REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
HIV AND PREGNANCY
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MAIN POINTS
o HIV Mother-to-child transmission (MTC) is preventable!
 Most centers treating HIV in pregnancy report <1%
 Do HIV testing at least once during pregnancy
 If testing not done in pregnancy, test neonate/child ASAP
 Consider re-testing HIV negative patients in the second or third trimester in selected areas and
with selected risk factors
 Need to institute appropriate therapy and plan for appropriate mode of delivery
 Use Antiretroviral agents recommended for use in pregnancy are relatively safe
o HIV MCT is largely preventable
 Five antiretroviral agents recommended
 C-section for VL> 1,000
 No breast-feeding
 Diagnosis of HIV during pregnancy
 Test older children
 An HIV infected infant is a potential sentinel event representing missed testing and treatment
opportunities
THE SCOPE OF THE PROBLEM
o HIV currently infects 34 million people worldwide (Dec 2012: UNAIDS) and millions have died from HIV and comorbidities
 23.5 million people in sub-Sahara Africa
 Up to 60% are women
o HIV transmission rates to infants in undeveloped countries can range from 14% - 33%
(up to 48% in one study)
 1.4 million in N. America
 Approximately 27% are women—HIV is becoming a disease of women
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Women infected with HIV (UNAIDS 2012)
 16.7 million women worldwide
 The vast majority of these women are of childbearing age (age 15 – 49)
 <100 max HIV infected babies born/year in US
o Due to ART for MTCT
 330,000 HIV infected babies born/year globally
o 300,000 infants born in sub-Sahara Africa
 Anti-retrovirals are expensive so in the beginning of the pregnancy they aren't
treated and women also are told to go home and breast feed which
counteracts any antiretroviral given before birth
An AIDS-free generation may one day be a reality
 3.4 million children (<15 y/o) now living with AIDS/HIV primarily by MCT (UNAIDS 2012)
 3.1 million children (<15 y/o) in sub-Sahara Africa
 4500 in US
o In 1994, it was around 16,000
HIV prevalence (%) among pregnant women attending antenatal clinics in sub-Saharan Africa, 1997–2007
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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NOTE: Analysis restricted to consistent surveillance sites for all countries except South Africa (by province) and
Swaziland (by region)
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* - in Ohio, 21% are women
AIDS IN WOMEN
o In order to prevent HIV transmission to the fetus/neonate/infant from HIV infected mother (MCT), you need to
give appropriate treatment
 In order to give appropriate treatment, you need to identify HIV infected women
 In order to identify HIV infected women, you need to perform HIV testing
o In order to perform HIV testing, you need to …ORDER THE TEST!!!!!!!!!! (and it’s now
easier to do!)
OPT-OUT HIV TESTING
o Ohio HIV testing laws have changed
 No special consent form needed for HIV testing
 BUT…HCWs must provide information about anonymous testing option to patients on whom an
HIV test may be performed BEFORE DOING THE TEST
 IF… a patient tests HIV +, then HCWs must provide post-test counseling that goes over 5 things
o Explanation of HIV test results (confirmatory steps), nature of HIV disease, list of
resources, safer sex info, Ohio HIV disclosure law info
o You DON'T NEED TO get a special consent form anymore for HIV testing. You have to provide information verbally
about the tests. You just have to indicate that. If they are HIV positive you have to go over information that covers
5 things.
o STANDARD OF CARE: EVERY women gets an HIV test!!!
o They might pull out the old consent forms in the offices but you can throw them out now!
HIV TESTING
o Anonymous – no links to the patient: results are identified by a number only
 Problem: if patient doesn’t pick up a + test result, you can’t find them!-- now we do a rapid test, they do a
swab, and it must be confirmed with a western blot
 30% of the positives are NOT PICKED UP so like 300,000 positives aren’t picked up!!! So there was a huge
push to get away from this.
o Confidential – a record of the test exists and is in the patient chart (negative or positive result). Used to require a
written consent but NOW IT DOES NOT!
 Problem: fear of disclosure discourages some patients from this testing method
o If you have a patient with a positive test….
 Call UTMC Ryan White Clinics!
 419 – 383 -3627
 For help with interpreting test results and delivering the HIV test results
 Referral of + patients into care
 Help with HIV related issues
CDC HIV TESTING RECOMMENDATIONS
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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“To promote informed and timely therapeutic decisions, health-care providers should test women for HIV as early
as possible during each pregnancy. Women who decline the test early in prenatal care should be encouraged to be
tested at a subsequent visit.” MMWR September 22, 2006 / 55(RR14);1-17
 You're supposed to ask them at every re-visit. So first test is kind of a must and the second test is a
consideration
o Second HIV Test
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“A second HIV test during the third trimester, preferably <36 weeks of gestation, is cost-effective even in
areas of low HIV prevalence and may be considered for all pregnant women. A second HIV test during the
third trimester is recommended for women who meet one or more of the following criteria:” (next slide)
 1) “Women who receive health care in jurisdictions with elevated incidence of HIV or AIDS among
women aged 15--45 years. In 2004, these jurisdictions included Alabama, Connecticut, Delaware, the
District of Columbia, Florida, Georgia, Illinois, Louisiana, Maryland, Massachusetts, Mississippi, Nevada,
New Jersey, New York, North Carolina, Pennsylvania, Puerto Rico, Rhode Island, South Carolina,
Tennessee, Texas, and Virginia.” MMWR September 22, 2006 / 55(RR14);1-17
 2) “Women who receive health care in facilities in which prenatal screening identifies at least one HIVinfected pregnant woman per 1,000 women screened.”
 3 who have signs or symptoms consistent with acute HIV infection” MMWR September 22, 2006 /
55(RR14);1-17
 But you screen women for a ton of things that are less prevalent and aren’t preventable like
HIV!!! It's crazy!!!
MOTHER CHILD TRANSMISSION (MCT) OF HIV
o MCT HIV transmission occurs relatively frequently without treatment
 There are no absolute parameters/thresholds for transmission or protection
 Multiple risk factors contribute to a graded response to transmission (eg – viral load, maternal
health)
 When does perinatal HIV transmission occur during the course of pregnancy?
 Important to understand the timing and pathophysiology of MTCT in order to evaluate treatment
strategies
o Usually occurs late in pregnancy in the 3rd trimester.
o 30% of transmission occurs intrapartum
o Timing of HIV Transmission
 Kourtis, et al JAMA 2001 285: 709 –712
 Analysis of ten treatment trials (PACTG 076, PETRA, SAINT, others) for non-breast feeding MCT
challenged this view
 Graphic depicts this in the next slide
o Around 30% intrapartum transmission
 it's very very rare for a transmission to occur during the 1st trimester. Studies
on aborted tissues 4-5 weeks old never have HIV either. It takes a while for the
tissues to express the co-receptor needed for HIV transmission
 There's a lot of time to get the test done and a lot of time to intervene
o Around 70% in utero transmission
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CD4 COUNTS AND VIRAL LOADS
 Need to define two terms - CD4 count and HIV viral load - and understand their clinical use
 CD4 count-o “T-helper cell” - Coordinating cell for immune system function and is also the cell that
HIV infects 
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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Initially the CD4 count falls after infection and then rebounds to levels slightly below
those seen prior to infection
 Some viruses are worse than others
A variety of factors (eg: host genotype, virus genotype, viral load 6 - 12 months after
infection) determine long term outcome
 Some people are genetically resistant to HIV infection
 Some people are CCR5 neg. If it's is gone than can't get HIV. if you
wipe out the immune system you can't get HIV
On average, the CD4 count falls by 10 cells/month: normal count>500 cells/mm
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CD4 counts
 CD4 Count > 500 (28%) often asymptomatic
 CD4 Count 200 - 500 increasing incidence of thrush, shingles, pneumococcal pneumonia, bad ear
infections etc.
 CD4 Count <200 (14%) at risk for opportunistic infections (PCP, candida esophagitis,
toxoplasmosis, etc.). Begin PCP prophylaxis. Clinically defined as AIDS
 CD4 Count <50 at risk for Mycobacterium Avium Infection (MAI), CMV. Begin MAC
(mycobacterium avium complex) prophylaxis
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HIV Viral Load
 The amount of virus in blood (either proviral DNA or genomic RNA) can be measured using
polymerase chain reaction (PCR) or other nucleic acid test
 Quantities of HIV in plasma can be detected down to 20 copies of virus per cc of blood
o This is a reasonable representation of the amount of virus in lymphoid tissue
 4 fold lower than in lymphoid tissue but it's still a great estimate
 This CD4 count isn't a great predictor of survival rates use the VIRAL LOAD
o Its like a train on a track. The CD4 tells you where you are but the viral load tells you
how fast you're going the viral load tells you the prognosis
 209 HIV + men enrolled in MACS study in Pittsburgh 4/84 - 3/85
 Extensive information available on patients - blood samples, CD4 counts, clinical progression
 Viral load is the best predictor of clinical outcome
 Like a train heading towards a cliff - CD4 tells you where the train is - viral load tells you how fast
it is traveling
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STRATEGIES TO PREVENT MCT
 PACTG 076:
 In 1994, a landmark study was released which demonstrated for the first time a specific, effective
therapy to decrease MCT
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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This study revolutionized the care of HIV infected women and set the gold standard for all
subsequent care
o Analysis of this study (eg. PACTG 219/076) has not turned up any issues of concern
Connor, et al. Reduction of Maternal-Infant Transmission of HIV Type 1 with Zidovudine
Treatment. NEJM Nov 3, 1994.
o USPHS issued AZT guidelines August, 1994
o Randomized, double-blind placebo controlled study
 477 HIV + pregnant women (14 to 34 week gestation) with CD4 >200 were
enrolled
 409 women went to term (415 live births)
Women received AZT or placebo
o Ante partum: 100mg po 5x/day
o Intrapartum: 2mg/kg IV AZT over 1 hour, then 1mg/kg/hr until delivery
o Postpartum: for the neonate 2mg/kg q6hrs po X 6 weeks beginning 8 - 12 hours after
birth : no breastfeeding
 Infants were evaluated for HIV infection by peripheral blood mononuclear cell
culture at weeks 12, 24, and 78
 ELISA and Western Blot were also performed at weeks 72 and 78
Results
o No differences in demographics or pregnancy outcomes between the placebo and AZT
groups
 Placebo group: 25.5% infected infants at 72 weeks age
 AZT group: 8.3% infected infants at 72 weeks age
 NEARLY 70% REDUCTION IN MCT
 Since publication of this study, use of AZT during pregnancy has been the
standard of care (“gold standard”)
 no bad problems for the kids who got IV AZT!
 No adverse effects for AZT in pregnancy
 (In mice there was vaginal/cervial cancers though so they're looking into that)
BEYOND AZT
o Recommended antiretrovirals
 NRTIs
 AZT (retrovir/zidovudine)
 Lamivudine/Epivir
 NNRTIs—useful in very very low CD4 count. If you have a high CD4 count and you use these drugs you can
get something called HELLP syndrome which is basically liver toxicity that goes wild.
 Nevirapine/Viramune*
o Avoid if CD4 >250
 avoid if there's a low CD4 count
 Protease inhibitors --safe and effective to use during pregnancy
 Lopinavir/ritonavir (Kaletra)
 Atazanavir/ritonavir
 **ritonavir is a booster agent
o Combinations of Antiretrovirals are used in pregnant women
 HART – highly active antiretroviral therapy
 Commonly used regimen
o Combivir (AZT + Lamivudine) & Kaletra (lopinavir + ritonavir)
 Alternative antiretrovirals are listed in the guidelines
 Use preferred agents including an NRTI with good placental passage if feasible
o AZT/3TC preferred -- FTC/TDV/ABC alternates
 You usually want to get an antiretroviral that easily gets across the placenta
 That's why AZT/lamovidine is one of the preferred. AZT actually gets
phosphorylated when it crosses the placenta to a more active compound
o Antiretroviral therapy to avoid
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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Zerit/Videx
Sustiva in the first trimester
 Avoid if pregnancy potential, but don’t switch if they are already on it and suppressed
 Nevirapine with CD4 >250
 oral amprenavir solution (dissolved in propylene glycol)
o Infected pregnant women should receive therapy as recommended for non-pregnant adults, taking into account
what is known about specific drugs in pregnancy
 For example, a pregnant HIV/HBV + woman may be treated with Truvada (tenofovir/emtricitabine) plus
lopinavir/ritonavir since this treats the Hep B as well
FOR THE HIV+ PREGNANT WOMAN, THE CDC SUGGESTS...
o Preferred NRTIs that cross the placental should be part of antiretroviral therapy during pregnancy when feasible
 Goal of therapy is an undetectable viral load before labor and delivery
 ART (anti retroviral therapy) should be given for MCT regardless of viral load or need for
treatment of the mother
 Resistance testing should be performed if the viral load is detectable
o Recommendations are outlined in clinical scenarios – July 31, 2012 Public Health Service Task Force – http://
AIDSinfo.nih.gov
 4 Clinic scenarios for ART use in pregnancy to decrease MTCT
 One scenario for preconception/one scenario for infant with no antepartum/intrapartum ART
exposure
 4 Clinical scenarios for mode of delivery to decrease MTCT
CDC Scenario #1
o HIV infected woman receiving ART who becomes pregnancy
 Continue ART if successfully suppressing viremia (<50 copies/cc)
 If stable on NVP or EFV, can continue
