Exam 1 Week 1 GU,breast Flashcards

Question

Cervix condition • Common, benign • Size: less than 3 cm • Can cause vaginal discharge, bleeding * Micro * See mucinous columnar epithelium * Thick-walled vessels • Cured by surgical excision

Answer 1

Endocervical polyp

Answer 2

• HPV cause of virtually all cases of cervical cancer • Condyloma- associated with low risk HPV(6,11) • Cancer- associated with high risk HPV - 15: high risk oncogenic HPV - 16: 60% cervical cancer - 18: 10%, also associated with endocervical adenocarcinoma Risk factors - cervical cancer • Early age at first intercourse; high parity • Multiple sexual partners • Smoking • Oral contraceptives • Male partner with multiple previous sexual partners • High risk HPV detected • HPV genital infection- very common • By age 50, 4 out of 5 women have been exposed • Most asymptomatic, cause no tissue damage and not detected on Pap test • Most infections are transient- 90% cleared within 2 years • Adolescents are especially vulnerable • Up to 60% infected - Professional groups do not recommend testing until age 21 • Often multiple types • Duration of infection related to HPV type • LONGEST WITH HIGH RISK TYPES • HPV 16 especially Persistence of HPV - crucial risk factor - If women negative for HPV, very low risk for development of cervical cancer

Answer 3

HPV - mode of infection • HPV loves immature squamous metaplastic cells • Sexual intercourse not required, can spread with skin-skin contact • Transformation zone very vulnerable • HPV cannot infect mature squamous cells- vagina, vulva - Can replicate in these once infection established ``` HPV Pathogenesis factors • Most women exposed to HPV, only few develop cancer • Multiple factors important to development of dysplasia & cancer - Immune status - Smoking - Nutrition - Other factors ``` * Once infection established, HPV replicates in mature squamous cells * Lead to koilocytic cells HPV- pathogenic factors A. HPV viral proteins- E6/E7 • Critical for oncogenic effect • Interacts with tumor suppressor genes Rb and p53 • Can test if women have integration of these B. Physical state of virus important • Cancer- integrated into chromosome • Dysplasia- exists as free viral DNA as episome

Answer 4

HPV testing 1. Four different FDA approved tests for HPV • Test for different targets of HPV virus • Measure either DNA or RNA • All are molecular tests with different methods of amplification 2. Several large clinical trials over a number of years have correlated presence/absence/copy number of HPV with development of high grade dysplasia 3. Tests for 12-14 high risk HPVs as a screen • One test (Cobas) approved for primary HPV screening • Do HPV test first, if positive, follow with Pap 4. If positive, then can do separate test for HPV 16 and 18 5. Due to the high prevalence of exposure, set a copy number of virus (approx 5000 copies) defined as cut-off for positive vs. negative • Less the 5000 copies= negative • Greater than 5000 copies= positive 6. This cut-off is set at the viral copy number at which there is increased risk of dysplasia 7. For example, a women could have 4000 copies of virus and would be reported as negative for HPV ; thus a negative does not mean no exposure 8. This is very different from other STD tests, such as Chlamydia/Gonorrhea where assays are designed to pick up any organism present HPV Vaccines • Vaccines now available • Approved for girls/women: 9-26 years • Boys- 9-26 • Only effective if given before exposure • Effective against 2, 4, or 9 types • Prevents approx. 70% of cervical cancer • All protect against 16 & 18

Answer 5

CIN (cervical intraepithelial neoplasia) Dysplasia Morphology • See increasing development of nuclear atypia, increased nuclear/cytoplasmic ratio • Often see koilocytosis Classification (Dysplasia morphology) • CIN 1- changes in lower 1/3 of epidermis (mild dysplasia) • CIN 2- changes in lower 2/3 of epidermis (moderate dysplasia) • CIN 3- changes involve entire layer (severe dysplasia/CIS) CIN 1- Mild dysplasia • Low grade • Can be associated with low risk HPV; Also seen with high risk HPV • Can spontaneously regress CIN 2- Moderate dysplasia • High grade • Associated with high risk HPV • More likely to progress CIN 3- Severe dysplasia/CIS • Associated with high risk HPV • More likely to progress to invasive carcinoma- if untreated Treatment • CIN1- most go away without treatment - 60%regress, 30% persist, 10% progress • CIN2- considered high grade, but may resolve • CIN3- severe/CIS- most likely to progress - HGSIL- 30% regress, 60% persist, 10% progress to cancer Cervical dysplasia - PROGNOSTIC FACTORS • Multiple factors determine progression of lesions • Not all related to HPV type • Lesion may enter at any point in sequence • Environmental & host factors important

Answer 6

PAP Smear **If it is BIG and DARK - DYSPLASIA

Answer 7

``` 1. Cervical Squamous Cell carcinoma • Peak incidence - 30’s; high grade dysplasia - 40’s; cervical cancer • Present in 3 forms - Fungating, ulcerating, infiltrative • Keratinizing or non-keratinizing ``` 2. Adenocarcinoma - arises from endocervical epithelium - precursor lesion; adenocarcinoma in situ

Answer 8

Definition: Laboratory test in which cells from the cervix and vagina of a female(rectum of male) are evaluated to look for cancerous or precancerous changes Overall Effectiveness 1. Prior to introduction of the Pap test, cancer of the cervix was the leading cause of cancer death in women.

Answer 9

1. Conventional papsmear Conventional (glass slide): use a plastic spatula to scrape cells from cervix; use brush inserted into cervical os to obtain cells from endocervical canal 2. Liquid based Pap smear - MORE ACCURATE DX sample can be obtained in the same manner, but placed in liquid in a vial, slide prepared from liquid in the laboratory - inflammation, blood can be removed prior to preparation of slide - additional test for HPV, Chlamydia, gonorrhea and others (HSV, Trichomonas) can be performed (out of the vial testing). **Thinprep, surepath

Answer 10

1. Assessment in lab A. Routine microscopy - cytotechnologist screens the slide - pathologist review slide if abnormal cells found B. Image guided analysis - Computer analyzes slide first, pick out most atypical cells - cytotechnologist reviews - PATHOLOGIST REVIES IF ATYPICAL CELLS FOUND 2. Image analysis prep - Imager scans the slide - Networked with motorized microscope - Moves to 22 fields that are most likely to contain atypical cells 3. Reporting * *BETHESDA REPORTING SYSTEM - specimen adequacy (satisfactorily or unsatisfactory) - general categorization (negative for CIN or malignancy, epithelial cell abnormality)

Answer 11

Epithelial cell abnormality 1. Squamous cell - atypical squamous cells of undertermined significance (ASCUS) - low grade squamous intraepithelial lesion (LSIL) - high grade squamous cell intraepithelial lesion (HSIL) - squamous cell carcinoma 2. Glandular cell - atypical glandular cells of undertermined significance (AGUS) - cervical adenocarcinoma in situ (AIS) - Adenocarcinoma

Answer 12

When considering performance characteristics of test, must look at natural history of cervical cancer - squamous cell cancer takes a long time to develop- more than 10 years, even up to 20 years - SCC usually preceded by dysplasia - most women with dysplasia never get cancer (most disappear without tx) - Only a tiny fraction of those infected with HPV develop cervical cancer and fewer still die of the disease - *However, because most cancers arise from high grade dysplasia, these must be detected and treated * *Due to above, the most meaningful way to look at performance of papsmear is - ABILITY TO PICK HIGH GRADE LESIONS - conventional pap; 50-70% sensitivity - liquid based ; 85% sensitivity - Liquid based plus high risk HPV; 100% sensitivity

Answer 13

1. Pap test is not perfect- can detect 50-90% precursor lesions - fails to detect 10-50% of significant lesions - adenocarcinoma on the rise, missed many of these lesions * **PARADOX- papsmear is less efficient in detecting INVASIVE CANCER than in finding preinvasive disease - UpTo 75% false negative for invasive cancer ; due to abundant blood and obscuring inflammation which is often present with invasive cancer along with poor sampling of actual cancer cells * *Problems in failure of test - sampling error - diagnosis error * Most important reason for failure - WOMEN WHO FAIL TO GET SCREENED NEXT STEP IS COLPOSCOPY

Answer 14

1. HPV (humanpapilloma virus) - family; papoviridae (papillomaviridae) - genome; circular, DS DNA - capsid; non - enveloped, icosahedral 2. HSV (herpes simplex virus) - family; herpetoviridae - genome; linear, DS DNA - capsid; enveloped, icosahedral 3. HIV complex virus (human immunodeficiency) - family; retroviridae - genome; Linear, SS RNA - capsid; enveloped 4. Hep B - family; hepadnaviridae - genome; circular, partially, DS DNA - capsid; enveloped, icosahedral In addition to these top ten viruses, other viruses can be transmitted at lower frequencies or rarely through sexual contact including: - Hepatitis C virus (Flavivirus), - Hepatitis D virus ( Deltavirus) - Hepatitis A virus ( Picornavirus) - Molluscum contagiosum virus (Poxvirus), - Cytomegalovirus and Human herpesvirus-8 (herpesviruses) - Human T Cell Leukemia virus-1 (retrovirus).

Answer 15

Like most viral diseases a variety of factors influence the ability of a virus to establish and maintain an infection in humans. Virulence of a virus and virus types relative to the human host is a primary consideration. Some types and subtypes are more virulent than others. The ability of the human host to thwart and control a viral infection is also important. Since the status of the immune system is paramount to controlling a virus infection, the integrity of natural and acquired immunity is key to protecting the host. Genetic factors of the human host play a role in susceptibility to infection to a particular virus. An individual, for example, may not be able to produce a cell surface receptor for a virus and therefore exhibits resistance to viral infection. In the context of viruses causing STDs additional factors can impact their infectivity. It has been recognized that if an individual has pre-existing lesions from another type of STD (syphilis for example) susceptibility to a viral induced STD is enhanced. The natural barriers of the skin or mucosal surface are impaired and offer little protection against virus infections. This is particularly the case for populations that receive poor medical care such as resource deprived countries. As stated relative to other discussions, viruses evade the immune system by a number of different mechanisms. One approach is that viruses can alter their antigencity as a result of mutations in those viral genes that encode key viral antigens. RNA viruses in particular, HIV being a good example, sustain mutations in the genes that encode gp120 - gp41 and p24 viral proteins. Pre-existing immunity against the original antigenic display may not be effective in neutralizing the altered form(s) of the virus. Recall that RNA viruses utilize a viral RNA polymerase or a reverse transcriptase (retrovirues) that lack proof reading features and mutations are not repaired. In addition some viruses, human papillomaviruses for example, exist as many different genotypes and infection by one type does not necessarily induce an immune response that protects the host from secondary infections by other types.

Answer 16

General - The members of the Papovaviridae cause a variety of human diseases. The family name Papova is an abbreviation for Papilloma (Pa), Polyoma (po) and Vacuolating (va , SV40) viruses. SV40 virus is the only papovavirus that has been extensively studied at the molecular level relative to its mechanisms for genome replication and viral protein synthesis. Virus/Host cell interactions - SV40 may cause one of two possible types of interactions with the host cells that they infect. SV40 can cause a lytic infection which results in the production of progeny virus. An alternative virus-host cell interaction results in transformation of the cell to cause foci formation in tissue culture and tumors in animals. (SV40 is an example of a DNA Tumor Virus) Lytic infection - SV40 binds to receptors on the surface of cells, enters the cell, the particle is uncontested to release the circular, double stranded DNA, into the nucleus of the cell. - As is the case for the other DNA viruses, a series of early events results in transcription of viral genomic DNA to form early mRNAs, which in turn translated in to early protein - Some of the early proteins are designated as large T or small t antigens - the early T and t antigens are REGULATORY PROTEINS and bind to viral DNA in order to initiate genomic replication - Following viral genome synthesis the newly replicated genomes are transcribed into late messenger RNAs, which are then translated into late (capsid) proteins of the virus. The virus assembles and the host cell is loses, thereby releasing infectious progeny virus Transformation - In this scenario, the initial stages of infection are the same but ONLY THE EARLY EVENTS OCCUR INCLUDING LIMITED VIRAL DNA REPLICATION - Late events, however DO NOT TAKE PLACE. - In addition, the viral genomes are integrated (provirus) into various locations within cellular DNA. From its integrated state the DNA is only transcribed to produce early mRNAs which are translated to form T and t antigens - T and t antigens interact with cell DNA to cause transformation of those cells (loss of contact inhibition, replicate with lower growth factor requirements may cause tumors) - Transformation requires nonpermissive cells, whereas lytic infection occurs in permissive cells - Although SV40 is an interesting replication prototype for the papovaviridae, other viruses within the family cause human disease

Answer 17

HPV (Human papillomaviruses) The majority of viruses in the Papovaviridae that cause human disease correspond to the 120 or more types (up to 170 in some references) of papilloma viruses. Some of these types are more common than others. These virus types have a predilection for infecting cells within human skin and mucosa. The infection in limited to cells of the skin and/or mucosa and a viremia does NOT developed. About 40 types of papillomavirus cause infections of the anogenital tract and are transmitted through sexual intercourse. ***HPV types 6,11, 16 and 18 are most common.

Answer 18

HPV types 6,11, 16 and 18 are most common. HPV 1 and 4 are commonly associated with plantar warts, whereas types 2, 3 and 10 cause warts on the knees and fingers. In addition to sexual transmission of papillomavirus infections, direct contact between individuals, one of which has a papillomavirus skin infections will cause the spread of the infection. In vivo papillomavirus infects cells of the basal layer of the skin, but viral replication only occurs in these cells as they differentiate into squamified and keratinized cells. The morphology of these infected cells is characterized by enlarged keratinocytes that appear to have a halo surrounding small nuclei. These latter cells designated as Koilocytes .(Note: Episomal viral DNA replication does occur in basal cells) Infected cells replicate over several months to form papillomas or warts. Depending on the papillomavirus type and the site of infection warts may assume different morphologies: - Filiform (Fibrous protrusions) - Flatten appearance (Plantar warts) - Cauliflower-like surface (condylomas or genital warts) - Dysplasia (flat areas) on the cervix

Answer 19

Skin and genital papillomas and as well as cervical dysplasia have the potential to transform into cancerous cells. Individuals who have extensive exposure to the sun have a higher incidence of transformation of papillomas into squamous cell carcinomas. HPV 6, 11, 16, 18 are associated with the development with cervical carcinomas. Whereas the T antigens of SV40 and polyoma virus played a role in tumor formation other early proteins of HPV are important for tumor formation. HPC early protein 5 (E5) is an oncoprotein that stimulates production of epidermal growth factor receptor (EGFR) that enhances cell replication. Early proteins E6 and E7 of HPV inactivate p53 and RBp105 which are important in controlling cell mitosis. This leads to cell proliferation. (See end of retrovirus lecture, Fall 2018)

Answer 20

Latent infections - Research suggests that HPV DNA can remain latent in cells of the basal layer of skin and mucosa. Individuals who are immunocompromised experience the reactivation of the virus and the production of crops of warts on areas of the skin. Treatment - Most of the time treatment is not required and after months the wart recedes. However in certain situations the dermatologist may use one of several treatments - Skin papillomas can be treated with podophyllin, an extract of the mandrake plant that has toxic properties or trichloroacetic acid. Both treatments are physician applied. - Cervical dysplasia may be removed by laser and other surgical procedures including cryosurgery

Answer 21

Prevention 1. Vaccine - QHPVV Approved June 8, 2008 -Vaccine Composed Of HPV L1 Protein, Which Is A Major Capsid Protein -L1 Gene Is Genetically Engineered Into Yeast Vector -Yeast Produce Noninfectious Virus-Like Particle -Vaccine: L1s from HPV Types 6, 11, 16, and 18 + Aluminum Adjuvant -Immunity To Four Vaccines Strains May Provide Immunity Against Other Types 2. Gardasil 9 (Merck); 9 types 3. Vaccine recommended schedule - QHPVV 0, 2 and 6 months. - Preferred age; Females 11-12 yrs but can be administered as early as 9 yrs. - catch up vaccination for unvaccinated, 13-26 yrs - Gardasil 9; 3 injections over 3 months; 0,2, 6 months; girls and boys 11 or 12 yrs of age. Diagnosis - Since HPV is not propagated in tissue culture, serology based diagnostic tests have not been developed. Nucleic acid based analyses are used to determine HPV type and virus load. - How West Virginia Fares !

Answer 22

In previous lectures the replication scheme, pathogenesis, epidemiology, drug therapy and vaccines (lack thereof) for HIV was discussed. As indicated the virus can be transmitted from one person to another by various infected bodily fluids. **Spread via; blood, semen, vaginal secretions, tissue transplants, breast milk The frequency of HIV transmission during sexual intercourse is influenced by a number of factors. These include heterosexual intercourse and males having sex with males (MSM). In resource rich countries heterosexual intercourse is not the primary means of transmission, whereas it the major route of infection in resource deprived countries. One hypothesis for this difference is that poorer countries lack adequate health care and have a higher incidence of genital infections, eg . syphilis. Genital lesions enable HIV to more readily infect these individuals leading to a 4 fold risk of HIV infection. In addition, HIV subtype differences may increase the risk of infection. HIV strains isolated from Asian and geographical regions in Africa have a greater affinity for cells in the genital mucosa which could explain a higher rate of infection. In more economically advantaged countries the primary mode of sexual transmission is MSM, even though heterosexual spread especially from infected males to their female partners is well recognized. Other observation. Uncircumcised males have a higher risk of infection than circumcised males. - Anal intercourse promotes HIV infection - Multiple sex partners increase risk especially with unprotected sex - Promiscuous, unprotected sex also increase risk

Answer 23

Hepadnavirus family; partially double stranded DNA genome. - HBV or Dane particle is composed of a core structure surrounded by an envelope. - HBcAg is the primary protein of the core structure whereas HBsAg is the major protein antigen associated with the envelop. - eAg is known as the infectivity antigen and correlated with infectious HBV is the patients serum * *Transmission - blood and blood products - sexual intercourse - mother to fetus/child

Answer 24

Herpes simplex virus is one of a number of members of the Herpetoviridae ( Herpesviridae) that cause human disease. In a previous lecture the replication cycle and virus structure were discussed in depth. Recall that herpesviruses replicates in the nucleus of the cell and acquires their envelop by budding through the nuclear membrane of the infected cell. The virus replication cycle has an early and late stage where viral enzymes and regulatory proteins are synthesized early and the structural proteins of the virus are synthesized late. The virus DNA replication occurs in the cell nucleus via a rolling circle mechanism, whereby a concatemer is formed. .

Answer 25

Genital infections - Herpes Simplex virus exists as two types, HSV 1 and HSV 2. HSV 2 is the primary type that causes genital infections. HSV 1 is usually the cause of gingivostomatitis , skin vesicular lesions and eye infections. Due to certain sexual practices such as oral sex HSV 1 infection can occur in the genital area. - The incubation time for genital infections of the penis or vulva is about 3 to 7 days. Vesicles lose their integrity to yield ulcers. Swelling of the regional lymph nodes is often seen along with fever, headache and malaise. Healing of the lesions takes about 2 weeks Latency - Following primary infection the virus HSV travel along the sensory nerves to establish a latent infection in the sacral ganglia - Reactivation of HSV 2 infections can occur to changes in the immune system, X irradiation, chemotherapy, stress, other infections and other factors. Recall that reactivation of HSV can occur even in the presence of high levels of immunity. Diagnosis - Type specific antibodies in conjunction with immunofluorescence can determine whether the infection is caused by HSV 1 or 2. HSV DNA diagnostic methods are also utilized to distinguish HSV types. Treatment - Nucleoside analogs such as acyclovir, valaciclovir and famciclorvir have been used to treat severe infection and acyclovir has been administered IV to thwart systemic infections that result from primary HSV 1 or 2 infections. Acyclovir has also administered during the prodromal state of recurring infections.

Answer 26

Viral infections of the fetus during pregnancy may originate from different sources. 1) Infections of the mother leads to infection of placental cells and crossing the placenta to infect the fetus. 2) A reactivation of a latent viral infection of the mother is another. 3) Finally, infections of the fetus by normal flora of the mother are possible. The placenta acts as a physical barrier to protect the fetus and once that is breached many viruses have the capacity to infect the fetus and cause death in utero. The actively replicating cells of the fetus offer an ideal cellular environment to promote viral replication. Alternatively, other viruses will infect the fetus and negatively impact fetal development by inhibiting cell replication resulting in slowed tissue development thereby causing various types of abnormalities. Intrauterine infections by some viruses may not cause obvious malformations, but may result in a chronic infection which results in virus being shed by the newborn for months to years after birth.

Answer 27

1. Polyomavirus - family; papovaviridae - genome; circular, DS DNA - capsid; icosahedral 2. CMV - family; Herpetoviridae (herpesviridae) - genome; DS DNA - capsid; icosahedral, enveloped 3. HSV 2,1 - family; herpetoviridae 4. EBV - family; herpetoviridae

Answer 28

1. Rubella - family; Togaviridae - genome; + polarity RNA - capsid; icosahedral, enveloped 2. Zika virus - family; flaviviridae, arbovirus - genome; + polarity RNA - capsid; icosahedral, enveloped 3. HIV - family; retroviridae - genome; + polarity RNA - capsid; complex, enveloped 4. CMV - family; herpesviridae - genome; DS DNA - capsid; icosahedral, enveloped 5. HBV - family; hepadavirus - genome; circular, partially DS DNS - capsid; icosahedral enveloped 6. Parvovirus B19 - family; parvoviridae - genome; SS DNA - capsid; Icosahedral

Answer 29

Rubellavirus is a member of the Togaviridae, genus Rubivirus . Unlike most of the Togaviruses that are transmitted by arthropod vectors (mosquitoes), rubellavirus is not considered an arbovirus. Rubella virus structure resembles that of the other Togavirues , as well as members of the Flaviviridae, in that they have single-stranded, positive stranded (polarity) RNA as their genomes. The icosahedral capsids of all Togaviruses are surrounded by an envelop with glycoprotein spikes on its surface. Like most other RNA viruses, togaviruses require an RNA polymerase that is encoded by the viral genome. Togaviruses replicate in the cytoplasm of the cell. Poliovirus (Picornaviridae) serves as the model for + polarity RNA virus replication.

Answer 30

Rubellavirus is moderately infectious in non-immune human populations. Primary infection occurs in the upper respiratory tract (URT) and regional lymph nodes as a result of droplet infection. The incubation period is rather prolonged, 2-3 weeks. A viremia is established following the URT infection and the virus spreads to secondary sites of infection including the skin and possibly in the placenta, joints and kidney. A macular-papular rash of the skin develops , but the rash only lasts one to 3 days. Enlargement of lymph nodes may also occur especially behind the ears. Several outcomes of infection in children and adults; 1. Infection that goes its course and resolves and is accompanied by a macular-papular rash 2. Inapparent infection without a rash Possible sequelae resulting from the infection include - Arthritis in females - Congenital infections in pregnant women

Answer 31

EXANTHEM - Immunological basis for rash (macularpapular), - Progression of the rash: appears first on face > trunk next > then extremities ** Other causes of macular-papular rashes are varied. Viral causes of macular-papular rashes include: - enterovirus also produce rash (eg. ECHO and Coxsackie A virus) - erythrovirus B 19 (see below) - herpesvirus 6 (HHV6), roseola - dengue virus - rubeolla virus - zika virus The locations where the rash first appears, the progression of the rash, the time of year, the geographic location where the viral infection was contracted, vaccination status and finally diagnostic methods will allow the physician to make the proper assessment of the case. Rubellavirus infections most often occur in the spring in the US.

Answer 32

Infection of nonimmune, pregnant woman can lead to a viremia and to rubellavirus infecting and then crossing the placenta and infecting the fetus. This results in death in utero or a more chronic process, Congenital Rubella Syndrome (CRS). Timing of the infection has a bearing on the consequences to the infected fetus. If the infection of the mother and transmission to the fetus takes place during the first month of pregnancy, the probability of fetal infection is highest and the consequences of the infection are most severe. Rubellaviruses infection cause abnormalities or death in utero in > 20% of infected fetuses during the 1st month of pregnancy and 15% of fetuses are infected when infection of the woman occurs during the 3rd month of pregnancy. Rubellavirus infection of the fetus does not cause lytic infection of cells within the fetus. Instead it prevents normal growth of tissues (slows cell replication) and causes chromosomal damage. Rubellavirus infection of the fetus can be highly teratogenic with multiple anomalies. The abnormalities seen in the infected fetus/newborn include defects in the brain ( mental retardation), heart and vessel defects, eye (cataracts), ear defects leading to deafness, and hepatosplenomegaly as a result of infection of the liver and spleen. In children with CRS rubellavirus can be excreted by infants for up to 2 years following birth, even though anti-rubella antibodies are present in the serum. Virus in nasopharyngeal secretions and urine in CRS may serve as a source of virus infection of human contacts. Rarely, CRS initiates Guillain Barre` syndrome, which leads to demyelination and paralysis.

Answer 33

Diagnosis - Diagnosis by detection of antiviral IgM in newborn from cord and infant blood indicate a recent rubellavirus infection. Isolation of virus is less commonly used as a diagnostic method. In a child or adult serological testing can be used to determine a 4 fold rise in antibodies in paired serum samples taken before day 7 and after day 17 from the time infection begins Vaccination - Rubellavirus strains, RA 273 and Cendehill, are currently employed in vaccine formulations and have been shown to produce protective immunity. Vaccination of pregnant woman (accidently) showed no congenital defects in the newborn when administered to mother before or after conception . It is recommended from a theoretical perspective, however, that pregnant woman are not vaccinated, since the vaccine is a live attenuated virus preparation. Vaccination may cause arthralgia and arthritis in females. A rubella vaccination program supported by CDC has 2 primary goals; 1. Identify and vaccinate all nonimmune women of childbearing age 2. Vaccinate all children >12 months of age. these children serve as a reservoir for infection Trivalent vaccine MMR is utilized unless the individual has allergies to neomycin or experience an allergic reaction to previous vaccination. Specialty vaccines Measles/rubella and Mumps/rubella or Rubella alone are available. MMRV is also available. (V = varicella) Rubella Hyperimmune Globulin is also available to the nonimmune, pregnant women who has been or may have been exposed. Possibly lessens the severity of CRS in the fetus.

Answer 34

Zika virus is a Flavivirus that is transmitted by Aedes albopictus and aegypti, sexual intercourse and blood transfusions The virus infection has been linked to encephalitis and Guillain Barre syndrome (rarely). Zika virus has been in the news over the last several years for its ability to cause congenital infections of the fetus, which can manifest a variety of symptoms in the affected individual (developing child) throughout life. Although the virus was first recognized in the late 1940s, it has not been a major concern of health officials until recently. Zika virus infections of humans appears to particularly prevalent in South America and particularly in Brazil. The 2016 summer Olympic Games was held in Rio de Janeiro and athletes, spectators and support agencies traveled to this destination from around the world. Without the implementation of appropriate health measures, these groups were susceptible to infection. Zika virus is an arbovirus that is spread by mosquito vectors, primarily the Aedes aegypti and Aedes albopictus. The virus is a member of the Flaviviridae along with dengue fever and yellow fever viruses, several encephalitis viruses and West Nile virus. A key component in controlling any arbovirus infection is to reduce numbers or eliminate the insect vectors that transmit the virus. Brazil and many other countries do not routinely have processes in place to control insects. Lack of screens on windows, failure to use of insect repellants, failure to eliminate standing water as breeding grounds and lack of air conditioning (windows opened) all contribute to the high prevalence of mosquito and exposure to insect vectors. Mosquitoes can lay their eggs in dry season which can remain dormant for about 4 months. Eggs exposed to rain can than develop into larvae.

Answer 35

Zika virus can also be spread by sexual intercourse and blood transfusions in addition to the mosquito bites. Symptoms include fever, rash, joint pain and inflamed eyes. Muscle pain and headache also reported. Symptoms may last for one week. Most people will have mild symptoms or be asymptomatic. Serological test and RT-PCR tests available - RT-PCR of serum collected in the first two weeks from the onset of symptoms - RT-PCR of urine collected within 14 days from onset of symptoms Trioplex - RT-PCR for Zika, Dengue and Chikungunya viruses Serum IgM specific to Zika virus is detectable at about one week after onset of symptoms. Clinician should order serology if RT- PCR is negative Serology (IgM) is also recommended for Dengue and Chikungunya viruses 80% + Have a limited disease - Infection of pregnant women can lead to birth defects, microcephaly - Guillain Barre Syndrome link being investigated Vaccine development 1) Inactivated Vaccines, 2) Live Attenuated, 3) DNA Vaccine, and 4) mRNA Vaccine Prevention: Do not travel to areas where Zika is prevalent Insect spray, barrier protection, fumigate modes of transportation (airplanes, ships, etc) to eliminate eggs Eliminate breading areas (standing water)

Answer 36

The family Parvoviridae is composed of two genera, 1) Dependoviruses and 2) Erythroviruses . The dependoviruses (adeno-associated viruses) are defective in their replication and require a helper virus such as adenovirus or herpes simplex virus in order to replicate. These viruses (dependo) have not been linked to human disease. Erythrovirus B 19 is an autonomously replicating parvovirus that can only replicate in actively dividing cells that are undergoing cellular DNA synthesis. Virus Characteristics: Members of the Parvoviridae are one of the smallest human viruses. They have an icosahedral capsid and lack an envelop. The genome is single-stranded DNA and has the capacity to encode only a few viral proteins. Only 3 proteins constituted the viral capsid. Viral replication Parvoviruses replicate in the nucleus of the cell like most other DNA viruses. Because the genome of the virus is small, its protein coding capacity is very limited. It does not have genes to encode for all of various enzymes and other proteins necessary to support its own replication. Besides the three capsid proteins two nonstructural proteins, NS 1 and NS2, are encoded by the viral genome and serve to promote the replication cycle. Therefore, virus replication is almost entirely dependent on the enzymes of the cell. More specifically, autonomously replication parvoviruses like Erythrovirus B 19 are dependent on actively dividing host cells that have all of the enzymes needed to support viral replication.

Answer 37

