Guided Studies W9/10 Flashcards
Define hypospadias, explaining the developmental cause of it.
Fusion of the urethral fold is incomplete, and abnormal openings of the urethra occur along the inferior aspect of the penis, usually near the glans, along the shaft, or
near the base of the penis. In rare cases the urethral meatus extends the scrotal raphe. When
fusion of the urethral fold fails entirely, a wide saggital slit is found along the entire length of the penis and the scrotum. The two scrotal swellings then closely resemble the labia major
Define epispadias, explaining the developmental cause of it. Which other genital defect is this associated with ?
Urethral meatus is found on the dorsum of the penis. Instead of developing at the cranial margin of the cloacal membrane, the genital tubercle seems to form in the region of the urorectal septum. Hence a portion of
the cloacal membrane is found cranial to the genital tubercle, and when this membrane ruptures, the outlet of the urogenital sinus comes to lie on the cranial aspect of the penis. Although epispadias may occur as an isolated defect, it is most often associated with exstrophy of the bladder.
Define exstrophy of the bladder, explaining the developmental cause of it.
(epispadias is a constant feature of it)
The bladder mucosa is exposed to the outside. Normally the abdominal wall in front of the bladder is formed by
primitive streak mesoderm, which migrates around the cloacal membrane. When the migration does not occur, rupture of the cloacal membrane extends cranially, creating exstrophy of the bladder.
Identify major congenital genital defects.
Female:
-Duplications of the uterus
Male:
- Hypospadias
- Epispadias
- Exstrophy of the bladder
- Eongenital inguinal hernia
- Hydrocele of the testis and/or spermatic cord
- Cryptochidism
Define duplication of the uterus, explaining the developmental cause of it and identify the main types of this.
Duplications of the uterus result from the lack of fusion of the paramesonephric ducts in a local area or throughout their normal line of fusion. In its extreme form the uterus is entirely double (uterus didelphys); in the least severe form, it is only slightly indented in the middle
(uterus arcuatus). One of the relatively common anomalies is the uterus bicornis, in which the uterus has two horns entering a common vagina.
Define congenital inguinal hernia, explaining the developmental cause of it.
The connection between the abdominal cavity and the processus vaginalis in the scrotal sac
normally closes in the first year after birth. If this passageway remains open, intestinal loops
may descend into the scrotum, causing a congenital inguinal hernia.
Explain how hydroceles of the testes and/or spermatic cord may arise developmentally.
The connection between the abdominal cavity and the processus vaginalis in the scrotal sac
normally closes in the first year after birth. Sometimes obliteration of this passageway is irregular, leaving small cysts along its course. Later these cysts may
secrete fluid, forming a hydrocele of the testis and/or spermatic cord.
What is the main cause of cryptorchidism ?
May be caused by decreased androgen (testosterone) production
Outline how CRISPR can edit DNA.
”
1) Clustered regularly interspaced short palindromic repeats, or CRISPRs, are repeating sequences found in the genetic code of bacteria. They are interspersed with ‘spacers’ — unique stretches of DNA that the bacteria grab from invading viruses, creating a genetic record of their malicious encounters.
2) On a repeat encounter with a virus, a bacterium can produce a stretch of RNA that matches the viral sequence, using the material in its spacer archive. This ‘guide RNA’ teams up with DNA-cutting Cas enzymes, encoded by nearby CRISPR-associated genes, to seek out and ‘cleave’ the matching viral sequences, stopping the virus from replicating.
3) By engineering the guide RNA, researchers can programme Cas enzymes — most commonly Cas9 — to match the DNA at specific sites that they want to cut in a cell’s genome. This triggers a DNA repair that can result in precise sequence changes to the gene of interest.”
Discuss 7 separate ethical concerns around the introduction of genome editing.
♦ Non-maleficence: If policymakers do not consult people with disabilities and their families, the technology could be used unthinkingly, in ways that harm patients and society, today and in the future.
♦ Non-maleficence: Mutations that predispose to genetic disease, such as the sickle-cell mutation, confer population-level benefits, such as resistance to malaria. So editing out one disease could backfire by increasing the risk of another. She argues that very little is known about the potential benefits of other mutations associated with disease, and applying genome editing too freely could have unintended consequences.