o If Viral Load <400 near delivery, do not need IV AZT
 HIV resistance testing if viral load >1,000 and med adjustment as needed
CDC Scenario #2
o HIV infected pregnant woman who is antiretroviral naïve -- she's been picked up on routine testing
 HIV resistance testing prior to start of meds
 Consider delay of ART til after 1st trimester
 just because the organogenesis is in the first trimester and they rarely transfer the virus at this
time
 Initiate ART regimen
 Use preferred agents including an NRTI with good placental passage if feasible
o AZT/3TC/FTC/TDV/ABC
 Repeat HIV resistance testing if viral load suppression sub-optimal by 2 – 8 weeks and adjust
meds
o Recheck the viral load. If it's working the viral load should be decreased by at least a log.
So if you start out with load of 100,000 and you re-check 2-8 weeks later and it should
be 10,000 or less or else the person isn't taking them or the meds aren't working. Most
of the time the meds work right away. They shut it off replication very quickly.
 Woman w/ viral load of 3 million and in week 38 of pregnancy started on antiretroviral and in 72
hours when the woman went into delivery the viral load was down to <1,000
CDC Scenario #3
o HIV infected pregnant woman who is ART experienced but not currently receiving antiretrovirals
 Begin ART based on resistance testing and treatment history and information about potential medication
teratogenicity
 Use preferred agents including an NRTI with good placental passage if feasible
o AZT/3TC/FTC/TDV/ABC
 Repeat HIV resistance testing if viral load suppression sub-optimal
CDC Scenario #4
o HIV-infected woman who has received no ART prior to labor
o Give IV AZT during labor and give AZT to the infant postpartum as per PACTG 076 protocol
 Begin combination ART in infant as close to birth as possible
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
 Functional or sterilizing cure possible?!?!?
There was a patient in Mississippi "the Mississippi Patient" born in 2010 to a woman who was known to be HIV
positive diagnosed during pregnancy and dropped out of care until she started labor. They could not get the IV AZT
in her on time and so after birth they started the baby on AZT and what they give you for an IV needle stick and
baby was given meds for 18 months and the kid was tested at 2 y/o and was tested and had SUCH a small viral load
(<2 copies) and no HIV antibodies. This is what we call a "Functional cure"- kinda like EBV or chicken pox. Probably
wont be a sterilizing cure
CDC RECOMMENDATIONS
o The following are included in all scenarios
 Resistance testing at start of therapy and if failure to suppress viral load
 Continue oral regimen during labor and delivery and add IV AZT if VL >400 near delivery as per PACTG 076
 Use preferred agents including an NRTI with good placental passage if feasible
 AZT/3TC/FTC/TDV/ABC
CDC Scenario #1 – Delivery
o HIV infected woman presenting > 36 weeks gestation, no ART, no labs available before delivery
 Start ART ASAP
 Consider C-section at 38 weeks to reduce MCT
 The current push is to NOT do C-sections early. Worse outcome before 39 weeks—b/c you want
full lung maturity
 If scheduled c-section, give AZT beginning 3 hours before surgery (1 hour loading dose and 2
hours infusion)
o 30% of the transmission occurs transpartum as the baby is going through birth canal
 Continue all other standard c-section management recommendations
CDC Scenario #2 - Delivery
o HIV infected woman who is on ART, but has a viral load >1,000 at 36 weeks
 Continue ART
 Consider additional ARV to decrease VL
 Think about more meds to drive down the viral load
 Consider C-section at 38 weeks to reduce MCT
 If scheduled c-section, give AZT beginning 3 hours before surgery (1 hour loading dose and 2
hours infusion)
 Continue all other standard c-section management recommendations
CDC Scenario #3 - Delivery
o HIV infected woman who is on ART, and has an undetectable viral load at 36 weeks
 No information on elective C-section reducing the <2% MCT when VL undetectable to an even further
level
 Study in CID Feb 2005 challenges that view
 Vaginal delivery if feasible
 PACGT 076 postpartum protocol
CDC Scenario #4 – Delivery
o You want the baby's face out of the vaginal secretions as early as possible!!! When the baby is coming out you
want to take the baby out of there!!!
o HIV infected woman scheduled for elective C-section who presents with early labor or rupture of membranes
 Start IV AZT immediately
 Labor progressing rapidly, deliver vaginally
 If minimal cervical dilation, can administer loading dose AZT and proceed with C-section
o Try to get loading dose of AZT in before the C-section
 Can use pitocin to expedite delivery
 Avoid scalp electrodes, other invasive monitoring procedures
 Post-partum PACTG 076
CONCLUSIONS
o HIV MCT is largely preventable
 PACTG 076 rates @25% without treatment
 Most centers treating HIV in pregnancy report <1%
 HIV testing should be done at least once during pregnancy
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REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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If testing not done in pregnancy, test neonate/child ASAP
Consider re-testing HIV negative patients in the second and third trimester in selected areas and
with risk factors
 Need to institute appropriate therapy and plan for appropriate mode of delivery
 Antiretroviral agents recommended for use in pregnancy are relatively safe
HIV MCT is largely preventable
 Five antiretroviral agents recommended
 C-section for VL> 1,000
 No breast-feeding
 Diagnosis of HIV during pregnancy
 Test older children
 An HIV infected infant is a potential sentinel event representing missed testing and treatment
opportunities
FALLOPIAN TUBES AND OVARIES
FALLOPIAN TUBE PATHOLOGY
 PELVIC INFLAMMATORY DISEASE (PID)
o Pelvic pain, adnexal tenderness, fever, vaginal discharge
o Most commonly caused by Gonococcus, Chlamydia
o Puerperal infections (infections after spontaneous or induced abortions and deliveries)
 Polymicrobial infections: Staph, strept, coliform bacteria, Clostridium
o Infection usually begins in the Bartholin gland or periurethral glands as an acute suppurative reaction and may
spread upwards (skips endometrium and goes to the fallopian tubes through the lymphatics and vascular channels
in the myometrium and once its in the fallopian tubes you get a little acute pus collection (neutrophils)
 Start low and spread upwards
 We don't know why it skips the endometrium—might have something to do with the endometrium
sloughing off every month of the antibody-antigen complexes in the endometrium
o Once in the fallopian tubes, an acute suppurative salpingitis ensues and tubo-ovarian abscess (TOA) may occur
 60% of the time when there is pus in the tube it will be gonococcus
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COMPLICATIONS OF PID
 Peritonitis
 Bacteremia—once in the blood stream can go anywhere
 Endocarditis
 Meningitis
 Suppurative arthritis
 Infertility
 Tubal obstruction
 Risk of ectopic pregnancy
 Adhesions with intestinal obstruction
ECTOPIC PREGNANCY
o Implantation of the fetus in any site other than the uterus
 90% within fallopian tube
o 1/150 pregnancies
 35-50% of patients have history of PID—big deal b/c it can rupture and it's a medical emergency
o Most common cause of hematosalpinx (blood in the fallopian tube)—ectopic pregnancy so don't send her home
because it will most likely rupture and she is going to bleed
o Severe abdominal pain, usually 6 weeks after last normal menstrual period, when ruptured tube leads to pelvic
hemorrhage
 Medical emergency
ENDOMETRIOSIS
o The presence of normal endometrial tissue in abnormal locations (most commonly in the ovaries)
o Causes infertility, menstrual irregularities, dysmenorrhea, dyspareunia, pelvic pain
o Most common in 3rd and 4th decades
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
 Affects approximately 10% of women
Red-blue or yellow-brown nodules on mucosal / serosal
Requires 2 of 3 elements
 Endometrial glands
 Endometrial stroma
 Hemosiderin
FALLOPIAN TUBE TUMORS AND CYSTS
o PARATUBAL CYSTS (HYDATIDS OF MORGAGNI)
 Benign translucent cysts derived from Müllerian duct remnants—they stick off the fallopian tube
 Causes no symptoms and stays small
o ADENOMATOID TUMORS
 Small proliferation of benign mesothelial cells
o PRIMARY ADENOCARCINOMA
 0.2% of primary female genital malignancies—rare
 5th and 6th decades with BRCA1 and BRCA2 mutations
 Present with vaginal discharge or bleeding, pelvic pain and a pelvic mass
 60 % 5-year survival
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OVARIAN FOLLICULAR AND LUTEAL CYSTS
 FOLLICULAR CYST
o Multiple, thin-walled, unilocular
o Originate in unruptured graafian follicles and in follicles that have ruptured and
immediately sealed
o Lined by granulosa cells (like a normal follicle)
o It's a physiological cyst
 LUTEAL CYSTS
o Formed by the immediate sealing of a corpus luteum hemorrhagicum
o Lined by rim of bright yellow luteinized cells
o May rupture → peritoneal reaction (peritonitis)
 If it involves a big BV and it ruptures can have some hemorrhage
o Cant tell on CT that these are physiological cysts
 POLYCYSTIC OVARIAN DISEASE
o Formerly Stein-Leventhal Syndrome
o 5% of women of reproductive age
o Oligomenorrhea, infertility (persistent anovulation), hirsutism, obesity
 Abnormal estrogen:progesterone balance leads to Persistent anovulation with excessive production of
androgens (increased conversion of androgen to estrogen, and an elevated LH/FSH ratio)
o Enlarged ovaries (2x normal) with multiple subcortical follicular cysts
o Believed to be due to abnormal regulation of enzymes involved in androgen synthesis
 Make sure you r/o other causes of excess androgens
 Androgen secreting tumor
 Congenital Adrenal Hyperplasia
 Hyperprolactinemia
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These ovaries have cysts all over the surface and entire parenchyma and they are big (physiological cysts
are usually just 1-2)
OVARIAN TUMORS
 Categorized as benign, borderline or malignant
o 80% benign and occur in 20-45 y/o—so most are young women and they are benign
 Younger age group than women developing cervical cancer
 Endometrial cancer was 55-65
o Borderline tumors at slightly older ages
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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Malignant tumors in 45-65 y/o
 Same age range as cervical and endometrial cancer
DX difficulty (Vague symptoms): pain, GI/GU symptoms, bleeding
o Unexplained abdominal fullness, more frequent urination, loss of appetite, weight gain
o Because the symptoms are so vague when they go in to get it checked out the tumors are spread beyond the ovary
Malignant tumors have usually spread beyond the ovary at the time of diagnosis
o Disproportionate number of deaths from cancer of the female genital tract
o 3% of all cancers in females, but 5th most common cause of cancer death—because of the nonspecific symptoms
leading to later need to see a doctor
3 major groups of primary ovarian tumors according to the most probable tissue of origin (surface epithelial, germ cell, sex
cord-stromal)
o I. Tumors of Surface (coelomic) Epithelium (women >20)
 Constitute about two thirds of all primary ovarian tumors and 90% of all malignant ovarian tumors
o II. Germ Cell Tumors (0-25 y/o)
 Younger patient population
 Derived from the primitive germ cells which migrate to the ovary from the yolk sac and are pluripotent
 There are strong morphologic resemblance between the testicular germ cell tumors and their ovarian
counterparts
 Most are benign
o III. Sex Cord-Stromal Tumors (lots of age)
 Originate either from the sex cords of the embryonic gonad or from the stroma of the ovary
 Constitute about 10% of all ovarian tumors
SURFACE EPITHELIAL TUMORS
o Three major histologic types of tumors
 SEROUS (TUBAL COLUMNAR CILIATED, SEROUS FLUID)
 tubal columnar ciliated cells that are serous adenomas/adenocarcinomas
 MUCINOUS (CERVIX COLUMNAR NON-CILIATED, GELATINOUS FLUID)
 will look like cervix which are nonciliated and have mucin
 ENDOMETRIOID (ENDOMETRIUM)
 Look like they came from endometrium
o Most of these tumors are cystic
o Histologic grade of the neoplasms range from benign → borderline → malignant:
 Clearly benign
 Single cell layer, cystic tumor, younger women
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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Frankly malignant
 Piled up cells, stromal invasion, cystic/solid tumor, older women (60-70s)
 Carcinomas of low malignant potential (tumors of borderline malignancy) are histologically between
these two extremes
 Stratification and clusters of epithelial cells, moderate mitotic activity and nuclear atypia, but lack
of obvious stromal invasion
 Looks worse than benign
 They remove them as if they were malignant and do peritoneal biopsy them to stage them b/c
you’d rather err on the side of doing everything during one procedure
Uncertain etiology for these tumors
 Transformation of coelomic epithelium that has been incorporated into the ovarian cortex
Categorized into 2 types based on pathogenesis
 Those that arise in association with borderline tumors (which is why we treat them as if they were
malignant)
 Those that arise as de novo carcinomas
Bilateral tumors are common, so surgery is almost always TAH/BSO (Total abdominal hysterectomy-bilateral
salpingo-oophorectomy)—both ovaries out unless they are very young and they want to be fertile in the future
Mesothelial (cortical) inclusion cysts
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SEROUS TUMORS OF THE OVARY
 Cystic neoplasms filled with clear serous fluid (like we see in fallopian tube)
 lined by tall, columnar, ciliated and nonciliated epithelial cells
 30% of ovarian tumors; 50% of ovarian epithelial tumors (serous tumor most common); 40% of malignant
ovarian tumors
 70% benign or borderline
 Epithelial tumors have high propensity to be bilateral—serous is the most common type of
epithelial tumor
 Risk factors: Increased risk with nulliparity (never have had children), family history, and genetics
 5% of patients have BRCA 1 mutations
 20-60% risk of ovarian cancer with BRCA 1 or BRCA2 mutations
 Commonly bilateral—which is why most women will have a bilateral salphingo--oophorectomy
 20% of benign, 30% of borderline, 66% of carcinomas
 most of these are large ovaries and the doctors will ink the surface to check for invasion into the
wall