``` Clinical Parvoviruses (erythrovirus B 19) are transmitted most commonly by respiratory droplets but transmission through blood products has been documented. Pregnant woman to fetus transmission is also an established fact. ``` Erythrovirus B 19 can cause human infections including erythema infectiosum (slapped cheek, macular papular rash) or Fifths disease, especially in children. In adults B 19 can cause an arthropathy and papular and purpuric lesions on feet and hands that has been labeled gloves and socks syndrome. Rarely B 19 can cause a transient aplastic crisis through the reduction of red blood cell formation. This is seen more frequently in individuals with AIDS, sickle cell disease, thalassemias and other predisposing conditions. Primary infection of a pregnant woman especially during the first few months of pregnancy can lead to fetal infection. In about 5 -10 % of the cases fetal infection can lead to death in utero or a hepatosplenomegaly and anemia. Hydrops fetalis results from the infection that also includes accumulation of fluid in the abdomen and subcutaneous tissues. Immunity - Approximately 50 % of the population has antibodies against erythrovirus B19 and indicate wide spread infections during childhood. Diagnosis - IgM specific to erythrovirus B 19 or nucleic acid test of fetal blood to detect B 19 DNA

Answer 38

CMV infection of the fetus. See previous discussion on CMV. Two possible modes of fetal infection may take place: 1) fetal infection following a primary infection of the mother and 2) reactivation of a latent CMV infection. In the first scenario if pregnant women contracts primary CMV infection approximately 40% of the fetuses are likely to be infected. Unlike rubella, differences in susceptibility of the fetus to CMV infection at certain times during pregnancy have not be determined. On a global basis it is difficult to determine the number of primary CMV infections of pregnant woman. In one study it was estimated that 95% of CMV infections of pregnant woman were asymptomatic . It has also been shown, however, that females with lowered T cell responses to CMV antigens have elevated rate of fetal CMV infection. Newborns may exhibit hearing loss and mental retardation, eye defects, hearing deficits, heptosplenomegaly and thrombocytopenic purpura have been linked to these primary infections. Hearing and mental retardation may not be obvious until childhood. In the case of reactivation of latent CMV infections in the mother and the subsequent infection of the fetus usually does not lead to fetal abnormalities. Reactivation of CMV is most often seen during the last trimester of pregnancy when fetal development is well established. Also anti-CMV antibodies in the mother may help control the CMV infection of the fetus thereby minimizing the infectious process. Diagnosis - The presence of Anti-CMV IgM levels in the serum of newborns is used to determine fetal infections. In addition nucleic acid based test are used to detect viral DNA in blood and urine immediately after birth. Virus isolation is also possible from throat swabs and urine samples.

Answer 39

Varicella zoster virus has also been shown to cause congenital infections when the mother experiences a primary infection during the first trimester. Malformation of the limbs and muscles and CNS defects have be linked to VZV infection of the fetus. Primary infection of pregnant women can produce abnormalities which are exhibited in the newborn or later in childhood. Reactivation of latent HSV infections in the mother seldom cause fetal infections. It is also recognized that HSV infection can occur as the newborn passes through the infected birth canal (perinatal infection)

Answer 40

Congenital infections caused by HIV - It has been noted that women in resource poor countries have a higher level HIV infections than in resource rich countries. Therefore, it is expected that there is a higher frequency of congenital infection with HIV in these countries. HIV infection can occur in utero or perinatally. - Congenital infections can result in a variety of clinical symptoms that are seen at the time of birth or develop during the first year of life. These include under development and weight deficit, pneumonitis, thrush, heptosplenomegaly and diarrhea. CNS symptoms and AIDS may be evident in the newborn. Preventions and control - Anti- AIDS drugs and be administered to pregnant females during the last trimester or at the time of delivery in order to reduce the HIV load in the mother. This may reduce the chance of HIV infection at the time of birth. Other recommendations may include a C- section and not breast feeding.