♦ Slippery slope: Many people are concerned about where that line would be drawn. Although it may seem now that only a few, very severe conditions should be subject to gene editing, disability activists point out that the list of conditions considered as illnesses, and possibly subject to medical treatment, is expanding (e.g. obesity, predispoition to alcoholism)
♦ Beneficence: Accommodations originally intended for people with disabilities often end up benefiting everyone. For example, the development of closed captioning — subtitles for the hearing-impaired on television. Similarly, legislative mandates, such as the 1990 Americans with Disabilities Act in the United States, have helped to integrate people with disabilities into society — in workplaces, schools and other public spaces. As a result, the world is much more humane for everyone The idea that parents should edit out characteristics that are considered debilitating goes against this drive towards inclusion, Garland-Thomson warns, and could create a harsher social climate for everyone. The experience of disability, she adds, is universal; all people inevitably experience sickness, accidents and age-related decline. “At our peril, we are right now trying to decide what ways of being in the world ought to be eliminated
♦ Beneficence: People without disabilities consistently underestimate the life satisfaction of those with them. Although people with disabilities report a slightly lower overall quality of life than those without, the difference is small. One study3 found that half of people with serious disabilities ranked their quality of life as ‘good’ or ‘excellent’. People also overestimate how severely health affects their happiness compared with other factors, such as economic or social support.
♦ Autonomy: Pressure exists to make women who carry a child with an abnormality (e.g. Down’s Syndrome) terminate their pregnancy. This is troubling and that it could get worse if embryo editing were to become readily available. “Women should not be given the responsibility of ensuring the genetic fitness of their children based on lack of support for children with disabilities.”
♦ Inequality: And if it were adopted, the technology would almost certainly be applied unevenly around the world. Aleksa Owen, a sociologist at the University of Illinois at Chicago, predicts that genome editing would be used first in countries that approve of and support assisted reproductive technologies, such as the United Kingdom, some other European Union countries, China and Israel. But it would probably be too expensive for many people in developing countries.
Describe the histological appearance of small follicles.
Small follicles = primordial follicles
They consist of a large oocyte surrounded by a layer of flattened follicular cells (refer to http://141.214.65.171/Histology/Female%20Reproductive%20System/239_HISTO_40X.svs/view.apml?X=0.0679240044988367&Y=-0.0432043349683487&zoom=75)
Describe the histological appearance of medium follicles.
Medium follicles = primary follicles
Large oocyte is surrounded by a layer of cuboidal follicular cells. These follicular cells proliferate to form a loose multi-layer, the granulosa cell layer. A rim of neutral glycoprotein, the zona pellucida (clear zone), surrounds the oocyte separating it from the surrounding granulosa cells (refer to http://141.214.65.171/Histology/Female%20Reproductive%20System/239_HISTO_40X.svs/view.apml?X=0.234444232680326&Y=0.350062709638043&zoom=75)
Describe the histological appearance of large follicles.
Large follicles = pre-ovulatory follicles
With continued development, the follicle becomes a Graafian or ovulatory follicle. The granulosa zone now consists of many layers of cuboidal follicular epithelial cells located at the periphery of the large, well-formed follicular antrum. The oocyte has attained its full size, is located eccentrically within the follicle in a small hillock, the cumulus oophorus which protrudes into the antrum. The zona pellucida is surrounded by a continuous layer of follicular cells, the corona radiata. The theca interna is separated from the granulosa cells by a distinct basement membrane (refer to http://141.214.65.171/Histology/Female%20Reproductive%20System/Extra%20Slides/269-2_HISTO_40X.svs/view.apml?X=0.168370491899853&Y=0.0912543984633872&zoom=17.5)
Describe the histological appearance of the corpus luteum.
Appears pale and very folded. Inner granulosa lutein cells (formed from the remaining granulosa cells) and outer theca lutein cells (come from the remaining theca interna cells). Both cell types are filled with lipid droplets and have centrally located nuclei. The theca lutein cells are, however, considerably smaller, more darkly staining and have fewer lipid filled vacuoles than the granulosa lutein cells. They are found most prominently in the infoldings right up against the granulosa lutein layer. Granulosa lutein cells contain a pigment, lipochrome, which produces the yellowish color of the corpus luteum in an unfixed ovary.