A. Normal –stroma and single layer of cells--Benign
B. Papilary projection and now multiple layers of cells but no invasion into the underlying tissue-Borderline
 C. Not invading into stroma yet—but multiple layers of cells--Borderline
 D. Piled up mess of cells. Making glands. Invasion of the stroma--Malignant
PAPILLARY SEROUS CYSTADENOCARCINOMA WITH PSAMMOMA BODIES

o
o
o
Serous—because it serous fluid. It has tubal columnar ciliated cells.
Cyst-its cystic
Adencocarcinoma-malignant w/ glands
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay

o
o Fibrovascular core tells us its papillary
o Psammoma bodies—concentric calcifications
TWO MAJOR GROUPS OF SEROUS CARCINOMAS
 Low-grade serous carcinoma
o Well-differentiated with little cytologic atypia
o Some arise in association with serous borderline tumors
o KRAS or BRAF mutations
 High-grade serous carcinoma
o Moderately to poorly differentiated
o Most arise de novo without precursor lesion
o P53 mutations
o BRCA1 or BRCA2 mutations
 Significant percentage arise from epithelial lining of the fimbriated end of the
fallopian tube—so will have family history of ovarian cancer, etc
MUCINOUS TUMORS OF THE OVARY—still epithelial cell tumor
 Large cystic neoplasms filled with sticky, gelatinous fluid—will look like endocervical cells w/ mucin caps
 Lined by tall, columnar epithelial cells with apical mucin
 30% of ovarian tumors; 5% of malignant ovarian tumors—2nd most common ovarian tumor and most are
benign. And its 2nd or 3rd most common malignant ovarian tumor
 78% benign or borderline
 Primarily occur in middle adult life
 KRAS proto-oncogene mutation
 Bilateral 5% of cases—so less likely to be bilateral but they still take out both ovaries
 95% 10-year survival for benign tumors
 90% 10-year survival for malignant tumors confined to the ovary