Answer 41

Primary infection of the pregnant woman with hepatitis B virus can cause congenital infections. In addition, a woman may have a chronic active HBV infection during pregnancy and the infection can be transmitted to the fetus. Remember individuals who are e antigen positive also have high levels of HBV which in their blood and bodily fluids and this can be transmitted to the fetus. Remember anti HBV drugs are also available to treat children who have been infected in utero or perinatally as well as pegylated interferon. Prevention and control - Newborns of HBV positive mothers should be vaccinated with the vaccine immediately after birth. HBV specific hyper-immune globulin should be administered to the newborn in an attempt to neutralize the virus and the vaccination series begun. (See Hepatitis B virus lecture)

Answer 42

1. Proliferative - Time from end of menses until ovulation - Glandular mitoses** - Estrogen ``` 2. Secretory phase • From time of ovulation to menses • No mitoses ** • Increasing gland complexity • Basal vacuolation=ovulation • See increasing secretion in glandular lumen ```

Answer 43

Abnormal Uterine Bleeding

Answer 44

Dysfunctional Uterine Bleeding (DUB)

Answer 45

Inadequate Luteal phase • Corpus luteum does not function properly - Puts out inadequate amounts of progesterone - Results in irregular cycles • Presents with infertility - Get either bleeding or amenorrhea • Diagnosis- perform bx after ovulation; endometrial biopsy shows secretory endometrium that lags behind expected changes

Answer 46

CHRONIC ENDOMETRITIS * See plasma cells in endometrium**** * Treat with antibiotic therapy

Answer 47

ENDOMETRIOSIS • Presence of endometrial glands & stroma in abnormal locations outside the uterus • See most commonly in; Ovaries, uterine ligaments, rectovaginal septum, peritoneum • Common problem, seen 10% of women • Seen in active reproductive time • Causes infertility, dysmenorrhea, pelvic pain Endometriosis theories 1. Regurgitation theory; get retrograde menses 2. Metaplastic theory; may arise directly from coelemic 3. Lymphvascular; may spread through pelvic vessels

Answer 48

Morphology • See as little powder burn marks • Responds to hormonal influences & may bleed Micro • See as collection of endometrial glands and stroma • If chronic, can be difficult to diagnose In ovary • Most often occurs as large cyst filled with brown material • Called chocolate cyst or endometrioma • See endometrial glands & stroma along with hemosiderin-laden macrophages ADENOMYOSIS; displaced endometrial glands found in the WALL OF UTERUS • Closely related to endometriosis • See foci of endometrial glands & stroma within uterine wall • Can cause similar symptoms as endometriosis • Can form hemorrhagic nests within the wall

Answer 49

Endometrial Polyps • Common polypoid mass that occurs in endometrium • Can cause bleeding • 2 types 1) Contains functional endometrium 2) Contains cystic, hyperplastic epithelium • Benign lesion, cured by removal • Only rarely does adenocarcinoma arise within a polyp

Answer 50

ENDOMETRIAL HYPERPLASIA • Cause of excessive uterine bleeding • Depending upon type of hyperplasia, differing risks for development of endometrial adenocarcinoma • Caused by prolonged estrogen stimulation; Unopposed estrogen ``` Associated conditions • Menopause • Polycystic ovarian disease • Excessive ovarian cortical function • Prolonged estrogen replacement therapy ``` Genetic Alterations • See inactivation of PTEN tumor suppressor gene • Without PTEN, endometrial cells become more sensitive to stimulation to by estrogen • Estrogen is growth factor • May explain why hyperplasia/carcinoma occurs

Answer 51

``` 1. Simple • See in creased gland to stromal ratio • Can see cyst formation • Rarely progresses to carcinoma • Generally treated medically ``` 2. Complex • Increased glands with more crowding, enlargement • If has associated cytologic atypia, called atypical complex hyperplasia - Has significant risk for progressing to adenocarcinoma - Generally hysterectomy is performed

Answer 52

ENDOMETRIAL CARCINOMA ``` • Most common invasive carcinoma of female genital tract • 7% of all invasive cancers in women • 55-65 years • Risk factors - Estrogen - obesity - nulliparous - hypertension - diabetes ``` DIAGNOSIS • Most often will present with postmenopausal bleeding • Ultrasound will show thickened endometrial lining • Must do endometrial biopsy to diagnose***** • Pap smear is NOT the way to diagnose endometrial lesion • Can show up on a Pap smear but INSENSITIVE way to diagnose

Answer 53

Pathogenesis - 2 groups 1. Associated with prolonged estrogen stimulation • Tend to be more well differentiated • More favorable prognosis 2. Not associated with excessive estrogen • Patients tend to be older • More poorly differentiated • Resemble adenocarcinoma in ovary; papillary serous • Less favorable prognosis Morphology 1. Gross • Thickened endometrium • polypoid mass 2. Microscopic ; ADENOCARCINOMA - papillary serous type • Similar to tumor in ovary • More aggressive • Poor prognosis

Answer 54

Endometrial Adenocarcinoma • Present as bleeding, can see thickened endometrial lining on ultrasound • Can be asymptomatic • Generally present confined to uterus (stage 1) • 5 year survival rates - stage 1; up to 96% survival - stage 2 and 3; up to 70% survival

Answer 55

Carcinosarcoma(Malignant Mixed Mullerian Tumors) • Endometrial Adenocarcinoma and associated malignant stromal component • Can see variety of malignant stromal components - Muscle, osteoid cartilage • Highly malignant - overall 5 year survival is very poor

Answer 56

LEIOMYOMAS - called Fibroids • Each tumor is unique clonal neoplasm - most have normal karyotype - 40% have simple chromosomal abnormality Morphology • Form well circumscribed firm white masses • Can be quite large and distort the entire uterus • On microscope- see whorled bundles of bland muscle with low mitotic count Clinical course • Can be asymptomatic • Can be associated with abnormal bleeding, urinary frequency, pain, impaired fertility • Rare- malignant transformation

Answer 57

1. Benign metastasizing leiomyoma - extends into vessels - can appear at other sites 2. Disseminated peritoneal leiomyomatosis - presents as multiple small peritoneal nodules

Answer 58

LEIOMYOSARCOMA Gross • Bulky fleshy mass within wall • Grows as polypoid mass • May just look like large leiomyoma Microscopic • Increased mitotic rate • >10 mitoses per 10 high power fields • Cytologic atypia ** Large, fleshy mass with irregular surface contours. Mitoses and marked atypia * Peak 40-60 years old * Strong tendency to recur * Can spread to lungs, bone, brain * 5 year survival- 40%

Answer 59

Infections • Suppurative salpingitis - Most often associated with gonococcus Benign lesions • Endometriosis- very common

Answer 60

``` Paratubal cysts • Common • Small to prominent cysts hanging off fallopian tubes • Little clinical significance • Also called hydatid cyst of morgagni ``` Fallopian tube Adenocarcinoma • Rare tumor • Often not suspected • have minimal symptoms, so diagnosed late in course of disease • Can present with a watery discharge • Overall poor prognosis- worse than ovarian carcinoma

Answer 61

• Decidua- outer boundary of myometrium - Maternal vessels originate & deliver blood to & from intervillous spaces • Umbilical vessels branch & terminate in placental villi where nutrient exchange takes place **See vasculature on fetal side of placenta (chorion)

Answer 62

SPONTANEOUS ABORTION • 10-15% of recognized pregnancies terminate in spontaneous abortion • Fetal & maternal causes; - Main cause- defective implantation& death of ovum or fetus in utero - Chromosomal abnormalities in>50% of those occurring <10 weeks - Trauma is rare cause of abortion - Infectious agents can cause

Answer 63

Ectopic pregnancy * Implantation of fetus in any site other than normal uterus * 90% occur within fallopian tube * Other sites- ovary, cornu of uterus, abdomen * Predisposing factors- * MOST IMPORTANT= PID; 50% occur in normal tube * Can cause hematosalpinx • Presents with severe abdominal pain 6 weeks after LMP • HCG will be elevated • Endometrial biopsy shows no chorionic villi • Rupture of tubal pregnancy; MEDICAL EMERGENCY

Answer 64

PLACENTA ACCRETA Possible sequelae A. Postpartum hemorrhage; can be life threatening, can require hysterectomy. B. Can be associated with placenta Previn (60% of cases) • Placenta implants in lower uterine segment or cervix • Causes antepartum bleeding & premature labor C. Placenta previa-accreta can occur in women with previous c section scar

Answer 65

• Two ova = dizygotic (fraternal) • One ova = monozygotic (identical) • Three types of placentas A. amnion-refers to # of sacs; chorion-refers to # of placentas • Mono-di; di-di; mono-mono B. Identical twins can be any of the three • Depends upon when splitting occurs during first 2 weeks of pregnancy • Later splitting happens, more structures are shared - differentiate di- mono from di-di (fused) - Di- mono: monzygotic - Di-di- either monzygotic or dizygotic (more likely)

Answer 66

Twin-Twin Transfusion Syndrome **High mortality rate; exceeds circulation in one twin, too little circulation in the other twin.

Answer 67

* Villitis: inflammation in placental villi * Chorioamnionitis: inflammation in fetal membranes * Funisitis: inflammation in umbilical cord Pathway of Infection 1. Ascending infection through birth canal • Most common • Most often bacterial • Can cause premature rupture of membranes • Sexual intercourse can enhance ascending infection 2. Hematogenous • Can occur by spread of bacteria to placenta • Most often affects villi

Answer 68

Preeclampsia - eclampsia (6% of pregnant women) • Characterized by - Hypertension, proteinuria, edema • More likely in primiparas • Eclampsia; more severe form of toxemia - seizures - DIC (disseminated intravascular coagulation) ``` Pathogenesis ; 3 important events 1. Placental ischemia • Abnormality in placentation • Shallow implantation • Desidual vessels not adequate ``` 2. DIC • Results from decreased uteroplacental perfusion • Leads to stimulation of vasoconstrictor substance • Activation of coagulation factors 3. Hypertension • Due to arterial vasoconstriction, various other factors

Answer 69

Placental Morphology • Increase in infarctions • Walls of vessels- fibrinoid necrosis • See variety of fibrin thrombi & hemorrhage in- liver, kidney, brain ``` Toxemia - Clinical course • Usually starts after 32 weeks • See hypertension, edema, proteinuria • Can lead to headaches , visual disturbances, can go into shock • Only definitive therapy- delivery ``` **Only way to cure Preeclampsia - eclampsia is to deliver the baby

Answer 70

Gestational trophoblastic disease Hydatidiform Mole (complete & partial) • See cystic swelling of chorionic villi; Associated trophoblastic proliferation • Patients can present in 4th or 5th month with uterus that measures larger than would be expected for dates; If patient has ultrasound early in pregnancy, can be diagnosed early • Can occur any time in active reproductive life; Most likely to occur during teen or in 40’s-50’s 1. Complete mole • All villi are edematous • >90% have 46xx; All from sperm -paternal Fertilization by 1 or 2 sperm of egg that has lost its chromosomes, sperm DNA duplicates • No fetal parts 2. Partial • Some villi are edematous • Triploid karyotype(69xxx,69xxy); fertilization of egg with two sperm • Fetal parts may be seen

Answer 71

1. COmplete mole - uterine cavity filled with delicate friable mass - cystic grape like structures, see swollen edematous villi - associated with chorioca B. 1 in 40 cases results in choriocarcinoma; overall only 4% of cases C. 10% develop invasive mole 2. Partial mole • Findings not as dramatic • With spontaneous abortion, will see focal areas of swollen chorionic villi • Association with chorioca; rare to have choriocarcinoma develop Clinical course A. With both kinds of moles, patients present with • spontaneous abortion • picked up by ultrasound B. Follow patients with quantitative HCG • With complete mole, much higher HCG than expected for dates • Following removal with either type, HCG should decrease • If not, evaluate for choriocarcinoma