Describe the histological appearance of the endometrium in the proliferative phase.
Glands have proliferated and cover the surface. Spiral arteries are elongated and convoluted, and extend from the basal layer into the functional layer.
Describe the histological appearance of the endometrium in the secretory/ischemic phase.
The glands of the secretory phase endometrium appear convoluted. Toward the end of this phase, apical tissues become ischemic and glands take on a characteristic “saw tooth” appearance. The endometrium reaches its maximal thickness during this period, and spiral arteries continue to grow and extend into the superficial regions of the functional layer. There is also considerable leukocyte infiltration in the stroma
Describe the histological appearance of the endometrium in the menstrual phase.
Much of the stratum functionalis has sloughed away, and amongst the debris are numerous blood cells (RBCs and leukocytes). The stratum basalis remains intact.
Describe the role of genes in the development of breast cancer.
Mutated BRCA1 and BRCA2 genes predispose women to breast and ovarian cancer (particularly BRCA2)
If the mother had one faulty copy and one normal copy of one of these genes, resulting children will have 1/2 chances of inheriting the faulty gene.
Having relatives with breast cancer (despite lack of mutations in BRCA1/2) increases risk of breast cancer.
Examine the role of the genetic services in providing risk assessment, diagnosis, management options and genetic testing in the Scottish context (for breast cancer).
- Risk assessment: Based on familial history. e.g. if mother had breast cancer but at old age that is less likely to be due to a BRCA1/2 inherited mutation. However, given that there is still some family history (esp if first degree relative), likely increased risk of breast cancer. Blood test can be performed to test for presence of faulty genes, if high risk. MRI can also be performed if positive for the mutations.
- Diagnosis/Screening: mammograms
- Management options: prophylactic mastectomy + prophylactic salpingo oophorectomy
How can breast cancer be spread ?
Breast cancer can spread by:
a) Direct invasion e.g. to the skin, to pectoralis major or minor or to serratus anterior.
b) Lymphatic system to axillary and supraclavicular nodes.
c) Blood (haematogenic) via intercostal veins to the vertebral venous plexus and to vertebral bodies.
Describe lymphatic drainage of the breast.
1) Nipple, areola, and breast lobules drain to the subareolar lymphatic plexus. From here, approximately 75% of lymph drains to the axillary nodes - the axillary nodes consist of the pectoral (anterior), humeral (lateral), subscapular (posterior), central, and apical nodes. The remainder (particularly from the medial half of the breast) drains to the parasternal nodes, or to the opposite breast.
2) The inferior part of the breast may drain to the abdominal nodes. Many of these nodes are not readily palpable on examination but on examination you can, and should, examine the pectoral (anterior), humeral (lateral), subscapular (posterior), and supraclavicular lymph nodes.
How many levels of lymph nodes are there in the axilla ? What does this mean ?
There are three levels of lymph nodes in the axilla. You will often hear the axillary nodes being referred to as level I, II or III nodes in relation to treatment of axillary spread of breast cancer.
Identify the level 1, 2, and 3 lymph nodes in the axilla. How many are there of each level ?
- The nodes that lie lateral to pectoralis minor are level I nodes.
- Level II (central nodes) lie posterior to pectoralis minor
- Level III (apical nodes) lie medial to pectoralis minor.
There are on average 20 nodes in the axilla, with about 13 nodes at level I, five at level II, and two at level III. The drainage from level I nodes passes onto level II and onto level III.
Which breast nodes are palpable, and which are not ?
The parasternal nodes (draining the medial portion of the breast) are inaccessible to clinical examination.
The axillary lymph nodes (draining the central and lateral portions of the breast) may be palpable if enlarged due to inflammatory reaction or malignant infiltration. There are 5 groups of axillary lymph nodes but the number of nodes present and their distribution are in fact highly variable.
What are the main predictors of survival of breast cancer ?
1) The presence or absence of tumour in the axillary lymph nodes (initial site of metastatic spread of cancer) is the single best predictor of survival of breast cancer, and important treatment decisions are based on it.
Other predictors of survival:
-number of nodes involved
-level (I, II or III) of nodal involvement
At diagnosis, what proportion of breast cancer patients will have metastatic spread to lymph nodes ?