apical mucin caps. This cut is tangential and shows areas of
normal ovary because of the cut.
PSEUDOMYXOMA PERITONEI—this is not a clinical dx (the clinical dx is mucinous cystadenocarcinoma)
 Clinical condition with extensive mucinous ascites, cystic epithelial implants on peritoneal
surfaces, adhesions and mucinous tumor of the ovaries—JELLY BELLY
o Primary appendiceal tumor with secondary ovarian involvement and peritoneal spread
 Most start in the appendix and then go to the ovary secondarily. So when they
find this they will take out other ovary and then the appendix
o Bilateral mucinous tumors of the ovaries requires exclusion of non-ovarian origin (GI
tract—usually appendix)
 These are more likely to involve both ovaries so you take both out
 May result in intestinal obstruction and death—because of all the mucin accumulation

o
epithelium w/ mucinous caps and you can see a lot of free mucin (arrow
is pointing to that)
ENDOMETRIOID TUMORS OF THE OVARY—least common epithelial cell tumor
 Tubular glands resembling endometrium
 May arise in association with endometriosis
 Usually carcinomas, benign and borderline lesions are rare
 20% of ovarian cancers
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay

o




15-30% associated with concurrent endometrial carcinoma—b/c have similar mutations like PTEN and
p53
 15-20% cases coexist with endometriosis
 PTEN, KRAS, β-catenin mutations
 p53 mutations in poorly differentiated tumor
 40% bilateral—more likely to be bilateral if malignant and most of these are malignant
 75% 5-year survival for stage I tumors
CYSTADENOFIBROMA & BRENNER TUMOR
 CYSTADENOFIBROMA—cystic, gland forming, fibroma—benign epithelial component as well as stromal
proliferation
 More pronounced stromal proliferation underneath the lining epithelium
 Rarely have borderline or malignant features
 BRENNER TUMOR
 Adenofibroma with transitional-type epithelium +/- mucin secreting cells
o Epithelial tumor of the ovary that resembles bladder epithelium
CLINICAL COURSE OF SURFACE EPITHELIAL TUMORS
o Present with lower abdominal pain and abdominal enlargement (no big symptoms)
 Usually no early manifestations of ovarian cancer; advanced cancers at the time of diagnosis are
responsible for the high mortality rate
o Benign tumors are resected for cure
o Malignant tumors extend locally and seed the peritoneal cavity
o Elevated CA-125 in 80% of patients with serous and endometrioid carcinomas
 Also raised in nonspecific irritations of the peritoneum (which is why we don't screen all women for CA125)
 Endometriosis (10% of women have this), inflammation
 So test for this marker when you see a mass or post-therapy of cancer to monitor progress
TREATMENT OF SURFACE EPITHELIAL TUMORS
o Total abdominal hysterectomy and bilateral salpingo-oophorectomy are usually performed for all ovarian tumors,
both benign and malignant, in the premenopausal and postmenopausal women
o Removal of the involved ovary constitutes adequate therapy for the benign tumors and stage I borderline tumors
in young women
o The 5-year survival rate for carcinomas ranges from 25% (peritoneal involvement) to 70% (confined to the ovary),
but for borderline tumors it is 90-100%--good prognosis but still are treated as malignant tumor
 HUGE RANGE
OVARIAN CANCER STAGING (FIGO)—don't really need to know this
o Stage I
 Tumor limited to ovaries (one or both)
 IC – Malignant cells in ascites or peritoneal washings
o Stage II
 Tumor involves one or both ovaries with pelvic extension and/or implants
 IIA – extension and/or implants on uterus and/or tubes
 IIB– extension and/or implants on other pelvic tissues
o Stage III
 Tumor involves one or both ovaries with peritoneal metastasis outside the pelvis
 IIIA – microscopic
 IIIB – macroscopic <2cm
 IIIC – macroscopic >2cm or lymph nodes metastasis
o Stage IV
 Tumor involves one or both ovaries with distant metastases
 Parenchymal liver metastases equal Stage IV
GERM CELL TUMORS
o Derived from the primitive germ cells of the embryonic gonad
 strong morphologic resemblance between testicular germ cell tumors and their ovarian counterparts
o 15-20% of ovarian neoplasms, and are found principally in children and young adults
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o
o
 Approximately 95% of germ cell tumors are benign cystic teratomas
In children and adolescents, more than 60% of ovarian tumors are of germ cell origin and one-third of them are
malignant
If low grade tumor you only have to remove the one ovary
neoplastic transformation of multipotential cells
o
MATURE (BENIGN) TERATOMA
 AKA dermoid cysts
 Young women during reproductive years
 Incidental discovery or rarely paraneoplastic syndromes
 10-15% bilateral
 Thin-walled, unilocular cysts containing sebaceous material, hair and teeth, part of an eyeball, etc
 1% may undergo malignant transformation, usually to squamous cell carcinoma (b/c most common
component in the tumor is ectoderm—skin)
 Cured by resection
 BENIGN CYSTIC TERATOMA
 Wall composed of mature squamous epithelium with sebaceous glands and hair shafts
o Other structures from other germ layers can be identified, such as bone, cartilage,
thyroid tissue, etc
 Rarely, benign teratomas are solid, but still histologically mature and behave in a benign fashion

SPECIALIZED (MONODERMAL) TERATOMAS
 Benign teratoma composed of one component (not multiple)
 Always unilateral
 STRUMA OVARII → thyroid tissue is the only element
o Most cases are benign and rarely functional
o Malignant change is extremely rare—papillary thyroid carcinoma if this tumor becomes
malignant and spreads
 Ovarian carcinoid arises from intestinal epithelium in a teratoma
o One-third associated with carcinoid syndrome—comes from intestinal epithelium that
develops in the teratoma
 More likely to see paraneoplastic syndrome
o Seen in woman after the 4th decade, are slow growing and potentially malignant
o Metastatic carcinoids are always bilateral
 So if you see it in both ovaries you better start looking in the GI tract because it
was probably a met from the GI tract
IMMATURE MALIGNANT TERATOMA
 Embryonal and immature fetal tissue

o
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
 Instead of cystic these tissues are more likely solid
Prepubertal adolescents and young women
Solid structure with necrosis and hemorrhage
Variable amounts of immature elements
 Histologic grade based on proportion of tissue with immature
neuroepithelium (brain)—when you see this tissue you immediately
think about it being a malignant teratoma
 Grow rapidly with local or distant rapid spread (as opposed to the mature
cystic teratoma)
 Low grade tumors have excellent prognosis—is the neuroepithelial brain tissue in one low power
field or more? If there isn’t a lot of neuroepithelium it is low grade and there is an excellent
prognosis
 High grade tumors treated with chemotherapy—lots of neuroepithelium
o DYSGERMINOMA (Counterpart to Seminoma in the testes)
 Ovarian counterpart to testicular seminoma
 2nd and 3rd decades but may occur in children
 2% of ovarian cancers, 50% of malignant germ cell tumors
 1/3 are aggressive
 Overall survival over 80%
 Unilateral early encapsulated tumors can be treated by unilateral salpingooophorectomy and have over 90% chance of a 5-year survival
 Advanced and/or bilateral tumors are treated by hysterectomy and bilateral
salpingo-oophorectomy followed by radiation therapy
 This is worst prognosis scenerio
 Unilateral solid tumors with pale gray to yellow cut surface
 Large vesicular cells with abundant pale polygonal cells w/ cytoplasm containing glycogen and big central
nucleoli
 Like testicular seminoma in males
 Arranged in sheets separated by scanty fibrous stroma with lymphocytes
 May have syncytiotrophoblastic giant cells and granulomas
 Do stains to make sure this is the only component b/c can also get mixed germ cell tumors (like
we saw in males)
 Express OCT4, c-KIT, and PLAP (placental alkaline phosphatase)
YOLK SAC TUMOR (ENDODERMAL SINUS TUMOR)
o Derived from a multipotential embryonal cell carcinoma by selective differentiation toward yolk sac or vitelline
structures
o Most occur in children or young women
 Rare, but 2nd most common germ cell malignancy after dysgerminoma
o Highly malignant with initial spread to surrounding structures and regional
lymph nodes –usually get unilateral salphingo-oophorectomy
 Used to be fatal within 2 years of diagnosis, but better survival with
chemotherapy
 Not sensitive to radiation therapy
o α-fetoprotein (AFP) and α1-antitrypsin are produced by the tumor
 Serum AFP is useful in diagnosis and monitoring the result of therapy
o Encapsulated, lobular and firm with hemorrhagic or cystic cut surface
o Variable histology
o Schiller-Duval body is characteristic
 Germ cells lining a space with a central blood vessel surrounded by germ cells
o Intracellular and extracellular hyaline droplets present
 Stain with AFP
CHORIOCARCINOMA (0-25 y/o)
o Malignant tumor of trophoblastic cells
 More commonly of placental origin





REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
 Prepubertal girls only, after this age cannot rule out ovarian ectopic pregnancy
High -HCG
Very aggressive tumor with widespread metastases to lungs, liver and bone
 Its from premature cells that are normally found in the placenta and its big job is to just destroy the
surrounding tissue and proliferate rapidly (normal job of trophoblasts)
o Proliferation of malignant syncytiotrophoblasts and cytotrophoblasts
 Can be found in males too as a mix germ cell tumor
o Generally unresponsive to chemotherapy
SEX CORD-STROMAL TUMORS (less common than germ cells; occurs in women of all ages)
o Tumors that are derived from the ovarian stroma, which is derived from sex cords
 Sex cords make Undifferentiated mesenchyme produces granulosa cells, theca cells, Sertoli cells, Leydig
cells and fibroblasts (can have combos of tumors in these cells)
 These cells normally secrete estrogens (granulosa cells and theca cells) or androgens (Leydig
cells), so the tumors may be feminizing or masculinizing
o 8% of ovarian tumors, 2% of ovarian malignancies
GRANULOSA-THECA CELL TUMOR
o Composed of varying proportions of granulosa cells and theca cells
o Most common type of sex cord-stromal tumors
 5% of all ovarian tumors
 Most common clinical estrogen-producing ovarian tumors (occasionally produce androgens)
 May result in endometrial hyperplasia and carcinomas
o Most often found in postmenopausal women
 Under 5% of granulosa cell tumors are diagnosed before puberty and in young adults (juvenile-type
granulosa cell tumor) and result in sexual precocity—rare in young adults
o Low malignant potential
 5-25% have local recurrence or spread
 85% 10-year survival
o Unilateral tumors of varying sizes
o Granulosa cells produce inhibin—good for dx and monitoring
 Elevated tissue and serum levels
 Useful for ID and monitoring
o Granulosa cells show variable histologic patterns
 Sometimes form Call-Exner bodies
 Small gland-like structures simulating immature follicles
o Pure thecomas are composed of sheets of plump spindle cells (resembling fibromas) with lipid droplets
o
o



o
inhib stain
FIBROMAS, THECOMAS, AND FIBROTHECOMAS
o 4% of ovarian tumors
o Unilateral masses composed of fibroblasts (fibromas), plump spindle cells with lipid droplets (thecomas), or both
(fibrothecomas)—pure solid tumor that is unilateral
 Most tumors are pure fibromas
 Hormonally inactive
 Pale gray and solid, and consist histologically of bundles of mature fibroblasts
 The more theca cells, the more likely to secrete estrogen
o Associated with ascites in 40% of cases
 Hydrothorax seen occasionally
 Meigs syndrome = ovarian fibroma, hydrothorax and ascites (peritoneal effusion and pleural
effusion related to a ovarian fibroma) –once you take care of the fibroma the pleural and
peritoneal effusions don't occur and we don't know why this is
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o
o
o
A lot of the epithelial tumors like the serous tumors also have ascites and when you tap
their ascites you look for malignant cells in the fluid
Also seen with basal cell nevus syndrome
 Patients under 20 years with multiple basal cell carcinomas and other tumors, especially medulloblastoma,
ovarian fibroma, and other congenital abnormalities
Although the fibromas are benign they are associated with other things and need to be removed
o
FIBROTHECOMA
--lots of clear cells (which
is lipid from the thecal
cells) The fibroma cells
are the splindled fibroblasts

--lots of lipids associated with it
which is why you have this yellow
color.

pure solid yellow (can r/o cystic tumors and suface
epithelial tumors, r/o the mature cystic teratoma, etc)
What we cant r/o is a germinoma b/c they look similar but
usually are multilobulated. Fibroma has like strands like
fibrous tissue
SERTOLI-LEYDIG CELL TUMOR—for the most part these are benign but they will be estrogen/androgen producing tumors
o Recapitulate male-directed Sertoli cells, Leydig cells or combinations
 May produce masculinization or defeminization (because of the androgens)
 Block female sexual development in children
 Atrophy of breasts, amenorrhea, sterility, loss of hair (male pattern baldness), clit enlargement
 Rarely have an estrogenic effect
o Peak incidence in 2nd and 3rd decades
o Unilateral, pale gray and solid
o Histologic features vary from well-formed Sertoli cell tubules and/or aggregates of Leydig cells to sarcomatous
patterns—lots of Sertoli cells w/ or w/o Leydig cells
o Low malignant potential
 5% have local recurrence or spread
o

FIBROMA
predominantly a Sertoli cell tumor
- Tubules are the Sertoli cells. The Leydig cells are found in the
background (she doesn't see any here but they are single cells with
abundant pink cytoplasm. Crystals of Reinke are made by the Leydig
cells
METASTATIC TUMORS OF THE OVARY
o The ovary is more often involved by metastatic processes than any of the other pelvic genital organs
 If there is a METS to the female reproductive system it will be to the ovary
 Mets will present as bilateral involvement of the ovaries
o Most common metastases come from uterus, fallopian tube, contralateral ovary or pelvic peritoneum
o Extra Müllerian metastases come from breast, colon, stomach, biliary tract, and pancreas
o Pseudomyxoma peritonei (jelly belly) derived from appendix
o Need to remove the primary tumor so find it if you have mets
KRUKENBERG TUMOR
o Bilateral, metastatic ovarian tumors composed of mucin-producing signet ring type cancer cells
o Vast majority of such metastases are of gastric origin (stomach)
 Next most commons sites are from carcinomas of the large intestine, appendix and breast (but signet ring
tumors in breast are so rare we wont even discuss them when we talk about breast lecture)
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o
Mucin positive signet ring cells (nucleus is displaced by mucin)
SUMMARY
 Pelvic inflammatory disease
o Lower abdominal pain, fever and vaginal discharge in sexually active women, most commonly caused by
Gonococcus and Chlamydia
o Complications
 Ectopic pregnancy
o Hematosalpinx 6 weeks after normal period
o Transvaginal ultrasound
 Endometriosis
o Benign, chronic, estrogen-dependent disorder associated with pelvic pain, dysmenorrhea, dyspareunia and
infertility, or it may be asymptomatic
o Benign endometrial glands, stroma and hemosiderin
 Follicle and luteal cysts
o Benign physiologic cysts
 Polycystic ovarian disease
o Menstrual irregularity due to oligo- or anovulation
o Evidence of hyperandrogenism
o Exclusion of other causes of hyperandrogenism and menstrual irregularity
 Serous tumors
o Most common malignant ovarian neoplasm
o Most common bilateral ovarian neoplasm
 Mucinous tumors
o Cystic neoplasm filled with sticky gelatinous fluid and lined with tall, columnar cells with mucin
 Teratoma
o Most common germ cell tumor, usually benign
o Mature tissue of ectodermal (eg, skin, hair follicles, sebaceous glands), mesodermal, and endodermal origin
 Dysgerminoma
o Adolescents and young adults with abdominal enlargement with pain due to rupture or torsion
o Most common malignant germ cell tumor
o Summary
 Yolk sac tumor
o Serum AFP levels
o Invaginated papillary structures with a central vessel (Schiller-Duval bodies)
 Granulosa-theca cell tumor
o May estrogen with symptoms related to hyperestrogenism
 Fibrothecoma
o Meigs syndrome
 Sertoli-Leydig cell tumor
o Large mass in adolescents and young adults with virilization
BREAST PATHOLOGY

DISORDERS OF DEVELOPMENT
o SUPRANUMERARY NIPPLES (3rd nipple)
 Results from persistence of epidermal thickenings along the milk line (axilla to perineum)
 Rarely effected by breast pathology
 Hormonally responsive
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay

 Painful premenstrual enlargements
AXILLARY BREAST TISSUE
 Even if a patient had an complete mastectomy she could still have breast tissue way up in her arm pit
there can be breast tissue  can get breast cancer here
 These can also be hormonally responsive and be painful etc.
 May undergo lactational changes
 May give rise to carcinoma
o CONGENITAL NIPPLE INVERSION
 Commonly seen; may be unilateral
 May be confused with nipple retraction (could have had it her whole life and that's just congenital)
 OR it could be secondary to invasive cancer or an inflammatory disorder**
LIFE CYCLE CHANGES


Mammogram demonstrating “dense” breast of young women—harder to pick things up
Young women have increased amounts of fibrous stroma with very little adipose tissue
Enlargement of TDLU in pregnancy
Older women have fewer TDLUs and less fibrous stroma with abundant adipose tissue
Mammography in older women is more radiolucent and easier to detect calcifications & masses
 a lot more fat and less lobules
Clinical Presentations of Breast Disease
o
A.
B.
C.
D.
E.



o
as age  the risk of CA 
Clinical Presentations –Pain
o Diffuse cyclic pain has no pathologic correlate
 Secondary to hormonal changes-- right before the period
o Noncyclic pain is usually localized (not associated w/ time right before menses—not related to hormonal changes)
 Ruptured cysts, physical injury and infections
 Most often no specific lesion identified
 Exception to this is if she’s in a MVA and she has trauma to both breasts
o 95% of painful masses benign, but 10% of breast malignancies are painful
 pain is less concerning than a masses
Clinical Presentations –Palpable Mass
o Lesions >2 cm
 Masses under this can't be felt
 Masses over 1cm can be picked up on the mammogram
o Fibroadenomas, cysts, carcinomas that keep growing
o Likelihood of malignancy increases with age
 10% of masses in women under 40
 60% of masses in women over 50
o 50% of carcinomas arise in the upper outer quadrant (by the armpit)
 10% each in the upper inner, lower inner and lower inner quadrants
 20% in central or subareolar region
Clinical Presentations -Nipple Discharge
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o