Answer 72

``` INVASIVE MOLE • Penetrates myometrium - May even perforate uterine wall • Locally destructive • Villi may embolize to distant sites - Liver, brain - Not true mets ``` * Clinically present with persistent elevation of HCG; Vaginal bleeding * Responds well to chemotherapy * Can result in uterine rupture and require hysterectomy

Answer 73

Gestational Choriocarcinoma • Originates from previous normal or abnormal pregnancy • Uncommon -1:20000; More common in some areas such as Africa • 50% come from hydatiform moles • 25% from previous abortions • 25% from normal pregnancies Morphology • Soft fleshy white-yellow masses • Often not very large • Have extensive areas of necrosis • Microscopically - Proliferation of cytotrophoblasts and syncytiotrophoblasts - Can be very atypical with areas of anaplasia Clinical course • Present irregular spotting after miscarriage, D&C, or normal pregnancy • Often has spread by time of diagnosis • Common mets to; lungs, vagina, liver, kidney Treatment • Great results from chemotherapy • Some patients even have subsequent normal pregnancies

Answer 74

1. Estrogens | 2. Progestins

Answer 75

• Estrogen is formed in ovary, placenta, adrenals, liver & adipose. • Premenopausal: estrogen is predominantly made by granulosa cells of ovary • During pregnancy it is the fetoplacental unit. • Men and postmenopausal women: estrogen synthesis occurs in adipose & hepatic tissue -androstenedione & testosterone converted to estrone • 17 β-estradiol, is the most potent endogenous estrogen 17β-estradiol >> estrone > estriol • Hepatic metabolism reversibly converts estradiol to estrone; estrone also converted to estriol

Answer 76

* All gonadal hormones are synthesized from cholesterol in a series of steps that include shortening of the hydrocarbon side chain and hydroxylation of the steroid nucleus. * Steroidal estrogens arise from androstenedione or testosterone by aromatization of the A ring. This is catalyzed by Cyp450 monoxygenase (aromatase or CYP19) * Placenta – uses fetal dehydroepiandrosterone (DHEA) to produce large amounts of estrone and estriol * All three of the estrogens are excreted in the urine along with their glucuronide and sulfate conjugates

Answer 77

1. On sexual Organs - OVARIES: stimulate follicular growth, large doses causes atrophy of ovaries - UTERUS: endometrial growth - VAGINA: cornification of epithelial cells with thickening and stratification of epithelium - CERVIX: increase of cervical mucous with a lowered viscosity (favoring sperm access) 2. Others - Skin: increase in vascularization, development of soft, textured and smooth skin - Bone: increase osteoblastic activity - Electrolytes: retention of Na+, Cl- and water by the kidney - Cholesterol: hypocholesterolemic effect **IN WOMEN – Developmental effects: largely responsible for pubertal changes in girls and secondary sexual characteristics. Development and maintenance of internal and external genitalia – Neuroendocrine actions: Control of ovulation and the preparation of the reproductive tract for fertilization and implantation * *IN MEN - Bone - Spermatogenesis - Behavior

Answer 78

A. BIOSYNTHESIS • The major endogenous progestin is progesterone. • Synthesis: ovary (corpus luteum), placenta, adrenal cortex and testis B. PHYSIOLOGICAL ACTION • Important intermediate in steroid biogenesis • Development of secretory endometrium • Endocervical glandular fluid: increases viscosity and decreases amount • Abrupt decline of progesterone initiates menstruation

Answer 79

Regulated by a neuroendocrine interaction of the hypothalamus, pituitary and ovaries A. FOLLICULAR PHASE • Gonadotropin-releasing hormone (GnRH) is released into the hypothalamic-pituitary portal vasculature in INTERVALS. • GnRH stimulates the PULSATILE secretion of gonadotropins- FSH and LH from the pituitary. • LH and FSH regulate the growth and maturation of the graafian follicle in the ovary and the ovarian production of ESTRADIOL (E) AND PROGESTERONE (P). • The effects of E on pituitary are inhibitory at this time and cause the amount of LH and FSH released from the pituitary to decline (decrease in LH pulse amplitude). So the levels of gonadotropins drop. B. MIDCYCLE SURGE • Serum E rises above threshold for approximately 36 hours. This exerts a brief positive feedback effect on the pituitary to trigger the PREOVULATORY SURGE of LH and FSH. • Progesterone may contribute to the mid-cycle LH surge. This surge is essential for ovulation. • This surge in gonadotropins, stimulates follicular rupture and ovulation within 1 to 2 days. C. LUTEAL PHASE • The ruptured follicle develops into corpus luteum, which produces large amounts of P and less E under the influence of LH during the second half of the cycle. • P controls the frequency and amplitude of LH • In the luteal (secretory) phase, elevated P limits the proliferative effect of E on the endometrium by stimulating differentiation. • P is thus important in preparation of implantation • If implantation does not occur, there is decrease in P and E • WHEN PROGESTERONE LEVELS DROP IT SIGNALS THE ONSET OF MENSES, the pulse generator resets and the new ovarian cycle occurs. • If pregnancy occurs, embryo secretes human chorionic gonadotropin (hCG) which maintains elevated E and P.

Answer 80

* Contraception (E & P)** * Postmenopausal Hormone therapy (E & P)** * Osteoporosis (E) (now replaced by other drugs such as bisphosphonates) * Conditions where there is deficiency of estrogens: lack of development of ovaries, menopause or castration * Dysfunctional uterine bleeding (P) * Dysmenorrhea (P) * Endometriosis (P)

Answer 81

COMBINED ESTROGEN AND PROGESTERONE - most common hormonal contraceptive in US ``` Types 1. Monophasic (28 pills) 2. Multiphasic - biphasic or triphasic (21 day dose) 3. Alter number of pill free days A) Mircette B) YAZ 4. Other COCs - continuous pills A) Seasonale B) Lybrel ```

Answer 82

1. Monophasic (28 pills) - Constant amount of Estrogen and Progesterone for 21 days - Placebo or iron supplement for 7 days - Estrogen varies from 20 to > 50 µg ethinyl estradiol; low dose ( < 35 µg estrogen) 2. Multi-Phasic - Biphasic or Triphasic (21 day dose) a) lower levels of hormones to reduce adverse effects b) biphasic - 2 levels of progesterone + constant estrogen (20/35 µg ethinyl estradiol) c) triphasic - 3 different progesterone levels with 20, 30 or 35 µg ethinyl estradiol - 1 level of progesterone and 20, 30 & 35 µg ethinyl estradiol 3. Alter number of pill free days a) Mircette: One 20 ug EE is formulated for 21 days followed by 2 days of placebo and 5 days of 10 ug EE. – Limits the number of days of hypoestrogenism after 21 days. – 5 days of unopposed estrogen would prevent FSH from rising and prevent early folliculogenesis during the usual placebo period – Fewer estrogen-withdrawal headache, bloating and menstrual pain b) YAZ: COC introduced in April 2006. 24 days COC (20 ug EE and 3 mg drospirenone (DSRP)) followed by 4 days of inert placebo pills. (YAZ is FDA approved for improving symptoms of premenstrual dysphoric disorder -PMDD). - Yasmin: (30 ug EE + 3 mg DSRP) followed by 7days of inert pills 4. Other COCs - continuous pills a) SEASONALE: In 2003, FDA approved levonorgestral-EE (0.6 mg + 120 ug of EE) combination taken continuously for 84 days followed by 7 days placebo tablets. Reduces menstrual bleeding to once every 13 weeks. - Seasonique similar to seasonale but has seven days of 10 ug of EE instead of placebo. Seasonique had better follicular suppression and less unscheduled bleeding b) LYBREL (EE 20 ug, levonorgestrel 90 ug) is the first low dose COC designed to be taken 365 days a year without placebo or pill free days.

Answer 83

1. Patch (Xulane, a generic version of Ortho-Evra Patch) - combination of 20 mcg ethinyl estradiol and 0.15mg Norelgestromin - apply once weekly for 3 weeks with a 1 week free period - high incidence of localized rash at site of patch - risk of thrombosis equal or greater to other OC - effect reduced in patient greater than 90kg (contraceptives soak in the adipose tissue) 2. Vaginal Ring (NuvaRing) – Contains 15 mg ethinyl estradiol and 120 µg of etonogestrel (active metabolite of desogestrel) daily – Inserted for 3 weeks with 1 week break period – Avoids hepatic first pass

Answer 84

1. Estrogen component (synthetic estrogens) - Mestranol and ethinyl estradiol - 80 µg of mestranol is equivalent to 50 µg ethinyl estradiol - mestranol must be metabolized to ethinyl estradiol to be active 2. PROGESTIN COMPONENT - Norethindrone - Levonorgestrel - Norgestimate - Norelgestromin (metabolite of norgestimate) - Desogestrel - Ethynodiol diacetate - Gestodene - Norgestrel - Drospirenone (YAZ, Yasmin)

Answer 85

a. Levonorgestrel is 2 times more potent than Norgestrel - Norgestrel, racemic mixture of Levonorgestrel & inactive isomer b. Drospirenone, antiandrogen activity and antimineralocorticoid (unique) 3 mg drospirenone comparable to 25 mg spironolactone Must monitor plasma K= in first month of use (risk of hyperkalemia) Less weight gain than levonorgestrel and is beneficial for acne c. Ethinyl Estradiol – Norelgestromin (Ortho Evra Patch) - norelgestromin active metabolite of norgestimate d. ANDROGENIC ACTIVITY: - Progestins with higher androgenic activity increase the chances of androgen-related side effects which mainly include acne and hirsutism. - Progestins with lower androgenic activity have little or no effect on carbohydrate metabolism ** Norgestrel and Levonorgestrel have most progestational & androgenic activity

Answer 86

1. Inhibit ovulation through a negative feedback on hypothalamus prevents midcycle surge of FSH and LH - progesterone GnRH & LH; estrogen inhibit FSH and LH (high doses) 2. Thicken cervical mucus 3. Endometrium unsuitable for nidation

Answer 87

• Contraceptive failure rate for COC is approximately 0.35% in perfect use and 8% in typical use. • Several variables lead to decreased contraceptive efficacy, including side effects, non-compliance, poor adherence to the treatment regimen, increased body weight and drug interactions leading to increased metabolism of steroid components 1. Required for 7 days to become effective for Tri cyclics (Ortho Tri-cyclen) and 21 days for monophasics (ortho cyclen); recommend use of additional method 2. Emphasize importance of taking doses at same time/day -lessens adverse effects - better therapeutic success when starting drugs 3. Pack started on first or fifth day of menses

Answer 88

Adverse effects 1. GENERAL: nausea, headache, breast tenderness, weight gain, bleeding, migraines, depression & lethargy 2. METABOLIC: decreased HDL, worsens abnormal glucose tolerance increase incidence of gall stones 3. CARDIOVASCULAR: - increased levels of coagulation factors II, VII, VIII, IX & X greater platelet aggregation. - higher incidence of thrombophlebitis and thromboembolism - higher incidence of hypertension and myocardial infarction thrombotic strokes (2-10x higher) 4. OTHER: - decreased incidence of ovarian & endometrial cancer - increased risk of benign hepatomas 5. Contraindications - Pregnancy - Thrombophlebitis or thromboembolic disease - Breast or estrogen dependent carcinoma (current) - Cerebrovascular or coronary artery disease - Liver disease - Cholestatic jaundice during pregnancy or with OC - Estrogen associated benign or malignant hepatic tumors - Diabetes with vascular disease - Cigarette smoker (> 15 cigarettes/day) over age 35

Answer 89

* Venous Thromboembolism: The rates of VTE in COC users are 3 to 4 fold higher than among non-users. The risk of VTE during the first year of use appears to be higher than subsequent years of use * Myocardial Infarction: In women taking COC containing > 50 mg of ethinyl 372 estradiol, MI rate increased 3 fold * Stroke: Increased risk of stroke in women taking COC containing > 50 mg of EE. COC users with hypertension have increased risk of stroke compared to COC users who are normotensive * Gall bladder disease: COC use increases the secretion of cholic acid in bile, thereby leading to a higher incidence of gallstone formation * Breast Cancer: The risk of breast cancer in COC users is still controversial

Answer 90

* Cycle regulation * Decreased menstrual flow * Increased bone mineral density*** * Decreased dysmenorrhea * Decreased peri-menopausal symptoms * Decreased acne*** * Decreased hirsutism * Decreased endometrial cancer * Decreased epithelial ovarian cancer * Decreased risk of fibroids * Possible fewer ovarian cysts * Possibly fewer cases of benign breast disease * Possible less colorectal carcinoma * Lower incidence of ectopic pregnancy * COC used off-label to treat polycystic ovarian syndrome

Answer 91

Many side effects can be corrected by adjusting the balance of estrogen:progestin ratio 1. S.E due to estrogen excess (LOWER E2 dose) - Nausea and bloating* - Headache * - cyclic weight gain, irritability, chloasma, hyperpigmentation - Hypermenorrhea* - Hypertension, breast fullness, leg cramps, edema 2. S.E due to too little estrogen (INCREASE E2 DOSE) - **Early spotting and bleeding (days 1-14) - Hypomenorrhea, nervousness, VASOMOTOR SYMPTOMS (HOT FLASHES), atrophic vaginitis 3. S.E due to progestin excess (DECREASE P DOSE) - Depression and fatigue - breast regression - hirsuitism - libido change 4. S.E due to too little progestin (INCREASE P DOSE) - **Late cycle bleeding (days 15-21) - Hypermenorrhea Side effects to excess androgenic activity (switch to P with less androgenic activity) * **Noncyclic Weight gaina - Oily skin, acne - Superscript indicates androgenic activity - Superscript indicates woman with acne may switch to triphasic Ortho Tri-Cyclen - Norgestimate & Ethinyl estradiol or ethinyl estradiol/drospirenone Yasmin

Answer 92

1. Missed pills increase risk of pregnancy esp. in beginning of cycle - 1 PILL: take pill immediately and continue pack (can take 2 in one day). if occurs in beginning use other method for 7 days - 2 PILLS (missed in first 2 weeks): take extra pill for 2 days, use other method for 7 days - 2 PILLS in week 3 or 3 PILLS: stop current cycle of pills; start new cycle and use additional method for 7 days - MISSED PILLS DURING 7 INACTIVE DAYS: Take remaining pills at regular schedule * * Check package insert for each individual preparation 2. Cigarette smoking & some Drugs increase OC’s clearance will increase risk of therapeutic failure for example: cigarette smoke, rifampin, barbiturates, 3. Anticonvulsants and OC: Carbamazepine, phenytoin, phenobarbital, primidone induce P450 and enhance clearance of OC’s, must use other contraceptive method or other anticonvulsants 4. Antibiotics can increase risk of therapeutic failure, estrogen undergoes enterohepatic recirculation following conjugation and excretion in bile. - Antibiotics such as Tetracycline, Penicillin V, erythromycin or ampicillin decrease the concentration of GI flora which are needed for hydrolysis of conjugates. - Should use other method while taking these agents. 5. Use with caution in patients with: depression, migraine or hypertension 6. Non-nursing mother can begin 4 weeks after delivery - not recommended for use during breast feeding - during breast feeding use progesterone only (minipill)

Answer 93

A. MECHANISM 1. Decreased frequency of GnRH and LH release; inhibit ovulation in 70-80% of cycles 2. Decrease volume and increase viscosity for cervical fluid 3. Alter endometrium B. USE AND SPECIAL CONSIDERATIONS 1. Taken throughout the cycle 2. Associated with menstrual irregularities 3. Used primarily in women who cannot take estrogen - cardiovascular disease - migraines 4. Use in nursing mothers C. AGENTS - Norethindrone - Norgestrel D. SIDE EFFECTS OF UNOPPOSED PROGESTINS • Irregular vaginal bleeding • Increase in ovarian cyst formation (due to lack of estrogen-inhibiting FSH release

Answer 94

A. MEDROXYPROGESTERONE ACETATE (DMPA) 1. MECHANISM OF ACTION Inhibits ovulation, suppresses midcycle LH surge - Thicken cervical mucus; - Atrophy of endometrium 2. EFFECTIVENESS one injection every 3 months; more effective than OC's 3. ADVERSE EFFECTS - Delay in fertility after withdrawal of drug (1 yr.) - Weight gain, insomnia, menstrual irregularities, - Risk of loss of bone mineral density, (long term use) (recommended discontinuing their use after 2 years unless no acceptable alternative is available) Other products 1. SUBDERMAL IMPLANT: Nexplanon: Progestin-based single rod formulated for 3 years continues use. 4cm long, 2mm in diameter. Placed under the skin. Central core contains 68mg etonogestrel encased by a membrane of ethylene vinyl acetate copolymer (radiopaque). Etonogestrel is slow-released. 2. INTRAUTERINE DEVICES (IUD-5 currently available in USA) i. ParaGard T380A:

Answer 95

1. ParaGard T380A; copper containing IUD, inserted for 10 years. Copper is spermcidal. Alters normal uterine contractions and may lead to decreased sperm transport through the reproductive tract. Progesterone containing IUDs 2. Mirena (2000): Progesterone containing IUD, releases low levels of progesterone 20 mcg/day of levonorgestrel initially which decreases gradually over 5 years to 10 mcg/day. Effective for 5 years. Replace once every 5 years. Affects implantation of egg, sperm migration. High incidence of irregular bleeding in first 6 months. IUD is inserted within 7 days of the onset of menstruation or immediately after first-trimester abortion. FDA recommended only in women who have had one child. 3. Skyla: (2013) 30x28 mm T-shaped polyethylene frame with a drug reservoir that contains 13.5 mg levonorgestrel. (releases 14 mcg/day initially and decreases gradually over 3 years to 5 mcg/day). Smallest of the IUDs. 4. Liletta (2015): Similar to Mirena releases 18.6 mcg/day of levonorgestrel which decreases to 12.6 mcg/day over 3 years. 5. Kyleena (2017): similar to Skyla in size, 30x28 mm T-shaped polyethylene frame with a drug reservoir that contains 19.5 mg levonorgestrel. (releases 17.5 mcg/day after 24 days, decreases to 9mcg/day at 1 year and 7.5 mcg/day after 5 years).

Answer 96

• Drugs used for the prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure • to be effective these must be taken within 72 hours of intercourse • two products are available: – Plan B: 0.75 mg levonorgestrel – Plan B one Step OTC: single 1.5 mg tablet taken once – Side effects: headache, abdominal pain – Efficacy decreases with increasing BMI OTHER ECP • Combined ECPs: Preven: 0.25 mg levonorgestrel and 0.05 mg ethinylestradiol (this product includes a pregnancy test kit) − 2 doses 12 hours apart − Taken within 72 hours after unprotected intercourse • Copper IUD: Inserted within 5 days after intercourse is most effective − Pregnancy rates as low as 0.1%. − Most effective method • Antiprogestin ECPs- (Ulipristal acetate –Ella), an antiprogestin FDA approved for ECP. − SPRM (selective progesterone receptor modulator) − Only available by prescription, approved for use up to 5 days after unprotected

Answer 97

A. OTC preparations of creams, gels, foams or suppositories B. Active ingredient is octoxynol-9 or nonoxynol-9**a nonionic detergent that permeabilizes the cell wall of sperm C. Used before intercourse D. Most effective when combined with diaphragm, condom or cervical cap E. Perfumes and additives may be irritating

Answer 98

A. Goal is to delay and/or prevent or delay osteoporosis, - reduce risk of CV disease - Reduce vasomotor disturbances (hot flashes): cause daytime discomfort and night sweats that may disrupt sleep - Reduce genitourinary syndrome of menopause (GSM): (thin, dry vaginal lining and urethral mucosa can cause vaginal and vulvar burning and irritation, pain during intercourse and an increased risk of urinary tract infections) **at menopause estrogen levels fall to 10% of premenopausal and progesterone is Negligible B. Recommendations for treatments • Low dose Estrogen- most effective for menopausal vasomoter syndromes and GSM • Systemic estrogen formulations preferred for treatment of vasomoter syndromes. Women with intact uterus should take systemic estrogen + progestin. • Low dose vaginal estrogen products preferred for women only with GSM. Addition of progestin not necessary • Nonhormonal therapies

Answer 99

1. Estrogen alone or combined with progesterone -unopposed estrogen associated with increased risk of endometrial cancer  For women who have not undergone hysterectomy, a progestin is always included with the estrogen therapy, because combination reduces the risk of endometrial cancer  For women who have undergone hysterectomy, unopposed estrogen therapy is recommended, because progestins may unfavorably alter HDL/LDL ratio.  Addition of progestin is generally not necessary in women with intact uterus who are using low-dose vaginal estrogen product. A. REGIMENS a. Cyclic estrogen 21 days + progesterone for last 10 days + 1 week off b. Estrogen + progesterone for first 10-13 days c. Continuous estrogen + progesterone B. Estrogen and progesterone components -conjugated estrogen -medroxyprogesterone acetate -norethindrone 2. Conjugated estrogens/selective estrogen receptor modulator – Approved by FDA (2013) – Fixed dose combination of conjugated estrogen and the new selective estrogen receptor modulator (SERM) bazedoxifene (Duavee by Pfizer) – Treatment of moderate to severe vasomotor symptoms – Prevention of osteoporosis in postmenopausal women with an intact uterus – Bazedoxifene is an estrogen agonist/antagonist with estrogen like effects on bone and antiestrogen effects on uterus. – Not approved for treatment of vulvovaginal atrophy or dyspareunia – Long term effect of VTE and ischemic stroke needs to determined

Answer 100

D. Adverse Effects - blood clots - hypertension (dose dependent) E. Contraindications - estrogen dependent neoplasia - breast cancer - thrombophlebitis

Answer 101

1. Must weigh benefits with risks in each individual 2. Will reduce hypo-estrogenic symptoms and reduce risk of osteoporosis 3. Greater risk of cardiovascular disease 4. Greater risk of breast cancer

Answer 102

• Menses are a sign of overall health ``` History: • Menarche • Cycle interval • Cycle length • Blood flow • Pain/cramping • Associated symptoms ```

Answer 103

Labs 1. CBC - check for anemia 2. Ferritin - iron stones 3. TSH and FSH, Prolactin - check ovulation status 4. VonWillebrand panel; factor VIII activity, ristocetin cofactor, VW antigen 5. Consider; PT/PTT/INR Pelvic ultrasound; • Assess thickness of endometrium • Rule out structural abnormality (rare) • Uterine anomaly

Answer 104

``` • Begins age 11-14 • Cycle interval 21-45 days • Cycle length <=7days - 3-6 pads/tampons a day -<80mL per cycle ```

Answer 105

Endocrine (3) - Anovulation - PCOS - Thyroid Bleeding disorder (4) - VWD - Platelet d/o - Thrombocytopenia - Clotting factor deficiency Pregnancy (3) - Abortion - ectopic - GTD Infection (2) - cervicitis - PID Uterine (4) - myomas - polyp - cancer - endometriosis Medication (2) - DMPA - Anticoagulant Other (1) - Trauma

Answer 106

ANOVULATION in adolescence - due to immaturity of HPO axis ``` Menorrhagia in Adolescents #1 cause- Anovulation • Immature hypothalamic-pituitary axis ``` #2 cause- Coagulation disorder • Von Willebrand disease • Thrombocytopenia • ITP, TTP, leukemia, aplastic anemia • Platelet function disorder

Answer 107

COmbined oral contraceptive pills - contains estradiol and progestin (Stabilize the lining - the only downside is NAUSEA) - MONOPHASIC • Estrogen provides stability to the endometrium so that irregular shedding and unwanted breakthrough bleeding are minimized • Progestin produces a decidualized endometrium with atrophied glands • Combined effect taken x3 weeks with then a “withdraw” of both hormones during the placebo week **Estrogen is the fertilizer and progestin is the lawnmower - progestin is the dominant horned at the level of the endometrium Side effects - nausea - HA - mood changes - risk of venous thromboembolism

Answer 108

Endometriosis ; can’t see on imaging, just see spots on peritoneum * Endometrial glands and stroma outside the uterine cavity * 66% of adult patients report onset of symptoms prior to age 20 * 47% patients report seeing MD 5x or more before diagnosis or referral * Family history * Progressive disease * Can lead to infertility • Dysmenorrhea (usually progressive) • Pelvic Pain (acyclic) • Dyspareunia • GI complaints • Menorrhagia (usually assoc with adenomyosis) **Interference with school and social activities

