risk of infection, and drug-specific reactions
    • Chemotherapy can be administered as a pill, liquid, shot, or intravenously
  • Radiation: Radiation therapy is the use of high-energy radiation waves to kill cancer cells, by destroying their DNA
    • This treatment modality may be used in combination with chemotherapy
    • The radiation may be administered by a machine placed outside the body, or by placing a radioactive material inside the body
    • The side effects of radiation therapy include nausea, vomiting, fatigue, pain, risk of cancer later in life, and risk of heart disease
    • Radiation can damage healthy cells in addition to cancer cells, causing further complications
  • Supportive treatment: Steroids, blood transfusions, anti-nausea medications, and antibiotics, may be used as supportive therapy. In combination with other treatment measures, these can help combat the symptoms of immunodeficiency
  • Undertaking treatment of underlying inflammatory bowel diseases/genetic disorders, as necessary
  • Targeted drug therapy: Specific medications are administered periodically to stop tumor growth, particularly for advanced stages
  • Immunotherapy: A patient’s immune system is activated to combat the cancer in this kind of therapy
  • Palliative care is provided for advanced cancer stages, which includes palliative surgery: In majority, diagnosis occurs after lymph node metastasis, and hence, palliative surgical care is proposed
  • Follow-up care with regular screening and check-ups are very important and encouraged

How can Signet-Ring Cell Carcinoma of Stomach be Prevented?

Current medical research has not established a method of preventing both syndromic and non-syndromic forms of Signet-Ring Cell Carcinoma of Stomach. However, in case it is associated with genetic disorders, then the following may be considered:

  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

The following measures may be taken to lower the risk for Gastric Signet-Ring Cell Carcinomas:

  • Early and appropriate treatment of Helicobacter pylori infection
  • Bringing about certain lifestyle changes such as diet adjustments to reduce fatty food and caffeine intake, reduction of alcohol intake, and cessation of smoking
  • Consuming a diet that is rich in whole grains, vegetables, and fruits
  • Correcting any nutritional imbalances through adequate vitamin and mineral supplementation
  • Physical activities and regular exercising
  • In order to avoid a relapse, or be prepared for a recurrence, the entire diagnosis, treatment process, drugs administered, etc. should be well-documented and follow-up measures initiated
  • Use of certain antioxidant supplements, such as minerals (selenium) and vitamins A, C, and E, in case of any nutritional-deficiency

Regular medical screening at periodic intervals with blood tests, scans, and physical examinations, are mandatory, due to its metastasizing potential and possibility of recurrence. Often several years of active vigilance is necessary.

What is the Prognosis of Signet-Ring Cell Carcinoma of Stomach? (Outcomes/Resolutions)

  • The prognosis of Signet-Ring Cell Carcinoma of Stomach is poor for advanced-stage tumors, when metastasis to the lymph nodes, peritoneum, uterine cervix, and ovary are noted. Early-stage stomach cancers may have a better prognosis with prompt and appropriate treatment
  • In general, the prognosis of Gastric Signet-Ring Cell Carcinoma depend upon a set of several factors, which include:
    • Stage of tumor: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
    • Grade of the tumor (whether high-grade or low-grade)
    • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
    • Age of the individual: Older individuals generally have poorer prognosis than younger individuals
    • The size of the tumor: Individuals with small-sized tumors fare better than those with large-sized tumors
    • Individuals with bulky disease may have a poorer prognosis
    • Involvement of vital organs may complicate the condition
    • The surgical resectability of the tumor (meaning, if the tumor can be removed completely)
    • Whether the tumor is occurring for the first time, or is a recurrent tumor. Recurring tumors have worse prognosis compared to tumors that do not recur
    • Response to treatment: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment
    • Progression of the condition makes the outcome worse
  • An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and delayed treatment
  • The combination chemotherapy drugs used, may have some severe side effects (such as cardio-toxicity). This chiefly impacts the elderly adults, or those who are already affected by other medical conditions. Tolerance to the chemotherapy sessions is a positive influencing factor

Additional and Relevant Useful Information for Signet-Ring Cell Carcinoma of Stomach:

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http://www.dovemed.com/diseases-conditions/cancer/

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Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: Nov. 29, 2018
Last updated: Nov. 29, 2018