Small amount of discharge associated with manipulation of normal breasts
 Repeated simulation can induce lactation
o Galactorrhea associated with elevated prolactin levels, hypothyroidism, endocrine anovulatory syndromes,
medications
 NOT associated with malignancy
o Bloody or serous (clear or straw colored) discharges associated with carcinoma
 Spontaneous (not associated with manipulation) and unilateral
 7% of discharges in women under 60 years
 30% of discharges in women over 60 years
Clinical Presentations -Mammographic Lesion
o Picks up lesions that are 1 cm.
 Feeling them picks up 2cm masses
o Identifies irregular densities
 10% probability of malignancy at age 40
 25% probability of malignancy at age 50
o Identifies calcifications
 Numerous small, irregular, clustered microcalcifications associated with malignancy
 They get BIRAD scores from the radiology report
 DCIS presents as linear, branching pattern of calcs
 Most calcifications seen end up being benign
 Benign calcs associated with apocrine cysts, fibroadenomas and sclerosing adenosis
o 10% of carcinomas missed by mammography
 Usually ones with no calcifications or ones where the woman has very dense breast tissue so you cant tell
tissue from mass or if mass is peripheral or very close to the chest wall it will be missed and a mass
smaller than 1cm
ANATOMICAL ORIGINS OF COMMON BREAST LESIONS
o


Papillomas in large ducts cause bloody discharge
Tumors really close to chest wall or very lateral could be missed
INFLAMMATORY DISORDERS
 Inflammation of the breast is uncommon
o Account for less than 1% of women with breast symptoms
o Only a few forms of acute and chronic disease
 Most important is ACUTE MASTITIS
o Confined to the first month of breast feeding-- fever, breast is red, hard, and tender
o Caused by skin contamination Staphylococcus aureus or Streptococcus species
o Antibiotics and continued milk expression
 Must exclude “inflammatory carcinoma”-- rule this out bc you can also get a discharge in this cancer
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay


o tumor emboli in dermal vessels
PERIDUCTAL MASTITIS
o Recurrent subareolar abscess
o Presents as painful mass
o Keratin plug of nipple duct leads to duct rupture and
inflammation
 Keratin plug blocks the excretion of the secretions
and you get neutrophils back there
 Can develop a Secondary bacterial infection possible
o 90% of cases are in smokers
 You need vitamin A for the normal specialized cell
growth and smokers have less
o Cracking and fistula formation
o Treated with surgical excision +/- antibiotics
 You must excise the area and give them antibiotics
MAMMARY DUCT ECTASIA
o 5th-6th decade, multiparous women (many children)
o Results from obstruction of ducts due to inspissation of secretions
 Inflammation with dilation of the subareolar ducts
o Dilated ducts filled with granular debris and periductal and interstitial chronic inflammation
 If its >2 cm it will be palpable
 It's a mimicker of a mass
o Usually affects a single area of the breast, poorly defined palpable area of induration or thickening with white
nipple secretions-- green/brown nipple discharge
 The ducts just get filled with debris and it causes an inflammatory condition
 Irregular palpable mass that mimics carcinoma
 You're worried about cancer so must r/o!!
 Biopsy shows chronic inflammation with plasma cells!!!




 fat and then a regular spiculated lesion
Irregular spiculated lesion amidst a sea of fat. palpable if >2cm or see it in mammogram.
Ducts filled w/ debris inflammation
FAT NECROSIS
o History of trauma or prior surgery
 Sometimes they don't remember the trauma (car accident, or hit to the breast, etc)
o Hemorrhage → liquefactive necrosis → neutrophils and macrophages → fibroblasts, neovessels, chronic
inflammation (granulation tissue) → foreign body giant cells and calcium salts → scar or surrounded by fibrosis
o Possible confusion with carcinoma
o
fibrous tissue and inflammation
 Still see fat still alive and dead fat and inflammation
 You can see associated calcifications and giant cells
BENIGN EPITHELIAL LESIONS – CLINICAL SIGNIFICANCE
 Produce masses that must be differentiated from carcinomas
o Calcifications & irregular densities (and spiculated) on mammogram
 Association between fibrocystic change and cancer is proportional to the degree of epithelial hyperplasia and atypia
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay


Divided into 3 groups, according to risk of subsequent breast cancer and the increased risk is in BOTH BREASTS!!!
o **Typically found in association with each other
o NONPROLIFERATIVE BREAST DISEASE (FIBROCYSTIC DISEASE)
 Cysts, apocrine metaplasia, fibrosis, adenosis
 No increased risk of carcinoma
o PROLIFERATIVE BREAST DISEASE WITHOUT ATYPIA
 Epithelial ductal hyperplasia, sclerosing adenosis (these are associated with calcifications), complex
sclerosing lesion, papilloma
 More layers of cells within the lumen
 1.5-2x increased cancer risk
o PROLIFERATIVE BREAST DISEASE WITH ATYPIA
 Atypical ductal hyperplasia, atypical lobular hyperplasia
 4-5x increased cancer risk
NONPROLIFERATIVE BREAST CHANGES (FIBROCYSTIC CHANGES)
o Single most common disorder of the breast
o Affects women frequently between the ages of 20-40-- PREMENOPAUSAL, rarely develops after menopause
o Hormonal imbalances are thought to be the cause
 Oral contraceptives decrease the risk of fibrocystic change, presumably because they supply a balanced
source of estrogen and progesterone
o Morphologic changes: cyst formation, apocrine metaplasia, fibrosis, adenosis
o Cysts formed by dilation and unfolding of lobules
 Grossly, large cysts and their contents may appear blue in color → blue-dome cysts
o Fibrosis due to ruptured cysts, leading to scarring
o Apocrine metaplasia characterized by large polygonal cells having an abundant, granular, eosinophilic cytoplasm
with small, round nuclei
 Resembles normal apocrine epithelium of sweat glands
o Adenosis = an increased number of acini per lobule
o Apocrine Cysts
 NO INCREASED RISK FOR CANCER!!!


big and dilated with secretions within them. These have undergone apocrine metaplasia inside
the cyst there is a calcification and fluid big and pink and abnormal. Usually just a single lining. So
big and pink = APOCRINE metaplasia!
PROLIFERATIVE BREAST CHANGES – EPITHELIAL HYPERPLASIA
o Hyperplasia = more than 2 cell layers in ducts
o Classified as moderate to florid when more than 4 layers
 The additional cells are both luminal and myoepithelial cell types
o Duct may be filled or distended by cells
o Irregular lumens seen at the periphery of the duct are characteristic
o Moderate or florid hyperplasia increases CA risk 1.5-2x
 Must tell the difference between the typical ductal hyperplasia (usual ductal hyperplasia) -2x risk of
cancer versus the Atypical ductal hyperplasia that carries a risk of 4x for carcinoma!
o


 Usual ductal hyperplasia= typical ductal hyperplasia
 Luminal cells and myoepithelial cells lots of hyperplasia
PROLIFERATIVE BREAST CHANGES – SCLEROSING ADENOSIS
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o
o
o
Adenosis = increase in the number of acini per lobule
 Risk of cancer = NONE if it's just ADENOSIS
Sclerosing adenosis = at least double the the number of acini per lobule compared to normal combined with
intralobular fibrosis, creating compressed acini in the center and dilated acini at the periphery
 risk of cancer =2x
 Occasionally, the fibrous growth may totally compress the lumina of the acini to create an appearance of
solid cords of cells lying within dense stroma, which may mimic carcinoma
Increased risk (1.5-2X) for subsequent development of invasive carcinoma
o

More busy looking—on higher power looks like no lumen and pathologist actually has to do a stain
for myoepithelial cells to make sure its not an invasive CA b/c it looks scary
PROLIFERATIVE BREAST CHANGES – RADIAL SCAR
o Most common of the complex sclerosing lesions
 Components of sclerosing adenosis, papilloma and epithelial hyperplasia
o Stellate appearance with entrapped glands in a fibrous stroma
 Not really a “scar” – no association with previous trauma or surgery
o Mammogram, gross and microscopic appearance can mimic carcinoma
o Increased risk (1.5-2X) for subsequent development of invasive carcinoma
o

PROLIFERATIVE BREAST CHANGES – INTRADUCTAL PAPILLOMA
o Branching fibrovascular cores covered by myoepithelial and luminal cells
o Grows within a dilated duct; especially common in lactiferous sinus (subareolar)
 These women tend to have bloody nipple discharge
o Epithelial hyperplasia and apocrine metaplasia seen
o Increased risk (1.5-2X) for subsequent development of invasive carcinoma
o

Stellate look. Looks like a scar but not associated with trauma (no fat necrosis associated with it) . It's
just a stellate shape.
the normal myoepithelial and luminal cells
 Bx to w/o CA and DCIS
PROLIFERATIVE BREAST CHANGES WITH ATYPIA
o NOW WE'RE TALKING ABOUT THE TYPES with 4x-5x the RISK OF CANCER!!!
o Atypical ductal hyperplasia (ADH) = cellular proliferation resembling carcinoma in situ but lacking sufficient
qualitative or quantitative features for diagnosis of carcinoma
 Can be difficult to distinguish from DCIS
 It pretty much looks like DCIS (DCIS- ductal carcinoma in situ) but there's just not enough to
diagnose it as DCIS
o Harbors some of the same acquired genetic changes seen in DCIS
o Associated with a 4-5X increased risk for subsequent development of invasive carcinoma
 Versus hyperplasia without atypia, which is associated with a 1.5-2X increased risk
o ATYPICAL DUCTAL HYPERPLASIA
 5-17% of biopsies for calcifications
 Usually adjacent to calcifying lesion
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay

Relatively monomorphic proliferation of regularly spaced cells, sometimes with cribriform spaces, that
partially fill ducts
 Resembles DCIS
 Normally what makes the pathologies worried is the number of these atypical glands or that only
parts of the gland are involved