Answer 109

``` Empiric Treatment • Menstrual suppression • Oral contraceptives- continuous or extended duration (1-4 menses per year) regime • Depo Provera • Progestin containing IUD ``` If fails empiric treatment • GnRH agonist x 6 months (if >18 ) • Laparoscopy; if unresponsive to medical therapy - 70% found to have endometriosis on laparoscopy ``` Use of GnRH agonist 1. Down regulate HPO axis • Hypoestrogenic state • Atrophy of endometriotic implants 2. Recommended use for 6 months • Side effects: bone loss, hot flashes, • Need for “add back” therapy; norethindrome 5mg daily - limited duration of use ```

Answer 110

Surgical treatment 1. Diagnostic laparoscopy • Diagnose and grade severity of disease • Remove or destroy all visible lesions at time of surgery 2. Preservation of fertility paramount 3. Normal pelvis; Consider cul-de-sac biopsy 3% microscopic endometriosis in normal pelvis For the patient that presented (21 yrs) 1. Uses combined OCP in continuous manner for complete menstrual suppression 2. 6 months later- menses improved • Pain with intercourse and some pill compliance issues • Decision to proceed with laparoscopy • Endometriosis diagnosed at the time of surgery and lesions ablated • Mirena IUD placed at time of surgery for menstrual suppression/contraception • Currently doing well

Answer 111

Evaluating Dysuria 1. history • Onset and duration • Nature of sxs (intensity, timing, nocturia, incontinence, hematuria, fever, chills, back pain, discharge) • Sexual activity, contraception, partner sxs. • Past history of UTIs • Complicating conditions (diabetes, pregnancy, recent antibiotics, urologic instumentation, anatomical problems) • Med allergies 2. Physical exam; vitals, appearance, abdomen, CVA tenderness, pelvic exam if history suggests. 3. Lab; A. UA; dipstick for leukocytes, microscopic i. UA for pyuria • Dipstick (+) for leukocyte esterase • = > 5 WBC/HPF on spun sediment microscopic examination • 8,000 WBCs per mL of urine = 2-5 WBC/HPF (spun) • Sensitive but not specific for UTI • Contamination with vaginal secretions in women II. UA; UTI Diagnosis (sensitivity vs specificity) - microscopic pyuria; >90 (sensitivity), >50-75 (specificity) - Leukocyte esterase; 75-95 (sensitivity), 94-98 (specificity) - Nitrite*; 35-85 (sensitivity), 90-100 (specificity) * * Nitrite only (+) for enterobacteriaceae (not Staph, enterococcus, pseudomonas). Thus, (-) tests must be interpreted with caution. B. urine culture • Not necessarily needed in women likely to have uncomplicated cystitis by history and urinalysis • Most valuable in patients with acute pyelo, recurrent infections, complicated UTIs • Indications: Suspicion of complicated UTI, Atypical symptoms, Treatment failure, Recurrent symptoms (< 1 month after Rx of previous UTI) • >100,000 CFU/mL (colony-forming units) considered reliably (+) for proper clean catch urine • No clear cutoff and affected by various factors • Some say >1000 CFU/mL should be used in patients with symptoms; Diluted, washed out urine, Early infection, On antibiotics already, Men contamination less likely

Answer 112

1. Conditions that present with dysuria (In Men) • Men: generally acute cystitis very rare (anatomic problems) • Men: urethritis more common in young sexually active men (dysuria alone suggest CHLAMYDIA, dysuria and discharge suggest gonorrhea) • Men: UTI more common in older men with prostatic hypertrophy 2. UTI Epidemiology • Mostly women (shorter urethra) • 40%- 50% of adult women have had or will have a UTI; 20% will have recurrent episodes • 9,000,000 doctor visits in U.S. annually • 250,000 cases of pyelonephritis yearly • 100,000 hospital admissions yearly • >$2.4 Billion annually • Men have 1 per 1000 years (longer urethra and prostate produces antibacterial substances) ``` UTI (risk factors) 1. Women; • Female >>>male • Sexual intercourse (3 fold) • History of UTI (5 fold) • Diaphragm use • Spermicidal use • Pregnancy • Urethral catheterization • Postmenopausal ``` 2. Men • Prostatic hypertrophy • Urethral catheterization UTI common pathogens • Escherichia coli (90%) • Enterococcus • Pseudomonas aeruginosa (nursing homes, hospitalized) • Proteus mirabilis • Klebsiella pneumoniae • Staphylococcus saprophicitus (gram (+)) UTI pathogenesis • Urine nice medium for bacteria • Retrograde transmission (facilitated by sexual intercourse) or hematogenous spread • Sticky bacteria (25% E. Coli have fimbriae) • Sticky epithelial cells (some women stickier cells) • Flushing of urine protects • Epithelial cells slough • Fecal germs (E. Coli) close by entrance of urethra • Women shorter urethra that is closer to rectum • Male prostatic secretions are bacteriostatic 3. Vaginitis • Dysuria with vaginal discharge or odor, itching, dyspareunia • Urinalysis shows little or no pyuria • Pelvic exam with examination of discharge • 3 common etiologies: - CANDIDA VAGINITIS ; thick white cottage cheese, normal vaginal pH (<4.5), hyphae and budding yeast, negative whiff test - TRICHOMONAS VAGINITIS; copious yellow green malodorous discharge, vaginal pH >4.5, motile Trichomonas, WBSs, may be positive or negative whiff test - BACTERIA VAGINOSiS; thin off white “fishy odor” discharge, vaginal pH >4.5, CLUE CELLS, positive whiff test. **Atrophic vaginitis; post menopausal, estrogen deficient women. May experience dysuria, UA normal and culture no growth. Topical estrogen often effective.

Answer 113

Upper vs Lower UTIs Cystitis (bladder infection) • LOWER tract infection • Affects bladder wall - symptoms; dysuria, frequency, urgency, suprapubic pain - exam; OK except suprapubic tenderness sometimes • Lab: urinalysis - PYURIA (culture not needed if uncomplicated UTI). If hematuria pressent = hemorrhagic cystitis. May have (+) nitrites (certain bacteria only) • UTI sxs in presence of leukocytes adequate to make diagnosis ``` Pyelonephritis (kidney infection) • UPPER tract infection • Affects tissue of the kidney - symptoms; flank pain, fever, abdominal pain, nausea/vomiting - UA; WBC CASTS ```

Answer 114

Upper UTI therapy; e.g kidney - flank pain, fever, abdominal pain, nausea/vomiting Lower UTI therapy; e.g bladder - DYSURIA, frequency, urgency, suprapubic pain 1. PHENAZOPYRIDINE • Urinary analgesics can be used once diagnosis is made • Turns urine red and leads to false (+) dipstick urinalysis. (sweat orange) • G6PD deficiency patients can get hemolytic anemia • Use for 2 days only Cystitis; Prevention • Cranberry Juice contains tannins which can decrease binding ability of E. Coli • Void soon after sex • Avoid prolonged bath soaking • Wiping direction front to back • Void when get urge – do not hold it in • Drink lots of water • Cotton underwear, loose fitting clothes, decrease warmth and lessen colonization of perineum. UTI in children • Recommendation is for 7-14 days of antibiotic Rx. In children even with simple cystitis (evidence inconsistent) • How sick they look affects decision for parenteral or oral therapy

Answer 115

Complicated vs Uncomplicated UTIs Uncomplicated - UTI in other wise healthy nonpregnant adult woman e.g honeymoon cystitis • Almost all of these patients have E. Coli (75-95%) or S. Saprophyticus (5-20%) Complicated - UTI with medical history e.g diabetes, pregnancy, hx of acute pyelonephritis in last year • Pregnancy • Diabetes mellitus • History of acute pyelonephritis in last year • Relapsing UTI in past year • History of UTI in childhood • 3 or more UTIs in past year • Uropathogen with multiple resistance pattern • Hospital acquired UTI • In-dwelling urinary catheter • Anatomic or functional abnormality of urinary tract • Antibiotic treatment within the last month • Urine culture should be obtained with sensitivities • Therapy may need to be adjusted (longer, different antibiotic) • May require further evaluation

Answer 116

Basic approach to managing UTIs 1. Common choices • Flouroquinolones (bactericidal, once daily dosing, less resistance) [ciprofloxacin, levofloxacin] • Trimethoprim/sulfamethoxazole (inexpensive, increasing resistance of E. Coli, avoid if sulfa allergy) • Tetracyclines (bacteriostatic, cover E. Coli and chlamydia and mycoplasma, useful in urethritis) [doxycycline] • Nitrofurantoin (bactericidal, very rare resistance for E. Coli & S. Saprophyticus, safe in pregnancy) Not good for Proteus, Psuedomonas • Cehalosporins [cephalexin] • Penicillins [amoxicillin] (increased resistance to E. Coli, safe in pregnancy) 2. Duration for uncomplicated cystitis (short vs long course) • Short course: 1-3 days (preferred) - TMP-SMX (or fluoroquinolone) for uncomplicated cystitis for 3 days - Amox-clavulanate not as effective short course - Nitrofurantoin 5 days • Long course: 7-14 days - Adverse reactions more common - No clear benefit in adults 3. Duration for complicated UTI • Longer course: 7-14 days • Broader spectrum floroquinolones • Amox, nitrofurantoin, sulfa poor choices • Parenteral therapy may be indicated • Culture guided Rx • Close follow-up if not admitted 3. Duration for complicated UTI

Answer 117

Assessing hematuria 1. Macro vs microscopic A. Macroscopic hematuria (or gross hematuria) = visible with the naked eye • Red or brown urine • If clots, usually means lower tract source • Centrifuge to see if truly blood • Vaginal blood during menstruation may contaminate sample • Color change usually not reflect large degree of blood loss B. Microscopic hematuria = only visible with microscopic examination of the urine • May be incidental finding • More than 2 RBCs per hpf abnormal but no real line • Dipstick may show false (+) so always do micro if (+) • False negative dipstick testing not a problem 2. Glomerular vs extraglomerular bleeding A. Glomerular bleeding • Red cell casts strongly indicate glomerular disease • Proteinuria (>500mg/day) • Dysmorphic cells • Absence of these do not exclude I) IF isolated (no proteinuria or renal insufficiency) transient hematuria think • Post infectious glomerulonephritis • Exercise induced hematuria II) IF isolated persistent hematuria think • IgA nephropathy • Alport syndrome (herditary nephritis) • Thin basement membrane nephropathy (benign familial hematuria) B. Extraglomerular bleeding • Though not common, blood clots in urine virtually never come from glomerular disease • In absence of symptoms or signs, there is no cause of low level hematuria that requires immediate diagnosis. • You have time to repeat in a few days to see if Persistent or Transient. 1) Transient Hematuria • Most patients no causes can be found • Fever, trauma, exercise • UTI (but usually has pyuria and bacteriuria as well) • BUT if >50 yo must think of malignancy anyway CYTOSCOPY • Cystoscopy for ALL adults with unexplained hematuria • Entire bladder can be seen • Video-assisted flexible cystoscopy under local anesthesia. • May see the source of bleeding in bladder or from one or both ureters. • Only test that visualizes urethra & prostate

Answer 118

Causes of hematuria (in adults) Upper - Glomerular Lower urinary tract - cancer, nephrolithiasis etc Causes of hematuria (in kids) - Not cancer - postinfectious glomerulonephritis, hypercalcemia, nutcracker syndrome

Answer 119

Urine and imaging studies 1. cystoscope in all ADULT patients with unexplained hematuria (check for cancer; only test that visualize urethra and prostate 2. Urine cytology • For at risk patients • 90% sensitivity for bladder cancer; but not good for upper tract cancers • Some recommend cytology for low risk patients, also 3. Imaging tests • Looking for lesions of kidneys, collecting system, ureters, bladder • No good guidelines for optimal test • Choices; CT urography (CT scan and IVP combined) - High sensitivity & high radiation dose - DO not use in pregnant women (use U/S) • Renal ultrasound (not very sensitive for small tumors) • Retrograde pyelography ***• IF evaluation negative, remaining causes are likely mild glomerulopathies or intermittent stones. • It is prudent to follow such patients with repeat urinalysis and maybe cytology. • Screening asymptomatic patients for microscopic hematuria is not recommended. CHILDREN • Microscopic hematuria common finding in children (3-4% at any time) • In children hematuria = > 5 RBCs/hpf • Isolated asymptomatic hematuria usuallly benign in children *Transient; UTI, trauma, fever, exercise *Persistent hematuria (5); IgA nephropathy, thin basement membrane disease, alport syndrome, postinfectious glomerulonephritis, hypercalcemia, nut cracker syndrome Evaluation in children 1. Asymptomatic isolated microscopic hematuria; check BP and UA weekly x2 then q 3 months. Urine culture. If persist for 1 yr, check for hypercalcuria, relatives for hematuria 2. Asymptomatic Microscopic Hematuria with Proteinuria • Check serum creatinine and 24 hr urine for protein • If elevated, significant renal ds. Very likely and further w/u indicated (serum C3, C4, albumin, CBC, ASO titer, antinuclear antibody; imaging; renal bx) 3. Symptomatic, microscopic or Gross Hematuria • History of trauma • Perineal irritation • New incontinence, dysuria, frequency, urgency (suggest UTI) • Unilateral flank pain radiating to groin suggests obstruction (stone) • Flank pain with fever (pyelonephritis) • Hx of pharyngitis or impetigo 2-3 weeks earlier (poststreptococcal glomerulonephritis) • Deafness and family history of hematuria (Alport syndrome) • Sxs of Sickle Cell disease or hemophilia • Rarely medications 4. Symptomatic or Gross hematuria • Trauma history – get CT abdomen/pelvis • UTI symptoms – get urine culture • Perineal/meatal irritation – local care • Possible stone – get renal ultrasound (preferred over spiral CT in children ) • If glomerular disease suspected (proteinuria, red cell casts, HTN) – get serum creatinine/BUN, electrolytes, CBC, C3, C4, serum albumin, ASO titer, ANA. 5. Gross Hematuria • Most common causes: UTI, meatus irritation, trauma • Much less common causes: stones, sickle cell ds/trait, coagulopathy, glomerular disease, malignancies (e.g. Wil

Answer 120

Nephrolithiasis - calcium oxalate most common - symptoms; PAIN (from obstruction, mild or excruciating, may wax and wane, site of obstruction may relate to location of pain), may be asymptomatic, the only symptom may be passions of a stone. - confirmatory test; Non- constrast helical/spiral CT scan (GOLD STANDARD). Others you can use is ultrasound, regular xray (calcium oxalate), IVP (no more, expose to radiation) - types; calcium oxalate, struvite (staghorn calculus - F>M), uric acid stone, Evaluation • The type and extent of evaluation depends in part upon the following: severity and type of stone disease, first or recurrent stone, systemic disease or risk factors for recurrent stone formation, family history of nephrolithiasis Nephrolithiasis - Confirmatory Tests; Non-contrast helical CT scan • HAS BECOME THE GOLD STANDARD • Almost 100% specific! • Picks up stones missed by KUB or IVP • Can find alternative dx. if not stones • Faster than IVP and slightly more costly Other tests (3) 1. Ultrasound • PROCEDURE OF CHOICE for those needing to avoid radiation (pregnancy or women of child bearing age who might be) • May miss small stones and ureteral stones 2. Abdominal plain radiograph • See radiopaque stones (calcium, struvite, cystine) • Misses uric acid stones or small stones • May be reasonable for hx of previous radiopaque stones 3. Intravenous pyelogram (IVP) • Previous best, no longer • Lower sensitivity, higher radiation than CT ACUTE THERAPY (4) 1. Pain control (NSAIDs, opioids) 2. Hydration 3. Medications to help stones pass; antispasmodic agents, calcium channel blockers, alpha blockers 4. Strain urine and save any stones; size and location determine likelihood, most <4mm pass spontaneously, most >10mm will not, can thus observe if <10mm, refer for active Rx if not pass in 4-6 weeks.

Answer 121

A. Normal adult prostate weighs ~20 gm. B. Encircles bladder neck and urethra C. Divided into four zones 1. Peripheral (carcinomas) 2. Central 3. Transitional (periurethral, hyperplasia) 4. Anterior firbromuscular stroma D. Composed of glands 1. Separated by fibromuscular stroma 2. Lined by two layers of cells - basal layer of low cuboidal epithelium and inner layer of columnar secretory cells 3. Secrete prostatic fluid, a component of semen, which helps protect and improve motility of spermatozoa E. Testicular androgens control growth and survival of prostate cells

Answer 122

1. Acute bacterial prostatitis a. Bacteria are similar to those that cause urinary tract infections (E. coli, gram-negative rods, enterococci, staph) b. Bacteria implanted by reflux of urine into prostate c. Clinical: fever, chills, dysuria, prostate TENDER and boggy on dre; urinalysis shows leukocytes and bacterial culture + 2. Chronic bacterial prostatitis a. Difficult to diagnose and treat B. Clinical 1) May have mild symptoms: back pain, dysuria, perineal and suprapubic discomfort 2) May be asymptomatic 3) May have h/o recurrent urinary tract infections with same organism 4) Expressed prostatic secretions show leukocytes and bacterial culture (+) 3. Chronic abacterial prostatitis A. Most common form of prostatitis B. Clinical; Indistinguishable from chronic bacterial except prostatic secretions have <10 leukocytes/HPV and bacterial cultures negative 4. Granulomatous prostatitis A. In the United States, most commonly from BCG instilled into bladder to treat superficial bladder ca b. If from BCG then clinically insignificant

Answer 123

BPH (Benign prostatic hyperplasia) or Nodular Hyperplasia Incidence - very common disorder in man > 50 yrs old (normal aging prostate) - seen in 20% of men 40 yrs old, 70% age 60, 90% age 80 Etiology/pathogenesis A. Increased number of epithelial cells and stromal components influenced by DHT B. Dihydrotestosterone (DHT) is the main prostate androgen 1. Testosterone is converted to DHT by type 2 5-alpha-reductase in stromal cells 2. DHT binds androgen receptor (AR) on stromal and epithelial cells 3. DHT-AR activates transcription of growth factor genes 4. DHT-induced growth factors - increase proliferation of stromal cells and - decrease death of epithelial cells

Answer 124

Morphology A) Prostate enlarges to a wt of 60-100 gms B. Originates in transition zone (periurethral) C. Early nodules are composed of stromal cells (pale gray, tough, no fluid) D. Later nodules are composed of epithelial cells / glands (pink- yellow, soft, exude milky prostatic fluid) E. Microscopic - nodules (stromal fibromuscular to fibroepithelail with glands) - glands are small to large to cysticaally dilated, lined by 2 layers - usually not diagnosed on needle biopsy because nodules are hard to appreciate in limited samples F. NOT considered to be a premalignnat lesion Clinical a. Urethral obstruction (caused by increase in size of prostate, nodules impinging on urethra and smooth muscle contraction of prostate) leads to: 1) Bladder hypertrophy and distension 2) Urine retention, residual urine which results in: a) Frequency, nocturia, difficulty starting and stopping, overflow dribbling, dysuria b) Infection 3) Sudden acute urinary retention Treatment a. Decrease fluids before bedtime, decrease caffeine and EtOH, timed voiding for mild cases b. Medical therapies for moderate to severe symptoms 1) alpha blockers decrease prostate smooth muscle tone 2) 5-alpha reductase inhibitors inhibit synthesis of DHT and shrink prostate C. Surgical therapies- transurethral resection of the prostate (TURP) is most common for cases that don’t respond to medical therapies

Answer 125

Prostate adenocarcinoma A. Diet - high fat diet may contribute to risk B. Androgens - induce progrowth and prosurvival genes in cancer cells as well as normal cells C. Genetics - mutations and epigenetic changes 1) Men with one first-degree relative with prostate ca: risk is 2X that of men without family history, two first-degree relatives: risk is 5X 2) Presence of BRCA2 mutations: 20X increased risk 3) Some genetic changes include A. Rearrangement of ETS transcription genes downstream from androgen-regulated TMPRSS2 promoter. Overexpression of ETS transcription factors is then androgen-dependent and makes normal prostate epithelial cells more invasive B. Deletions (PTEN tumor suppressor) & amplifications (MYC oncogene) C. Epigenetic alterations of GSTP1 (most common, protects against damage by carcinogens), tumor suppressor genes such as RB, CDKN2a, MLH1, MSH2, and APC D. Prostate intraepithelail neoplasia (PIN) - presumable a precursor lesion to cancer 1) Seen more frequently and extensively in prostates with cancer (about 80% of prostates with cancer) 2) Predominantly seen in peripheral zone same as cancer 3) Have some of the same genetic changes as cancer 4) Seen in a younger age group than cancer 5) Will all PIN progress to cancer? Not known 6) PIN - morphology - High grade PIN cells look the same as cancer cells - PIN glands differ from cancer glands; i. Larger than cancer glands with branching and infolding ii. Surrounded by patchy layer of basal cells and intact basement membrane

Answer 126

a. Arises in peripheral zone 70% of time, classically in posterior area where it can be palpated as hard nodule(s) on rectal exam b. Histology: 1) Glands are small, more crowded, without branching or infolding, separated by little or no stromal material “back-to-back” glands 2) Glands are lined by a single layer of cuboidal or columnar cells; OUTER BASAL CELL LAYER IS ABSENT 3) Cells may be hyperchromatic but pleomorphism and mitosis figures are uncommon C. Spread 1) Local extension is to periprostatic tissues, seminal vesicles, base of bladder 2) Metastasis first via lymphatics to obturator nodes then para-aortic nodes; via blood to bones (lumbar spine, proximal femur, pelvis, thoracic spine, ribs) to form OSTEOBLASTIC lesions

Answer 127

A. Grading is by Gleason system 1. Gleason 1 (lowest grade); most well-differentiated with uniform round glands in well-circumscribed nodules 2. Gleason 5 (highest grade); no glandular differentiation, cells infiltrate stroma in cords, sheets, nests 3. Tumors are scored by most prominent pattern + second most prominent pattern B. Staging by TNM - CLINICAL STAGING 1) extent of primary tumor T1- tumor not appreciated by palpation or imaging T2- tumor is palpable or visible, confined to prostate T3 - local extraprostatic extension (a-extracapsular extension, b-seminal vesicle invasion) T4 - invasion of contiguous organs 2) status of regional lymph nodes N0 - no regional lymph node metastasis N1 - regional lymph node metastasis 3) distant metastases M0- no distant metastasis M1- distant metastasis (a-distant LNs, b- bone Mets, c- other distant sites) C. Staging by TNM - anthologies staging . Primary tumor (pT) **PATHOLOGIC STAGING PT2- organ confined PT2a - unilateral, involving one-half of 1 slide or less PT2b - unilateral, involving more than one-half of 1 size but not both sides PT2c - bilateral disease PT3 - extraprostatic extension PT3a - extraprostatic extension or microscopic invasion of bladder neck PT3b - seminal vesicle invasion PT4 - invasion of rectum, levator muscles and/or pelvic wall ** Note: There is no pathologic T1 classification. Subdivision of pT2 disease is problematic and has not proven to be of prognostic significance.

Answer 128

a. Most incidentally discovered focal cancer (Stage T1a) found on TURP do not progress when followed 10+ yrs, workup depends on the age of the patient b. Stage T1b lesions are more concerning c. Local prostate cancer is asymptomatic; urinary symptoms occur late; uncommon for first presentation to be for back pain due to vertebral metastasis d. Digital rectal exam (DRE) 1) May detect early prostate cancers 2) Low sensitivity and specificity E. Transrectal ultrasonography - also low sensitivity and specificity F. Transrectal needle biopsy - confirms diagnosis G. PSA (prostate specific antigen)

Answer 129

1) Normally secreted into semen, minute amounts circulate in serum 2) Serum levels are elevated in localized and advanced prostate cancer 3) Factors other than cancer can elevate PSA: prostatitis, infarct, instrumentation of the prostate, ejaculation, uti, others. DRE does NOT appreciably increase PSA 4) Organ specific but not cancer specific 5) Useful for diagnosis and management of prostate cancer 6) Use as a screening test for prostate cancer is controversial, lacks both sensitivity and specificity 7) Cutoff for normal serum level is 4.0 Nig/ml in most labs 8) However, ~25% of men with a PSA 2.5-4 ng/ml have prostate cancer 9) Refinements which may improve PSA screening A) PSA density (serum PSA value/volume of prostate gland) B) PSA velocity (rate of change of PSA level with time) c) Age specific reference ranges (PSA normally increases with age, possibly due to BPH) d) Ratio of bound and free PSA in serum (men with prostate cancer have lower percentage of free PSA)

Answer 130

1. Surgery (radical prostatectomy) - most common treatment for clinically localized cancer 2. Radiation - localized cancer and cancer too locally advanced for surgical cure 3. Hormone manipulation (androgen deprivation) - advanced metastatic cancer 1) Orchiectomy 2) Luteinizing hormone-releasing hormone agonist 3) Tumors eventually develop resistance to androgen blockade 4. >90% of patients who receive therapy can expect to live 15 years 5. Serial PSA measurements are useful for assessing response to treatment

Answer 131