At diagnosis 40% of breast cancer patients will have metastatic spread to lymph nodes.
What are the main methods used to confirm or exclude metastatic spread of tumour to axillary nodes ? Which is the most recent of the three ?
1) Axillary clearance
2) Axillary node sampling
3) Sentinel lymph node biopsy (most recent of the three)
Describe the method of axillary clearance for confirmation/exclusion of metastatic spread of tumour to axillary nodes ?
AXILLARY CLEARANCE
Removal of all of the axillary nodes (axillary clearance), followed by pathological examination of the removed nodes.
What are the main issues associated with axillary clearance as a method to confirm/exclude metastatic spread of tumors to axillary nodes ?
1) In 60% of women the axillary nodes were found to be free of tumour (therefore the procedure may not have been necessary).
2) Involves a significant stay in hospital (5–7 days) and can be complicated by difficulties moving the shoulder following nerve damage, infection, numbness, and lymphoedema (swelling of the arm, caused by accumulation of lymphatic fluid).
What proportion of women who undergo axillary node clearance develop lymphoedema ?
10-20%
Describe the method of axillary node sampling for confirmation/exclusion of metastatic spread of tumour to axillary nodes ?
Involves removal of four level I nodes from the lower axilla. If any of the nodes are found to contain tumour then an axillary clearance is performed or radiotherapy is given. This procedure may be augmented by the use of a blue dye. This procedure is not common and now patients are more likely to have a sentinel lymph node biopsy (SLNB).
Describe the method of SLNB for confirmation/exclusion of metastatic spread of tumour to axillary nodes ?
LNB helps to ascertain if it is necessary to perform an axillary clearance and helps in planning of further therapy. It can also provide prognostic information about the patient’s survival and tumour recurrence. The theory behind SLNB is that cells from the primary tumour are likely to spread to the first node to receive lymph from the involved area. This node is known as the sentinel node. SLNB involves the use of a radioactive tracer (technetium-99m) and a blue dye. Prior to surgery, breast tissue around a tumour is injected with a small amount of radioactive fluid which migrates to the sentinel node over minutes to hours. During surgery, a blue dye is then injected into the breast tissue close to the tumour. This will also track to the sentinel node.
The sentinel node is then detected via a radiation detection probe (gamma sensor). A small incision is made in the skin at the site of the sentinel node and the node should also have turned blue, this is used for visual confirmation of the sentinel node. After identification, the node is removed and examined. If the sentinel node is free of tumour then removal of the remaining lymph nodes is not necessary.
What are the pros and cons of using SLNB as a method to confirm/exclude metastatic spread of tumour to axillary nodes ?
PROS
- Usually takes less time to perform than axillary clearance
- Less painful
- Associated with a shorter recovery period
- Less invasive than both axillary clearance and axillary node sampling
- Accuracy is comparable or better to that of axillary clearance
- The false- negative rate (cases in which no cancer cells are found in the sentinel lymph node but are in fact present in “downstream” nodes) is less than 5%.
CONS
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What is the management if axillary nodes are involved in the breast cancer ?
If axillary nodes are involved in the cancer then treatment involves radical radiotherapy or a level III axillary clearance (removal of level I, II and III nodes).
Identify other investigations which can bring further information on the extent of spread of the breast cancer (other than the axillary clearance, axillary node sampling, and SNLB).
Depending on the history and the results of the biopsy, certain imaging tests can be used to provide further information (chest x-ray, mammograms of both breasts, bone scans, computed tomography (CT) scans, magnetic resonance imaging (MRI), and/or positron emission tomography (PET) scans). Blood tests may also be used to evaluate overall health and help find out if the cancer has spread to certain organs.
Identify common sites of metastases for breast cancer.
Common sites of metastases are the bones, lungs, and liver. It also can spread to the brain and adrenal glands.
What type of cancers are breast cancers generally ? Where may these invade ?
Almost all breast cancers originate in epithelial tissue. Most breast cancers are adenocarcinomas (they develop from epithelial tissue, therefore are carcinomas, but most will also have glandular components and so are adenocarcinomas). Most cancers of the breast originate in the terminal ducts. The resultant cancers are known as ductal carcinoma in situ or lobular carcinoma in situ.
Either of these can invade the basement membrane and become invasive cancers.