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o
this is ADH
They look cribiform and cookie cutter—the nuclei start looking monomorphous and are lined up
together and all the cells start looking like eachother (normally you see variation in cells—
epithelial and myoepithelial cells) and you get rigid glands (vs free flowing glands seen in normal
hyperplasia)
Usually next to a fibrocystic change as well the other ducts might even look normal except for 1
 4-5x risk of cancer
this is ductal proliferations (Typical/usually ductal hyperplasia)
2x risk of cancer
Slit like spaces. Nuclei are going in all different directions. There are myoepithelial cells and
epithelial cells.
ATYPICAL LOBULAR HYPERPLASIA
 Seen in < 5% of biopsies performed for any reason
 Incidental finding!! It's ALWAYS incidental finding and will never be the reason they do a bx
 This will never form a mass
 Proliferation of discohesive cells with round to oval nuclei and small nucleoli that do not fill or distend
more than 50% of the acini within a lobule
 Identical histology to LCIS, quantitatively smaller

The cells are packed in the lobules
BREAST CARCINOMA
 Most common non-skin malignancy in women
 Second most common cause of cancer death in women
o A woman who lives to age 90 has a 1:8 chance of developing breast cancer
o About 20% of breast cancer patients are expected to die from it
 Heterogeneous disease with various histologic appearances; major classifications have important biologic and clinical
differences
 Breast Cancer Incidence & Mortality for Women >50 years—older you are the more  risk you are for breast CA
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o

shows that there is an  in identifying the DCIS in all women b/c  awareness and mammogram
technology, HRT ( in breast Ca b/c these are estrogen receptor + breast cancer),  when they found out
about HRT causing breast cancer
 We have not  incidence of invasive cancer
Change in Stage of Breast Cancer at Presentation from 1983-1996
o


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
There was increase in cancer rates of DCIS and small breast cancers from 86-93 especially (93-94 giving
estrogen to people). There was a slight decrease in stage 2,3,and 4 cancers. Well that's b/c mammograms
started being used and we're finding these tumors and treating them.
 We pretty much increased the incidence of those cancers b/c now when we find them when they're
smaller and not invasive.
RISK FACTORS FOR BREAST CARCINOMA
o Age
 Most cases >50 years old
 Rarely found in women <20 years old, except familial cases
o Early menarche and late menopause
 Increased endogenous estrogens (they are in your body for a longer period of time)
o Nulliparity or 1st live birth after the age of 35 years old
o First degree relatives (mother, daughter, sister) with breast cancer
 Increased further in families with BRCA1 or BRCA2 mutations
o Prior breast biopsies showing atypical hyperplasia (ADH=: atypical ductal hyperplasia)
 4-5x increased risk
RISK FACTORS FOR BREAST CARCINOMA – RACE / ETHNICITY
o Risk of developing invasive carcinoma between ages 50-70:
 1:15 Caucasians,1:20 African-Americans, 1:26 Asian/Pacific Islanders, 1:27 Hispanics
o African-American women have lower overall incidence, but typically present with a more advanced stage and have
higher mortality rates--usually the high grade tumors in these women
 More diagnosed in black women <40 years old
 Younger than other ethnic groups
 Tumors lack hormone receptors and have sporadic p53 mutations
 worse looking and bigger tumors and more cancerous tumors
RISK FACTORS FOR BREAST CARCINOMA
o Estrogen exposure
 1.2-1.7 increased risk with postmenopausal hormone replacement therapy
 75% decrease in risk following oophorectomy
 Or women that take drugs that block estrogenic effects or block formation of estrogen also
decrease risk
o B/c these tumors use estrogen
o Radiation exposure (not like exposure from x-ray and mammograms—radiation for cancers in the area, etc)
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o
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High breast radiodensity (more breast tissue if you have many more lobules)
 Maybe at the end of each menstrual cycle there isn’t complete regression of lobules when you have
hormonal changes
 Or wont see small DCIS on mammogram when you have dense breast tissue
o Carcinoma of the contralateral breast or endometrium
 80% of the endometrial cancers are associated w/estrogen as well
o Geographic influences
 4-7X higher risk in U.S. & Europe
 Thought to be due to reproductive history, breastfeeding, diet, obesity ( estrogen), physical
activity, environment
o Diet: moderate to heavy alcohol
 Higher estrogen levels and lower folate levels
o Obesity
 Synthesis of estrogens in fat deposits
o Breast feeding
 Longer breast feeding decreases risk
 Lactation suppresses ovulation (and  the estrogen) and may trigger terminal differentiation of
luminal cells
o The major risk factors for the development of breast cancer are hormonal and genetic
 Sporadic cases are probably related to hormonal exposure
 Hereditary cases are probably associated with germline mutations
HEREDITARY BREAST CA
o 12% of Breast Cancers
o Two major genes: BRCA1 or BRCA2
 3% of all breast cancers
o Both function normally as tumor suppressors; mutation causes loss of function
 2 hit hypothesis. You start w/1 mutation and the other is spontaneous
 0.1-0.2% Mutation frequency in general population
 One mutant allele is inherited, the second allele is inactivated by somatic mutation
 60-85% risk of breast cancer with mutation
 Lots of prophylactic mastectomy with h/o of cancer in the family and they are BRCA1 or 2
positive
o Increased risk with multiple affected 1st-degree relatives or cancer before menopause or multiple cancers (ovarian
Ca, male breast Ca)
 A couple of times you'll have a woman who has all sorts of 1st degree relatives with breast cancer and this
woman will have a small breast cancer already and shes 30 and then they test her for BRCA1 and BRCA2
and the woman is negative. Perhaps there is a BRCA 3 or other gene causing this? These women usually
get the prophylactic mastectomies (most of the time) or get tumors removed and come for frequent
screening.
o Mutation carriers may get prophylactic bilateral mastectomy and/or oophorectomy
o p53 mutations occur in hereditary and sporadic breast Ca; increased risk 18x in Li-Fraumeni syndrome
SPORADIC BREAST CA
o Major risk is estrogen exposure
o Usually occurs in postmenopausal women
o Prolonged estrogen stimulation related to
 Early menarche, late menopause
 No kids or first kids later in life >35
 No breast feeding the kids
 Exogenous estrogens, hormone replacement therapy (birth control pills unlikely to increase risk)
o Estrogen drives cell proliferation in both premalignant lesions and cancers
o TUMOR PROGRESSION
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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o
o
Ones associated with estrogens are the low grade ones
High grade tumors are usually estrogen receptor negative
Unidentified precursor--The only cell not responsive to estrogens is the myoepithelial cell so maybe that
has something to do with it but no proof yet
BREAST CARCINOMA CLASSIFICATION
 >95% of breast malignancies are ADENOCARCINOMAS
 Divided into in-situ and invasive carcinomas
o Problem is it's a duct system so if it does break through the BM and enter the duct it can
effect a large part of the breast even it never invaded into the stroma
 Present system of classification separates ductal from lobular carcinoma
 They all come from the same cell (terminal duct lobular unit—TDLU) they just look different and
behave differently
 Creates an erroneous impression that ductal carcinomas originate in the ducts and that lobular
carcinomas originate in the lobules
 Carcinomas arise in the TDLU and breast cancers are diagnosed on patterns of growth and cytologic
features, not by site of origin
 Morphologic differences between ductal and lobular carcinoma do not reflect a different
histogenesis, but rather a different biologic behavior
DUCTAL CARCINOMA IN-SITU (DCIS)
 Once <5% of carcinomas, but with increased use of mammography, earlier and smaller lesions are being
detected
 Now constitutes approximately 20-30% of carcinomas
 Almost 50% of carcinomas detected by mammography are non-invasive (haven’t invaded BM—
but nothing preventing it from spreading into the duct or laterally)
o You don't feel them yet but the mammogram picks it up
 Malignant population of cells that lack the capacity to invade through the basement membrane
 Nothing is stopping it from moving up the duct and spreading laterally
 May spread throughout a ductal system and involve an entire sector of a breast
 May migrate up the duct system to involve the nipple skin
o PAGET’S DISEASE OF THE NIPPLE (very different from Paget's disease of the vulva!)
 Historically divided into five architectural subtypes
 comedocarcinoma, cribriform, solid, papillary and micropapillary
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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Comedocarcinoma versus Noncomedo DCIS—Most important to classify into these subtypes
 Comedocarcinoma is associated with pleomorphic nuclei and luminal necrosis (necrosis in the
center), always high grade DCIS
o Some tumors are ALWAYS high grade due to their name so must know this!!
 Like clear cell tumors and papillary serous carcinoma of the uterus and the
ovaries
 Noncomedocarcinoma has low to high grade nuclear cytology
Many cases progress to invasive cancer
Treated with lumpectomy +/- radiation
 Depending on the size and how big the margins are and comedo or non comedo and the grade
will determine whether or not she gets radiation
 Lower rate of recurrence with low grade DCIS, smaller size and >1 cm margins
DUCTAL CARCINOMA IN-SITU, COMEDO TYPE


cheezy necrotic tissue in the center
Proliferation of cells
with cheesy necrosis
in the middle
DUCTAL CARCINOMA IN-SITU, NONCOMEDO TYPE
 Once you know it's noncomedo you determine the grade because it ranges.
 These are both low grade pictures.

Cribriform DCIS
"cookie cutter" small glands within the one gland.
No slits in the corner that we see with usual or
ADH-- very rigid. Has little calcifications
shows up on mammogram

Solid DCIS
Whole lumen if filled w/ cells. Nucleioli in there and
they are big. Sometimes you can see mitotic figures
in there
Papillary DCIS
Micropapillary DCIS
fibroblastic core limited by BM
They look like papilli but there's no true core
COMPARISON OF DUCTAL PROLIFERATIONS

Usual Ductal Hyperplasia
Little slit like spaces. Cells look
different from eachother. There are
myoepithelial and epithelial cells
Atypical Ductal Hyperplasia (ADH)
Starting to look Monotonous and cookie cutters.
Not many slit like spaces
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay

Atypical Ductal Hyperplasia
o
PAGET’S DISEASE OF THE NIPPLE
 The carcinoma moves up the duct to the nipple
 ALWAYS MEANS THERE IS UNDERLYING CARCINOMA
 Doesn't have to be invasive can be DCIS (50% chance of either)
 Seen in 1-4% of cases of breast cancer
 Unilateral erythematous nipple with scaly crust
 Pruritis may be mistaken for eczema so do bx
 If palpable mass present, 50% of patients have invasive carcinoma; rest have DCIS
 DCIS cells spread right up the duct and go into the epithelium
 Prognosis depends on features of underlying carcinoma
 Different than Paget's disease of the vulva!! There might not be underlying cancer with the
disease of the vulva but THERE IS ALWAYS underlying carcinoma of the breast.