``` 1. Penis A. Congenital; - hypospadias, epispadias, - phimosis B. Inflammation; - Balanoposthitis ( infection of glans and prepuce), - STI, - Peyronie’s disease C. Tumors - condyloma acuminatum - giant condyloma - dysplastic/CIS; Bowen’s disease, Bowen PID papulosis - SCC, rare primary neoplasms, metastatic neoplasms ``` ``` 2. Testis and epididymis A. Congenital - cryptorchid testis B. Regressive changes - atrophy of testis C. Inflammation - non specific - gonorrhea - mumps - syphilis D. Vascular disorders - torsion E. Tumors - benign paratesticular tumor; adenomatoid tumor - testicular tumors; Germ cell - seminamatous vs non seminamatous, sex cord-stromal tumors - ITGCN; intratubular germ cell neoplasia - seminoma - embryonal carcinoma - yolk sac tumor - choriocarcinoma - teratoma - mixed germ cell tumor - germ cell testicular tumors; SGCT vs NSGCT - tumor of sex cord gonadal stroma; Leydig cell tumor - Sertoli cell tumors ```

Answer 132

Malformation of urethral groove and ureteral canal **Associated with undescended testis, GU malformations. May hamper insemination 1. Hypospadias; abnormal opening of the urethra along VENTRAL aspect of penis 2. Epispadias; abnormal opening of urethra along DORSAL aspect of penis Phimosis - Orifice of prepuce too small to permit retraction - Congenital or acquired by inflammation - Hygiene: predisposed to infection, carcinoma

Answer 133

1. Balanoposthitis (infection of glans and prepuce) - Non-specific infection from bacteria and fungi; not sexually transmitted. 2. Syphilis 3. STI; syphilis, gonorrhea, chancroid, granuloma inguinale, herpes (superficial ulcer, mainly HSV 2) 4. Peyronie’s Disease - Painful curvature of penis toward lesion.

Answer 134

1. Condyloma Acuminatum • sessile or pedunculated; variable size; acanthosis and hyperkeratosis, koilocytosis • HPV related • Recurs but benign 2. Giant condyloma

Answer 135

Associated with high risk HPV, esp. type 16 Entities (REMEBER they are in situ carcinoma) 1. Bowen’s disease ► Bright red plaque with moist surface ► Single lesion, older patient ► Dysplastic and anaplastic cells in epithelial layer ► Intact basement membrane - no dermal involvement 2. Bowenoid papulosis ►Sexually active, young adults ►Multiple pigmented papules ►Hi

Answer 136

1. Squamous cell cancer - MOST COMMON - strongly related to HPV, type 16 and rarely 18 - older patient, uncircumcised, poor hygiene ►Clinical: Occurs in older population, circumcision confers protection, age of circumcision, hygiene. ►Slow growing; commonly starts at coronal sulcus. Plaque, ulceration or verrucous growth. ►Limited disease has 66% 5 year survival; 27% if regional nodes involved. ►Similar in histology to other SCC - well to poorly differentiated ►Papillary and flat patterns ►Verrucous carcinoma: exophytic, well differentiated, locally invasive ►Vaccine:• Both to low risk (6, 11) and high risk (16, 18) HPV ►Usual metastases to inguinal lymph nodes 2. Other malignancies • Rare primary neoplasms: Melanoma, soft tissue sarcomas, lymphoma • Metastatic neoplasms rare unless direct spread from other GU

Answer 137

CRYPTORCHID TESTIS ►Increased risk of injury and cancer. If bilateral, sterility ►Pathologic changes and increased cancer risk by age 2. Some increase in cancer even with correction in infancy **INCREASED RISK OF GERM CELL TUMORS ``` Pathology of cryptorchid testis ►Increased hyaline deposition ►FAILURE OF GERM CELL MATURATION ►Increased or normal Leydig cells ►Tubular atrophy; increases with age ``` ATROPHY OF TESTIS ►Causes: Age, atherosclerosis, perivascular inflammation, cryptorchidism, malnutrition, hypo-pituitarism, obstruction, radiation, hormonal therapy, genetic defects (Klinefelters).

Answer 138

1. Non-specific: Usually from UTI pathogens 2. Gonorrhea: Classically in epididymis. - Abscess formation and general inflammatory changes ``` 3. Mumps: Adolescent and adults; heavy mononuclear inflammation, edema. May have neutrophils and abscesses. Most resolve but severe cases result in atrophy ``` 4. Syphilis 5. Chronic orchitis 6. Tuberculosis

Answer 139

TORSION - Twisting of spermatic cord and blockage of venous drainage. - Hemorrhagic infarction of testis - Acute testicular pain and swelling

Answer 140

Benign paratesticular tumor: Adenomatoid Tumor * Cuboidal/flat cells in cords, cytoplasmic vacoule * Simple excision curative ** * Accurate diagnosis will spare orchiectomy

Answer 141

Germ cell tumors 1. Seminomatous tumors ►Seminoma (one cell type) ►Spermatocytic seminoma ``` 2. Non-seminomatous tumors ►Embryonal carcinoma ; extraembryonic ►Yolk sac (endodermal sinus) tumor ►Choriocarcinoma; extraembryonic ►Teratoma; somatic embryonal carcinoma ``` Sex Cord-Stromal Tumors • Leydig cell tumor • Sertoli cell tumor

Answer 142

Intratubular Germ Cell Neoplasia (ITGCN) **Isochromosome 12p****

Answer 143

Testicular tumors ►Germ cell tumors more aggressive, divide fast but respond to therapy ►Sex cord-stromal tumors are generally benign ►Incidence 6/100,000 US ►Peaks 15 - 34; small peak in early childhood and over 60. ►Present as painless testicular mass ►Germ cell tumors associated with testicular dysgenesis syndrome: Cryptorchidism, hypospadias and poor sperm quality ►Isochromosome 12p in nearly all tumors Molecular genetics (GERM CELL) ►Germ cell tumors contain isochromosome 12p ►Express OCT3/4 and NANOG ►25% seminomas also have KIT activating mutations GERM CELL (staging) ► Staging is most predictive of prognosis; type is usually less important ► Markers: Variable, helpful with follow-up if present initially  AFP: Always elevated in yolk sac tumors; never in choriocarcinoma, rare in seminoma; others may have mild elevation  HCG: Always in choriocarcinoma; never in yolk sac, rare in seminoma; others may have mild elevation

Answer 144

SEMINOMA ``` ► Serum markers  10% with hCG (gynecomastia)  AFP negative (unless liver mets or mixed with germ cell)  PLAP (serum) - 50% ► Most confined to testes at presentation ► Preceded by ITGCN ► Very radiosensitive ► Isochromosome 12p ```

Answer 145

Spermatocytic seminoma * *DIFFERENT TUMOR THAN SEMINOMA - 1-2% of all germ cell tumor Cellular pleomorphism (3 types) 1. Small cells; lymphocyte like 6-8 um 2. Intermediate cells; 15-20 um - filamentous granular chromatin; variable staining cytoplasm 3. Large cells; 50-100 um.

Answer 146

Embryonal carcinoma **Large anaplastic undifferentiated cells

Answer 147

YOLK SAC TUMOR * Endodermal sinus pattern: Characteristic - central core * Schiller-Duvall bodies – resemble primitive glomeruli; Schiller-Duvall body is a structure seen in the endodermal sinus pattern of yolk sac tumor. It consists of a central vessel surrounded by tumor cells – the whole structure being contained in a cystic space often lined by flattened tumor cells. * Spaces lined by flattened epithelium, may have solid and cord- like areas

Answer 148

Choriocarcinoma 2 cell types 1. Syncytiotrophoblastic cells ►Large cells with irregular nuclei (smudged nuclear chromatin) 2. Cytotrophoblastic cells ►Smaller regular cells with clear cytoplasm

Answer 149

TERATOMA * Ectoderm: Neural and epidermis * Endoderm: GI, respiratory, mucous glands * Mesoderm: Bone, cartilage, muscle

Answer 150

► 60% of testicular tumors are mixed type ►Common types • Teratoma, embryonal carcinoma, yolk sac • Seminoma with embryonal ca • Teratoma with embryonal ca ►Prognosis worsened by more aggressive element

Answer 151

Germ cell testicular tumors 1. SGCT - localized to testis longer (stage 1) - Mets lymph nodes - radiosensitive - better prognosis 2. NSGCT - 60% present with stage 2 or 3 - Mets hematogenous (chorio to lung and liver) - radioresistant - poorer prognosis Clinical stages ►Stage 1: Confined to testis, epididymis, or spermatic cord ►Stage 2: Retroperitoneal nodes below diaphragm ►Stage 3: Mets outside retroperitoneal nodes or above diaphragm ``` Serum markers ►LDH-Tumor burden/volume ►AFP-Yolk sac tumor ►HCG-Choriocarcinoma - help assess tumor burden - monitoring response to therapy ```

Answer 152

LEYDIG CELL TUMOR; tumors of sex cord-gonadal stroma

Answer 153

1. Sertoli cell tumors | 2. Testicular lymphoma

Answer 154

1. Bowen disease - CARCINOMA IN SITU 2. SEMINOMA 3. CHORIOCARCINOMA; hemorrhagic and necrotic areas, hCG is POSITIVE 4. TERATOMA

Answer 155

1. Functional or benign cysts - cystic follicles - luteal cyst (corpora lutea) - polycystic ovaries (formerly stein-levanthal syndrome) 2. Tumors - ovarian tumors; mullerian epithelial tumors, serous tumor, serous cystadenoma, borderline serous tumor, malignant serous cystadenocarcinoma, mucinous tumor, benign mucinous cystadenomas, borderline mucinous tumor, malignant mucinous cystadenocarcinoma, pseudomyxomatous peritonei - other epithelial tumors; endometriosis tumors, clear cell adenocarcinoma, cystadenofibroma, Brenner tumor (transitional cell tumor), - germ cell tumors ; benign teratoma, monodermal teratomas, immature/malignant teratomas, dysherminoma, endodermal sinus (yolk sac) tumor, choriocarcinoma - other germ cell tumors; Embryonal, polyembryoma, mixed germ cell tumors - sex cord- stromal tumors; granulosa cell tumors, granulosa - Theca tumors, fibroma/thecoma/fibrothecoma, sertoli-leydig cell tumors (androblastoma) 3. Inflammation - RARE!

Answer 156

1. Follicle - start as primordial follicle - primary follicle - SECONDARY follicle - Graafian follicle 2. Hormones A. LH (Leutinizing hormone) - theca cells - androgen B. FSH (follicle stimulating hormone) - granulosa cells - androgen - estradiol - proliferative endometrial cycle C. Estradiol ; increased LH surge - ovulation - secretory phase endometrial cycle

Answer 157

1. Cystic follicles 2. Luteal cyst (corpora lutea) 3. Polycystic Ovaries (formerly Stein-Levanthall syndrome) • 6-10% reproductive age women • Clinical: persistent hyperandrogenism, menstrual abnormalities, polycystic ovaries, chronic anovulation, decreased fertility • Associated with obesity, type 2 diabetes, and premature atherosclerosis • Insulin resistance and altered fat metabolism • Dysregulation of enzymes involved in androgen biosynthesis - resulting in increased androgen •

Answer 158

OVARIAN TUMORS Clinical Symptoms; POST MENOPAUSAL BLEEDING • Abdominal pain and distention • GI complaints • Urinary frequency/dysuria • Pressure • Vaginal bleeding • Benign lesions: asymptomatic, incidental on abdominal/pelvic exam or surgery Classification; based on tissue of origin 1. Surface epithelial-stromal tumors; form from outside capsule of ovary - overall frequency 65-70% - 90% of malignant ovarian tumors - 20+ yrs age group - types; serous tumor, mucinous tumor, endometriod tumor, clear cell tumor, brenner tumor, cystadenofibroma 2. Germ cell tumors - overall frequency 15-20% - 3-5% malignant ovarian tumors - age group 0-25+ yrs - types; teratoma, dysgeminoma, endodermal sinus tumor, choriocarcinoma 3. Sex cord-stromal tumors - overall frequency 5-10% - 2-3% malignant ovarian tumors - affect all ages - types; fibroma, granulosa theca cell tumor, sertoli-leydig cell tumor. 4. Metastatic Cancer: colon (appendiceal), gastric, pancreatobiliary, breast - metastasize to ovaries; 5% overal frequency, 5% malignant ovarian tumors, variable age group ***Most malignant tumors are SEROUS and BILATERAL

Answer 159

Mullerian/SURFACE epithelial tumors • Most ovarian neoplasms Three major types • Serous • Mucinous • Endometrioid • Range in size from small to massive Include cystic to solid areas • Cystadenoma (cystic) • Adenofibroma (fibrous) • Cystadenofibroma (cystic and fibrous) • Risk of malignancy increases as amount of solid epithelial growth increases • Tumors occur as benign, borderline or malignant

Answer 160

2 Different Types: • Type I tumors - benign tumors - borderline tumors - low-grade carcinoma (endometrioid and mucinous carcinomas) ``` • Type II tumors - inclusions cysts/fallopian tube epithelium via intraepithelial precursors that are often not identified – Seron intraepithelial carcinoma (STIC) – high grade serous carcinoma ```

Answer 161

Serous tumor (Ovarian tumors) Risk factors • Nulliparity (No child) • Family history • Heritable mutations • Reduced risk - age 40-59 with history OCP use or tubal ligation *BRCA1 or BRCA 2 increase susceptibility; 20-60% risk by 70 Serous tumor pathogenesis ; 2 major groups based on nuclear atypia 1. Low-grade (well differentiated); arise in association with serous borderline tumors 2. High grade (moderately to poorly differentiated) carcinoma - carcinomas arise from in situ lesions in the fallopian tube fimbriae or from serous inclusion cysts within the ovary MAJOR PATHOGENESIS **FALLOPIAN TUBE ORIGIN FOR HIGH GRADE SEROUD CARCINOMA

Answer 162

* *Remember, Fallopian tube origin for high grade serous carcinomas 1. Historically thought serous ovarian carcinomas arose from cortical inclusion cysts; these cysts were thought to arise through invagination of the surface epithelium, followed by serous metaplasia 2. A recent alternative hypothesis is that the cysts arise from implantation of detached fallopian tube epithelium at sites where ovulation has disrupted the surface of the ovary - the percentage of sporadic high grade serous carcinomas that arise in the Fallopian tube or from ovarian inclusion cyst is UNKNOWN - origin of the cortical inclusion cysts is UNKNOWN * *Studies being done to address these issues - management of women at high risk for ovarian carcinoma; undergo salpingo- oophorectomy, instead of simple oophorectomy * *Low grade arising in SEROUS BORDERLINE TUMOR; KRAS, BRAF, or ERBB2 oncogenes, and usually have wild type TP53 genes * *High grade; High frequency of TP53 mutations and lack mutations in either KRAS or BRAF. • Almost all ovarian carcinomas arising in women with BRCA1 or BRCA2 mutations are high-grade serous carcinomas with TP53 mutations • BRCA1/2 mutations are rare in sporadic high-grade serous carcinoma

Answer 163

Serous cystadenoma

Answer 164

Borderline serous tumor

Answer 165

Malignant serous cystadenocarcinoma ``` Concentric calcifications (psammoma bodies) characterize serous tumors, but are not specific for neoplasia **PSAMMOMA BODY ```

Answer 166

MUCINOUS TUMORS * Rarely involves surface of ovary** * Only 5% are bilateral ** * Produce larger cystic masses (ex. > 25 kg) * Multiloculated filled with sticky, gelatinous fluid rich in glycoproteins

Answer 167

Benign Mucinous cystadenomas ** Multicystic appearance, delicate septa, and the presence of glistening mucin within the cysts ➢ Columnar cells lining the cysts ➢ No cilia ➢ Looks like cervical orintestinal epithelium

Answer 168

1. Borderline mucinous tumor • Complex glandular structures with nuclear atypia • resemble tubular or villous adenomas of the colon • No frank stromal invasion 2. Malignant mucinous cystadenocarcinoma • More often solid • Cells resemble intestinal epithelium more than do benign which look more like cervical epithelium • Stromal invasion

Answer 169

Pseudomyxomatous peritonei (ovarian tumors) **Mucin-producing epithelium and free mucin

Answer 170

Endometrioid tumors Grade 1; less than 5% of solid component Grade 2; 6 to 50% of solid component Grade 3; more than 50% of solid component

Answer 171

Clear cell Adenocarcinoma

Answer 172

Cystadenofibroma ** Adenofibroma; Dense,fibrous connective tissue with interspersed glandular spaces

Answer 173

Brenner tumor (transitional cell tumor)

Answer 174

• Present with lower abdominal pain and abdominal enlargement, GI complaints, urinary frequency, dysuria, pelvic pressure • Benign lesions easily resected with cured • Malignant forms cause progressive weakness, weight loss, and cachexia • If extend beyond ovary can cause peritoneal seeding with massive ascites filled with malignant cells • Regional nodes often involved • Metastases: liver, lungs, gastrointestinal tract, opposite ovary • Often goes undetected until large and no longer confined to ovary • Poor prognosis • Tumor marker CA-125 monitors disease recurrence Prevention • Treatment with prophylactic salpingo-oophorectomy • Screening for BRCA mutations and strong family histories

Answer 175

``` Germ cell tumors 3 types of teratomas • Mature (Benign) • Immature (Malignant) • Monodermal (Highly Specialized) ```

Answer 176

MATURE (Benign) TERATOMAS Morphology • Unilocular • Contain hair and cheesy sebaceous material • Can find calcifications and teeth • Histologically can see any mature cell types, most commonly lined by squamous epithelium with underlying skin adnexal structures • Can have malignant transformation (1%) of any of the cell lines (thyroid carcinoma, melanoma); Most common is Squamous Cell Carcinoma Microscopically - Cyst wall is composed of stratified squamous epithelium with underlying : • Sebaceous glands • Hair shafts • Skin adnexal structures ``` - Can see tissues from other germ layers: • Cartilage • Bone • Thyroid • Neural tissue (MATURE BRAIN TISSUE) ``` Histogenesis • Matter of fascination for centuries • Probably derived from ovum after first meiotic division • All have 46 X,X Karyotype

Answer 177

MONODERMAL TERATOMAS (germ cell tumors) Struma ovarii: • Composed of mature thyroid tissue • May be functional and cause hyperthyroidism Ovarian carcinoid • Arises from intestinal tissue found in teratomas • May be functional (>7 cm) • Can produce sufficient 5-hydroxytryptamine to cause the carcinoid syndrome • Primary ovarian carcinoid vs. metastatic intestinal carcinoid (bilateral)

Answer 178

IMMATURE/MALIGNANT teratomas - resemble tissue in embryo Morphology • Bulky with smooth capsule • Predominantly solid • Gross - Hair, sebaceous material, cartilage, bone, and calcification, areas of necrosis and hemorrhage • Microscopically - Immature neuroepithelium, cartilage, bone, muscle, and other elements • Grading (I-III) based on amount of immature neuroectoderm present

Answer 179

Dysgerminoma • Express Receptor tyrosine kinase KIT (therapeutic target) • 1/3 have activating mutations in the KIT gene • Proteins are useful diagnostic markers • Malignant with one-third being aggressive • Radiosensitive • Overall survival > 80% Morphology • Wide range in size, usually unilateral • Solid, yellow- white to gray-pink, soft and fleshy • Large vesicular cells with clear cytoplasm and well- defined cell borders • Grow in sheets or cords separated by scant fibrous stroma • Infiltration by mature lymphocytes and occasional granulomas • Can be associated with a benign cystic teratoma

Answer 180

Endodermal sinus (Yolk Sac) tumor **Morphology • Characteristic histologic feature is a glomerulus-like structure composed of a central blood vessel with surrounding tumor cells (Schiller-Duval body)******* • Contains intracellular and extracellular droplets that stain for alpha-fetoprotein

Answer 181

Choriocarcinoma - Elaborate high levels of HCG****

Answer 182

• Derived from ovarian stroma which in turn has been derived from sex cords of embryonic gonads • Primitive sex cords differentiate toward male (Sertoli and Leydig) or female (granulosa and thecal cells) • Hormonally active - Cells secrete estrogens (granulosa and theca cells) or androgens (Leydig cells) - Corresponding tumors either feminizing (granulosa/theca cell tumors) or masculinizing (Leydig cell tumors)

Answer 183

Granulosa cell tumors (Sex cord - stromal tumors) Clinically important • Secretes estrogen (endometrial hyperplasia or cancer; 10-15%) • Can be malignant (low-grade) • Juvenile granulosa cell tumors - precocious sexual development • Occasionally produce androgens, masculinizing the patient • Likelihood of malignant behavior 5-25% • Tumors composed predominantly of theca cells almost never malignant • Recurrences after 10 to 20 years • 10 yr survival rate - 85%

Answer 184

Granulosa-theca tumors

Answer 185

Fibroma, Thecoma, Fibrothecoma • Associated with pelvic pain, mass, ascites and hydrothorax (right-sided) • Above clinical findings designated as Meigs Syndrome • Also associated with basal cell nevus syndrome • Most benign; Increased nuclear/cytoplasmic ratio with mitoses are fibrosarcomas Morphology • Unilateral • Solid, firm, spherical, lobulated glistening white covered by intact ovarian serosa • Histology: Well-differentiated fibroblast with collagenous connective tissue • Thecal differentiation confirmed by fat stain

Answer 186

Sertoli-Leydig cell tumors (Androblastoma) Morphology • Unilateral • Solid, gray to golden brown • Histology - Well-differentiated; tubules of Sertoli or Leydig cells with stroma - Intermediate; immature tubule and large eosinophilic leydig cells - Poorly differentiated; sarcomatous pattern, non or few leydig cells **May contain heterozygous elements; mucinous glands, bone, cartilage

Answer 187

``` 1. Most common derived from müllerian origin: • Uterus • fallopian tube • contralateral ovary • pelvic peritoneum ``` 2. Most common extra-müllerian tumors: • Breast • Gastrointestinal tract 3. Classic example is Kruckenberg tumor • bilateral metastases of mucin-producing, signet-ring cancer cells, gastric origin 4. Most commonly bilateral

Answer 188

2 cell types - line ducts and lobules Contractile MYOEPITHELIAL CELLS - lie on the BM - assist in milk ejection during lactation and provides structural support to the lobules EPITHELIAL CELLS - luminal - produce milk EPithelial and MYOEPITHELIAL cells lie on the BASEMENT MEMBRANE **Lifecycle changes; breast become fatty and lobules decrease in size as you get older - breast cancer more likely to develop post menopausal

Answer 189

1. Milkline remnants 2. Accessory axillary breast tissues ➢Normal ductal system extends into subcutaneous tissue of chest wall or axillary fossa ➢Mastectomy may not remove 3. Congenital nipple inversion; Failure of nipple to evert ➢Spontaneously correct during pregnancy or simple traction ➢Acquired may indicate cancer or inflammatory nipple disease

Answer 190

1. Pain (mastalgia or mastodynia) ➢ Cyclic with menses (premenstrual edema) or Noncyclic (ruptured cysts, physical injury, and infections) ➢ Almost all painful masses are benign, 10% of breast cancers present with pain 2. Palpable masses ➢ Must distinguish from “lumpiness” of breast ➢ Most common: cysts, fibroadenomas, invasive carcinomas ➢ Benign - premenopausal women - likelihood of malignancy increase with age - 50% of carcinomas are located in the upper outer quadrant - 1/3 of cancers are first detected as a palpable mass 3. Nipple discharge - spontaneous and unilateral; BAD - Small discharge by manipulation of normal breast; normal - milky discharges (galactorrhea); ➢ Elevated prolactin levels (e.g., by a pituitary adenoma) ➢ Hypothyroidism ➢ Endocrine anovulatory syndromes ➢ Also oral contraceptives, tricyclic antidepressants, methyldopa, or phenothiazines. - bloody or serous discharges; large duct papilloma and cysts - risk of malignancy increases with age Mammography screening - sensitivity and specificity increase with age, fibrous and radiodense tissue to fatty, radiolucent tissue Principal mammography signs 1. Densities ➢ Rounded densities are most commonly benign lesions such as fibroadenomas or cysts ➢ Invasive carcinomas generally form irregular masses 2. Calcifications ➢ Associated with benign lesions (apocrine cysts, hyalinized fibroadenomas, sclerosing adenosis) ➢ Calcifications associated with malignancy are usually small, irregular, numerous, and clustered

Answer 191

Rare <1%, Distinguish from carcinoma especially Inflammatory carcinoma ``` ➢ACUTE MASTITIS ➢SQUAMOUS METAPLASIA OF LACTIFEROUS DUCTS ➢DUCT ECTASIA ➢FAT NECROSIS ➢LYMPHOCYTIC MASTOPATHY (SCLEROSING LYMPHOCYTIC LOBULITIS) ➢GRANULOMATOUS MASTITIS ```

Answer 192

ACUTE MASTITIS ➢ Nursing renders breast vulnerable and usually occurs during the first month of breastfeeding ➢ Usually Staphylococcus aureus or, less commonly, streptococci ➢ Usually unilateral ➢ The breast is erythematous and painful, and fever is often present. ➢ Staphylococcal = abscesses ➢ Streptococci = cellulitis ➢ Treatment; abx, continued expression of milk from the breast, rarely - surgical drainage is required.

Answer 193

PERIDUCTAL MASTITIS ``` Morphology ➢ Squamous metaplasia extends into duct ➢ Produces Keratin accumulates and becomes trapped ➢ Dilates and ruptures duct ➢ Granulomatous inflammation ``` Etiology ➢ 90% are smokers suggesting tobacco use alters epithelium

Answer 194

Mammary duct ectasia

Answer 195

FAT NECROSIS Morphology ➢ Hemorrhage (early) ➢ Liquefaction necrosis and ill-defined nodule (later) ➢ Central necrotic fat cells surrounded by lipid-laden macrophages and neutrophilic infiltrate ➢ Later see foreign body giant cells

Answer 196

Lymphocytic Lobulitis Common in ➢Type I DM ➢Autoimmune thyroid disease ➢Possible autoimmune etiology

Answer 197

Granulomatous Mastitis Etiology ➢Systemic granulomatous disease such as Granulomatosis with polyangiitis (Wegener’s) ➢Infection

Answer 198

1. Non proliferative A. Cysts; e.g apocrine cysts (clustered, rounded calcifications) B. Fibrosis (fibrocystic change); cysts rupture - secretory material - adjacent stroma - Chronic inflammation, fibrosis - palpable firmness of the breast C. Adenosis (make sure it isn’t an invasive carcinoma) ``` 2. Proliferative A. moderate or florid hyperplasia B. sclerosing adenosis C. complex sclerosing lesion (radial scar) D. papillomas ``` 3. Atypical hyperplasia A. atypical ductal hyperplasia B. atypical lobular hyperplasia

Answer 199

COMPLEX SCLEROSING LESION - Radial sclerosing lesion (“radial scar”) - commonly occurring benign lesion - forms irregular masses (mimic invasive carcinoma) mammographically, grossly, and histologically

Answer 200

PAPILLOMAS 1. Large duct papillomas; SOLITARY - situated in the lactiferous sinuses of the nipple 2. Small duct papillomas; MULTIPLE - located deeper within the ductal system - >80% of large duct papillomas - nipple discharge - Large papillomas - torsion of stalk - infarction - blooding discharge - Intermittent blockage and release of normal breast secretions or irritation of the duct by the papilloma - non bloody discharge - Others; +nt as small palpable masses, or as densities or calcifications seen on mammograms

Answer 201

GYNECOMASTIA Causes: ➢Hyperestrinism: cirrhosis of the liver ➢Older males - ↑ estrogens as testicular androgen production ↓ ➢Drugs: alcohol, marijuana, heroin, antiretroviral therapy, and anabolic steroids ➢Klinefelter syndrome (XXY karyotype) ➢Functioning testicular neoplasms Leydig cell or Sertoli cell tumors ** Associated with a small increased risk of breast cancer Microscopic ➢ Increase in dense collagenous connective tissue ➢ Epithelial hyperplasia of the duct lining ➢ Tapering micropapillae ➢ Lobule formation absent

Answer 202

1. Atypical DUCTAL hyperplasia 2. Atypical LOBULAR hyperplasia ➢Clonal proliferation have some histologic features seen in carcinoma in situ ➢Moderate increase risk of carcinoma ➢Atypical ductal hyperplasia - 5% to 17% of biopsies performed for calcifications ➢Atypical lobular hyperplasia - incidental finding found <5% of biopsies

Answer 203

1. Non proliferative breast changes (fibrocytic changes) - 1 (3%) 2. Proliferative disease without atypia; 1.5-2 (5-7%) 3. Proliferative disease with atypia; 4-5 (13-17%) 4. Carcinoma in Situ; 8-10 (25% -30%)

Answer 204

Carcinoma of the Breast ➢Most common non-skin malignancy in women ➢2nd only to lung cancer as a cause of cancer deaths ➢1 in 8 chance of developing breast carcinoma woman living to 90 ➢Almost all breast malignancies are adenocarcinomas ➢3 major biologic subgroups based on the expression of estrogen receptor and HER2: 1. Estrogen receptor (ER)-positive, HER2-negative (50% to 65% of tumors) 2. HER2-positive (10% to 20% of tumors, which may either be ER-positive or ER-negative) 3. ER-negative, HER2-negative (10% to 20% of tumors) ➢Groups show striking differences with regard to patient characteristics, pathologic features, treatment response, and outcome

Answer 205

➢Rare in women younger than age 25 ➢Incidence increases rapidly after age 30 ➢ER-positive cancers increase with age ➢Incidence of ER-negative cancers and HER2-positive cancers remains relatively constant ➢ER-positive cancers in older women has ↑ - Mammographic screening (which preferentially detects ER- positive cancers) - Menopausal hormone therapy (which is associated with an increase in these cancers) ➢As a result, ER-negative and HER2-positive cancers comprise almost 1/2 of cancers in young women but fewer than 20% of cancers in older women. **Highest mortality rate in African Americans because they get the bad kind

Answer 206

➢ Beyond female sex (99% of those affected are female) ➢ Major risk factors: - Hereditary factors - Lifetime exposure to estrogen - Lesser extent, environmental or lifestyle factors

Answer 207

Germline mutations ➢ 5% to 10% occur in persons with germline mutations in tumor suppressor genes ➢ Lifetime risk of breast cancer can be > 90% First-degree relatives with breast cancer ➢ 15% to 20% have affected first-degree relative (mother, sister, or daughter), but do not carry an identified breast cancer gene mutation; Due to low-risk susceptibility genes and shared environmental factors ➢ Risk is not increased if the only affected relative is a postmenopausal mother with cancer Race/ethnicity ➢ Non-Hispanic white women have the highest incidence in the United States ➢ Overall incidence is less in African Americans, but present at higher stage ➢ Variation in the frequency of breast cancer genes across ethnic groups

Answer 208

Age ➢ Risk rises throughout a woman’s lifetime ➢ Peaks at 70 to 80 years and then declines Age at Menarche ➢ Menarche at ages younger than 11 years increases risk by 20% ➢ Late menopause also increases risk Age at First Live Birth ➢ Full-term pregnancy before 20 halves the risk compared to nulliparous women or woman older than 35 at first birth Benign Breast Disease ➢ Prior biopsy with atypical hyperplasia or proliferative changes increases the risk of invasive carcinoma

Answer 209

Estrogen exposure ➢ Menopausal hormone therapy, worse with estrogen and progestin together ➢ Oral contraceptives do not increase risk ➢ Oophorectomy decreases the risk up to 75% ➢ Drugs that block estrogenic effects (e.g., tamoxifen) or block the formation of estrogen (e.g aromatase inhibitors) decrease risk Breast density ➢ 4 to 6 fold higher risk in women with very dense breasts Radiation exposure ➢ Radiation to the chest increases risk, greatest with exposure at young ages and with high radiation doses Carcinoma of the contralateral breast or endometrium - 1% of women with breast cancer develop a second contralateral breast carcinoma per year - Endometrial carcinomas also causes prolonged estrogenic stimulation

Answer 210

Diet ➢ No correlations with dietary intake of any specific type of food ➢ Moderate or heavy alcohol consumption increases risk Obesity ➢ Decreased <40 as a result of anovulatory cycles and lower progesterone levels - increased postmenopausal due to synthesis of estrogens in fat Exercise - small protective effect for physically active Breastfeeding - longer breastfeeding reduces risk Environmental toxins ➢ Concern that environmental contaminants, such as organochlorine pesticides, have estrogenic effects ➢ Being investigated, but no definitive associations

Answer 211

Hereditary - Germline mutations Approximately 12% due to inheritance of an identifiable susceptibility gene or genes Probability of a hereditary etiology INCREASE - multiple affected first degree relatives - early onset cancers - multiple cancer - family members with other specific cancers Major susceptibility genes - BRCA1, BRCA2, TP53, CHEK2; are all tumor suppressor genes that have normal roles in DNA repair and maintenance of genomic integrity Mutations in BRCA1 and BRCA2 are responsible for 80% to 90% of “single gene” familial breast cancers and about 3% of all breast cancers Penetrance (the percentage of carriers who develop breast cancer) varies from 30% to 90% depending on the specific mutation present

Answer 212

BRCA1 (on chromosome 17q21) ➢Associated with poorly differentiated carcinomas, have “medullary features” - biologically similar to ERnegative/HER2negative of “basal-like” breast cancers, as well as to serous ovarian carcinomas - 20-40% of carriers increased risk of developing ovarian carcinoma BRCA2 (on chromosome 13q12.3) - associated with poorly differentiated carcinomas, but are more often ERpositive - smaller risk for ovarian carcinoma (10-20%) - associated more frequently with male breast cancer - BRCA1 and BRCA2 carriers increased risk such as prostatic and pancreatic carcinomas *The remaining known susceptibility genes accounts for fewer than 10% of hereditary breast carcinoma

Answer 213

``` SPORADIC **Major risk factors are related to hormone exposure: ➢Gender ➢Age at menarche and menopause ➢Reproductive history ➢Breastfeeding; decrease risk ➢Exogenous estrogens ; increase risk ``` **Environmental risk factors (radiation exposure and chemicals with estrogen-like effects)

Answer 214

➢95% are adenocarcinomas arise in the duct/lobular system as carcinoma in situ ➢70% are invasive when they are clinically detected ➢Carcinoma in situ = epithelial cells are confined to ducts and lobules by basement membrane ➢Invasive carcinoma cells penetrate basement membrane and grows into stroma Molecular mechanisms 1. Germline BRCA2; flat epithelial atypia (PIK3CA mutations) - atypical ductal hyperplasia - DCIS - ER positive, HER2 negative (50-65% of cancers), “luminal” 2. Germline TP53 mutations ; HER2 amplification - atypical apocrine adenosis - DCIS - HER2 positive (20% of cancers) “HER2 enriched” 3. Germline BRCA1 Mutations; TP53 Mutations - BRCA1 inactivation - DCIS - ER negative, HER2 negative (15% of cancers) “basal like” AFRICAN AMERICANS

Answer 215

DCIS (Ductal carcinoma in situ) ``` Detection - Majority calcifications - Less commonly; ➢Periductal fibrosis ➢Nipple discharge ➢Incidental finding in biopsy for another lesion ``` 2 major architectural subtypes A. Comedo B. Noncomedo ➢ Solid ➢ Cribriform ➢ Papillary ➢ Micropapillary

Answer 216

1. COMEDO DCIS ➢Cheesy appearance (resembling comedones) due to plugging of thick walled ducts with necrotic material ➢Produces vague nodularity ➢Linear and branching calcifications within the ductal system ➢It is defined by 2 features: - Tumor cells with pleomorphic, high-grade nuclei - Areas of central necrosis 2. Non comedo DCIS ➢ Multiple secondary lumens having round, regular spaces with sharp borders that appear to be made from "cookie- cutters," usually low grade ➢ The lumen of the duct is filled by small to medium, uniform polygonal cells

Answer 217

1. Papillary DCIS | 2. Micropapillary DCIS

Answer 218

PAGET DISEASE OF THE NIPPLE ➢ Rare form of breast cancer (1% to 4% of cases) ➢ Unilateral erythematous eruption with a scale crust ➢ Pruritus is common, and the lesion may be mistaken for eczema ➢ Malignant cells (Paget cells) extend up lactiferous ducts into nipple skin without crossing the basement membrane ➢ Tumor cells disrupt the normal epithelial barrier, allowing extracellular fluid to seep out onto the nipple surface ➢ Paget cells detected by nipple biopsy or cytologic preparations of the exudate

Answer 219

LOBULAR CARCINOMA in SITU ➢ Monomorphic population of small, rounded, loosely cohesive cells fills and expands the acini of a lobule ➢ Almost always expresses ER and PR ➢ Overexpression of HER2 is not observed ➢ Risk factor for invasive carcinoma, about 1% per year ➢ Unlike DCIS, risk is high contralateral and ipsilateral breast ➢ Three-fold more likely to be lobular carcinoma; however, most are of other morphologies. **Treatment ➢ Bilateral prophylactic mastectomy ➢ Tamoxifen ➢ More typically, close clinical follow-up and mammographic screening

Answer 220

1. ER positive, HER2 negative - most common - can have either low or high proliferation (BRCA 2) - respond better to chemo 2. HER2 positive (ER positive or negative) 3. ER-Negative, HER2 negative - African America - present at a higher stage - don’t survive long (<5yrs)

Answer 221

➢ Amplification of the region of chromosome 17q that contains the HER2 gene ➢ Detected by fluorescence in situ hybridization (FISH) using a HER2-specific probe (red signal) co-hybridized to tumor cell nuclei with a second probe specific for the centromeric region of chromosome 17 (green signal), allowing the chromosome 17 copy number to be determined ➢ HER2 protein overexpression can be detected by immunohistochemical staining with antibodies specific for HER2

Answer 222

Trastuzumab (Herceptin)

Answer 223

INVASIVE (Infiltrating) Carcinoma ➢Subset grow as masses that appear well circumscribed composed of sheets of tumor cells with scant stromal reaction OR ➢ Only show subtle architectural distortion on mammography and produce little or no stromal response ➢ Don’t produce palpable masses and not identified grossly **Microscopic; tumor cells found scattered within normal appearing fibroadipose tissue

Answer 224

1. Larger carcinomas | 2. Occult primary tumors

Answer 225

Nottingham Histologic Score ➢Scored for tubule formation ➢Nuclear pleomorphism ➢Mitotic rate 3 Grades: ➢Grade I (well differentiated) Score 3-5 - (well-differentiated) grow in a tubular or cribriform pattern with small round nuclei and have a low proliferative rate ➢Grade II (moderately differentiated) Score 6-7 - (moderately differentiated) show less tubule formation and more solid nests or single infiltrating cells greater nuclear pleomorphism and mitotic figures are present ➢Grade III (poorly differentiated) Score 8-9 - Invade as ragged nests or solid sheets of cells with enlarged irregular nuclei - High proliferative rate - Numerous mitotic figures - Areas of tumor necrosis

Answer 226

INVASIVE LOBULAR CARCINOMA Histologic ➢ Discohesive infiltrating tumor cells ➢ SIGNET-RING** cells containing intracytoplasmic mucin droplets ➢ Tubule formation is absent Metastasis ➢ Peritoneum ➢ Retroperitoneum ➢ leptomeninges (carcinomatous meningitis) ➢ gastrointestinal tract ➢ ovaries and uterus

Answer 227

Medullary carcinoma Microscopically: ➢ solid, syncytium-like sheets of large cells with pleomorphic nuclei, and prominent nucleoli ➢ frequent mitotic figures ➢ moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumor ➢ pushing (noninfiltrative) border ➢ DCIS is minimal or absent

Answer 228

1. Papillary carcinoma 2. Micropapillary carcinoma 3. Mucinous (colloid) carcinoma)

Answer 229

1. tubular carcinoma *Associated with; ➢flat epithelial atypia ➢atypical lobular hyperplasia ➢LCIS ➢Low grade DCIS 2. Apocrine carcinoma 3. Secretory carcinoma 4. Inflammatory carcinoma

Answer 230

- rare - similar risk factors as women - present as; palpable subareolar mass 2-3cm. Nipple discharge - metastasis; same with women - LUNGS, BRAIN, bone, liver - Most associated with BRCA 2 and ER+

Answer 231

1. Invasive versus in situ 2. DIstant metastasis 3. Lymph node metastasis 4. tumor size 5. Locally advanced disease 6. Inflammatory carcinoma 7. Lymphovascular invasion 8. Others; molecular subtype, special histology types, histologic grade, proliferative rate, estrogen and progesterone receptors, HER2

Answer 232

1. Intralobular A. Fibroadenoma ; most common in 20-30s in women B. Phyllodes 2. Interlobular stroma ➢Rare ➢Stromal cells with no epithelial component ➢Non-malignant and malignant ➢Myofibroblastoma desmoid syndrome, gardner syndrome - Composed of myofibroblasts equally common in males A. Lipomas ➢Palpable lesion mammographically fat containing lesion ➢Rule out malignancy B. fibromatosis ➢Clonal proliferation of fibroblasts and myofibroblasts ➢Irregular infiltrating mass ➢Involve skin and muscle ➢Locally aggressive/does not metastasize ➢Associated with trauma or surgery ➢Associated with familial adenomatous polyposis, hereditary desmoid syndrome, Gardner syndrome

Answer 233

1. Angiosarcoma ➢ Most common stromal malignant tumor ( <0.05% of breast malignancies) ➢ Sporadic ➢ Young women ➢ High grade ➢ Poor prognosis ➢ Treatment related; secondary to radiation, 5-10 yrs post treatment ``` 2. Others ➢ Rhabdomyosarcoma ➢ Liposarcoma ➢ Leiomyosarcoma ➢ Chondrosarcoma ➢ Osteosarcoma ``` ``` **Other malignant tumors of breast ➢ <5% ➢ Lymphomas (non-hodgkin, Burkett’s, most B cells) - skin - metastasis (ovary and melanoma) ```

Answer 234

ANSWER - depends on the patient D - all of the above (in severe patient, also 25 weeks pregnant so baby is somehow developed and steroids won’t interfere)

Answer 235

``` Analgesics Antacids Antibiotics Antiemetics Sedatives Antihistamine Diuretics Ethanol Iron Vitamins ```

Answer 236

TERATOGENS • DES, Thalidomide, Bendectin • Fetal alcohol syndrome recognized in 1973 1. Diethylstilbestrol (DES) - Clinical trials in 1950 demonstrated it to be ineffective, not withdrawn from market until 1971 when association with clear cell adenocarcinoma of vagina in offspring recognized. Remains the only known transplacental carcinogen. 2. BENDECTIN (doxyamine succinate and pyridoxine) * *TERATOGENS

Answer 237

1. Pre-organogenesis; ALL or NOTHING 2. Embryogenesis; 3-8 weeks 3. Fetogenesis; Various effects - typically gonadal or nervous system abnormalities * *Etiology of developmental defects - known genetic transmission - chromosome aberration - environmental - drug and environmental chemicals - unknown

Answer 238

1. Absorption - no effect 2. Distribution a. Increased plasma volume and total body water (late pregnancy) b. Decreased albumin (increased free fraction of drugs) 3. Biotransformation a. maternal liver b. placenta c. fetal liver 4. Excretion a. GFR increased by as much as 70% b. Renal excretion of drugs

Answer 239

1. Most chemicals pass through the placenta into the fetus by passive diffusion. 2. Larger molecular weight agents (>500 daltons) or polar molecules enter or leave the fetus slowly. 3. Nutrients (amino acids, glucose) can enter the fetus by active transport. 4. MOST drugs can enter the fetus-exceptions are insulin and heparin.

Answer 240

Early pregnancy 1. High risk; Androgens, methotrexate, corticosteroids in high dose, DES, TCA, warfarin, systemic retinoids 2. Strong suspicion of abnormality; chloroquine, lithium, phenytoin 3. Other drugs to avoid; co-trimoxazole, sulfa Late pregnancy Aspirin, aminoglycosides, antithyroid med, benzo, chloramphenicol, oral anticoagulant, sulfa, TCA, thiazide diuretics

Answer 241

Antibiotics-balance of risk-benefit ratio 1. UTI-nitrofurantoin, penicillins, trimethoprim/sulfamethoxazole 2. Common cold-symptomatic treatment 3. Bacterial Vaginosis-metronidazole 4. Vaginal candidiasis-topical azoles 5. Sinusitis-trimethoprim/sulfamethoxazole, penicillins, azithromycin Medical care during pregnancy Anemia-physiologic (dilutional) and iron deficiency. -iron or folic acid -treatment may lead to nausea and constipation -use minimum dosage (Fe: 30mg/d, 2nd and 3rd trimester; folic acid 1mg/d

Answer 242

STOP AMPHETAMINE - AMPHETAMINE ; not life changing, don’t affect mortality or morbidity if stopped. TAPER it - side effect is increased BP and HR Don’t stop - Levothyroxine - sertraline ; depends

Answer 243

Hyperthyroidism - carbimazole, methimazole, propylthiouricil - avoid radioactive iodine - surgical management optional - 10% risk of fetal hypothyroidism and goiter - avoid breast feeding

Answer 244

A. Pre-existing-insulin requirements increase throughout pregnancy. The standard has been switch from oral hypoglycemics to insulin. B. Gestational diabetes-occurs only during pregnancy. Utilize human insulin. Oral hypoglycemics may cause teratogenesis and fetal hypoglycemia but metformin(b) and glyburide (b/c) are being used C. Metformin 2nd and 3rd trimester and may need supplemental insulin

Answer 245

Pre-eclamptic hypertension-develops after 20 weeks of gestation. Associated with HELLP syndrome. - Only definitive treatment is delivery of fetus. - May use hydralazine for rapid results, also methyldopa or labetalol. - Avoid nitroprusside, ace inhibitors, arb

Answer 246

AVOID ACEI, ARB’s Medical care during pregnancy - Chronic HTN and pregnancy -methyldopa drug of choice, alternatives also: hydralazine,

Answer 247

Anticoagulation and pregnancy- pregnancy is hypercoagulable state (5-50x risk) Frequently there are indications for anticoagulation (DVT, prosthetic cardiac valve, recurrent fetal loss) -use heparin or low molecular weight heparin. Preferable to stop 2-3 weeks before delivery secondary to increase risk of peripartum bleeding. - heparin does not cross placental barrier - avoid warfarin, newer agents still pending

Answer 248

- Increased risk among children of epileptic mothers of birth defects. Occurrence of major and minor malformations and dysmorphic features is 6-8% - Seizures are dangerous to both mother and fetus. - Increased teratogenecity with all antiepileptics.** - Must monitor plasma levels since albumin decreases as pregnancy progresses. - Use monotherapy when possible and lowest effective dose.

Answer 249

Phenytoin- 5-10% risk of fetal hydantoin syndrome - craniofacial abnormalities - cardiac malformations - genitourinary defects Carbamazepine-neural tube defects in approximately 0.9% Valproic acid-neural tube deficits 1-2% Supplementation with folic acid 3 months before conception if possible and continue through first trimester, 4mg/day.

Answer 250

most common chronic respiratory condition of pregnancy-affects approximately 5% of pregnancies Associated with PRETERM LABOR, LOW BIRTH WEIGHT. Treatment-avoidance of environmental triggers Short acting

Answer 251

Inhaled glucocorticoids-first line also, betamethasone, fluticasone, others. No evidence of teratogenesis noted. Systemic glucocorticoids-prednisone, methylprednisolone may be used for severe exacerbations. May increase risk of cleft lip/palate up to 5 times. Leukotriene inhibitors-zafirlukast, montelukast-used as third line agents.

Answer 252

Nausea and vomiting-frequent. Treat only if severe. Hyperemesis gravidarium-severe form often requiring hospitalization due to dehydration. Pathogenesis possibly due to elevated estrogen, progesterone or B-HcG Non drug therapy attempts first, small frequent meals, ginger, pyridoxine (B6) Ondansetron is now Pregnancy Category B, data suggests safe but QT prolongation is a concern at higher doses.

Answer 253

* *Venlafaxine - SSRI | - may need to change to SNRI (duloxetine)

Answer 254

Depression- affects 3-5% of women during pregnancy and can be devastating postpartum. SSRI previousl

Answer 255

entirely PREVENTABLE! Malformations occur in up to 32% of offspring and are variable in manifestations. FAS - xteristics - Small birth weight - Small head circumference - Epicanthal folds - Small, widely spaced eyes - Flat midface - Short, upturned nose - Smooth, wide philtrum - Thin upper lip - Underdeveloped jaw

Answer 256

IQ may be borderline; no fear of strangers, can’t tell if someone is making use of her or raped May have been raped and not understand consequences - BABY! **Don’t stop medications Patient has high risk of pregnancy

Answer 257

Tobacco abuse - 12-22% of pregnant mothers smoke - Most important modifiable risk factor associated with adverse fetal outcome. - Associated with premature labor, low birth weight, increased fetal loss. Narcotic withdrawal- babies born to opiate addicted mothers will be physically addicted. - Treatment must occur to prevent withdrawal.

Answer 258

Signs of NARCOTIC WITHDRAWAL

Answer 259

• Drugs may enter by many mechanisms. • Dose to infant approximately 1-2% of maternal therapeutic blood levels. Range varies widely based upon drug and pharmacokinetics. • Dependent on passive diffusion, lipid solubility and protein binding ``` Questions • Is the drug necessary? • Use the safest medication? • Is there a possibility of risk to the infant? • Minimize exposure by timely dosing. ```

Exam 1 Week 1 GU,breast Flashcards

(283 cards)