LOBULAR CARCINOMA IN-SITU
 Always an incidental finding
 Not associated with calcifications or stromal reactions that produce
mammographic densities
 Clinically silent and incidence is unknown
o No fibrous stroma-- you find these by accident on a biopsy
 Bilateral in 20-40% of cases
 80-90% of cases occur before menopause
 Marker for increased risk of subsequent invasive carcinoma in either breast
 1% risk per year, 3x more likely lobular than ductal
 Tx choices include prophylactic bilateral mastectomy (esp w/ family hx), Tamoxifen, or
close clinical follow-up
 Give Tamoxifen b/c lobular ca are E receptor +
 Cell proliferation in one or more terminal ducts and/or acini
 The nuclei are small, uniform, round, and bland with marked lack of cohesiveness
 Lack of cell adhesion protein E-cadherin
 No calcifications—making it an incidental finding
MOST COMMON TYPES OF INVASIVE CARCINOMA
o Ductal, No Specific Type (NST) 70-80%
o Lobular 10%
 Different prognosis. Still came from the terminal duct lobular unit
o Tubular 6%
o Mucinous (colloid) 2%
o Medullary 2%
 Usually better prognosis w/medullary tubular and papillary
o Papillary 1%
o
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Cribriform DCIS
No slit like spaces and all cells are monotonous
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o
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Metaplastic <1%
 Histologic type of tumor is a minor prognostic factor
INVASIVE DUCTAL CARCINOMA
o Without mammographic screening, almost always presents as a palpable mass (>2cm)
 Axillary lymph node metastases in 50% of patients with palpable masses
 Most important prognostic factor
 Most important than any other prognostic factors
 Large carcinomas may be fixed to chest wall or cause dimpling of skin
o Peau d’orange
 Looks like an orange peal—dimpling of the skin
 Tethering of the skin to the breast
 Ligaments are still attached but breast is swollen and blocked
 Tumor involves lymphatics → block drainage → lymphedema and skin thickening
o INFLAMMATORY CARCINOMA
 Tumors present as swollen, erythematous breast
 Invasion and obstruction of dermal lymphatics WITHOUT discrete, palpable mass (spreads to
skin)
 May be confused with inflammatory condition
o INVASIVE DUCTAL CARCINOMA, NO SPECIAL TYPE
 Most common type, accounting for 70-80% of cancers
 These tumors generally present as a palpable mass (50% have LN mets) or
radiographic abnormality (20% have LN mets) in women in their mid to late 50’s
 Most commonly located in the upper outer quadrant of the breast
 Grossly, the tumors are retracted, firm, white, with chalky yellow streaks or gritty
calcifications
 May have a “stellate” or “crab-like” appearance
o
o
o


Fatty tissue and fibrous parenchyma
Stellate/crabs with arms sticking out
Looks kind of like the fat necrosis or radial scar so look at it
microscopically
Microscopically, the tumor cells are arranged as glands or sheets and infiltrate a
fibrotic stroma +/- intraductal component
Histologic grade minor prognostic factor
 A. Well differentiated—its forming good glands, not a lot of
mitotic figures and the cells look alike
 B. Poorly Differentiated—The cells are big and ugly, lots of
mitotic figures, doesn't look like normal breast parenchyma
Well Differentiated
Moderately Differentiated
Poorly Differentiated
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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GENE EXPRESSION PROFILING IN NST (NO SPECIAL TYPE)
 Measures relative quantities of mRNA
 5 major patterns of gene expression
o Correlate with prognosis and response to
therapy
 Luminal A (45-55%)
o ER+, Her2-; hormonal treatment
o Best prognosis & the majority of tumors are
this!!
 Luminal B (15-20%)
o ER+, Her2+; chemotherapy
 Normal breast-like (6-10%)
o ER+, Her2-; specific pattern?
 Basal-like (13-25%)
o ER-, Her2-; chemotherapy
 Triple negatives (ER, Her2 and Progesterone Receptor) are the worst!!!
 Quick growing and fast spreading
 Her2/neu positive (7-12%)
o ER-, Her2+; Herceptin & chemotherapy
o Not as good as ER+ but not as bad as Her2 INVASIVE LOBULAR CARCINOMA
o Less common; ~10% of breast cancers
o Some studies claim: More frequently bilateral than ductal carcinoma?
 Later studies refute that point: 5-10% chance of developing cancer in contralateral breast, similar to
ductal carcinoma, NST
 So there probably isn't an increased risk of getting it bilaterally actually
o Tend to be multicentric within the same breast
 ductal=1 mass, lobular= many masses
o Present as palpable mass or mammographic density
 THESE MAKE MASSES
o Mets to peritoneum, retroperitoneum, leptomeninges, GI tract, ovary and uterus
 They met slower than ductal carcinoma
o Loss of E-cadherin cell adhesion molecule—to tell the diff between ductal and lobular
o Grossly, tumor is rubbery and poorly circumscribed
o Microscopically, the tumor grows in single file or in a targetoid pattern around ducts
 It will look like a big target
 Benign duct in the center
 Lobular Carcinoma big circles and single file behind it
o Usually associate with LCIS (was an incidental finding)
 If you just see this make sure they re-bx to make sure they didn't miss the invasive component
o Well-differentiated lesions have gene expression profiles similar to Luminal A carcinomas (ER+ & Her2-)
o Bigger than ductal carcinomas better prognosis & older women get this usually
o Poorly differentiated lesions HER2+ ( mitotic figures and cells look bad)
 When it gets poorly differentiated then the Her2 gets positive (usually these keep the ER positivity)
MEDULLARY CARCINOMA
o THESE LOOK HORRIBLE--inflammatory cells, no tubule formation!, high mitotic rate!
TRIPLE NEGATIVE
 BUT it has a well-defined border with lymphocytes and a BRCA 1 carrier—
they actually have a better prognosis than NST
o Well-circumscribed mass with pushing border
o Solid sheet of cells
 Low tubule formation
o Large, pleomorphic cells with prominent nucleoli and mitoses
o Lymphoplasmacytic infiltrate
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o
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Slightly better prognosis, despite poor prognostic factors
 High nuclear grade, high mitotic rate, triple negative
 looks bad but it's actually not!!! has a well defined border with inflammatory cells to contain
o Medullary features common with BRCA1 carriers
o So check the lymph node status
MUCINOUS (COLLOID) CARCINOMA
o Slow growing tumors in older women (70s)
o Small clusters of tumor cells in a sea of mucin with a pushing border
 mucin with cells floating in it
o Slightly better prognosis
 Well to moderately differentiated
 Usually ER+
 Lymph node mets uncommon
TUBULAR CARCINOMA
o Women in late 40s
o Well-formed tubules
 Differential diagnosis is benign sclerosing lesion, which has myoepithelium
o Low degree of nuclear pleomorphism and not abnormal cells no myoepithelium
associated with it so you know it's invasive
o Angulated tubules lined by a single layer of cells with small uniform nuclei
o Associated with ALH, LCIS or low-grade DCIS
o Excellent prognosis
 Well differentiated
 ER+, HER2PROGNOSTIC FACTORS FOR BREAST CANCER
o Prognosis is determined by pathologic examination of primary tumor and axillary lymph nodes
o Major prognostic factors are strongest predictors of death from breast cancer
 Incorporated into AJCC staging system
 Invasive vs. in-situ
 Distant metastases (ie liver, bone, lungs)
 Lymph node metastases
 Tumor size
 Locally advanced disease (involve chest wall? down to ribs sometimes)
 Inflammatory carcinoma-- tumor in the lymphatics was the red breast inflamed (that's bad)
PROGNOSTIC FACTORS – LYMPH NODE STATUS
o Axillary lymph node status is the most important prognostic marker
 No involvement: 10 year survival rate 70-80%
 1-3 positive nodes: 35-40%
 >10 positive nodes: 10-15%
o “Sentinel nodes” determined by injecting a radiotracer or colored dye and see which nodes pick up that dye first—
those are the sentinel nodes
 Determining which nodes the cancer primarily drains to can limit the morbidity associated with extensive
axillary lymph node dissection
 If you take out all the axillar LN you will have problems with draining, lymphedema, etc So you don't want
to take out all their nodes!!! So first you check it before you take many!
MAJOR PROGNOSTIC FACTORS
o Primary tumor size
 Second most important prognostic indicator in both node negative and node positive patients
 < 2 cm associated with favorable prognosis
o Inflammatory carcinoma
 <10% 3-year survival
 Dermal signs of inflammation (surface tenderness, red, hard)
 Under the scope she sees tumor in the lymphatics
o Invasive vs. DCIS
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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 DCIS cured by treatment
 50% of invasive carcinomas have metastasized locally or distantly at the time of diagnosis
MINOR PROGNOSTIC FACTORS
o Histologic type and grade of tumor
 Well differentiated tumors have better prognosis
 The degree of nuclear atypia, tubule formation and mitotic rate determine grade
o ER, PR, Her2/neu status
 ER, PR positivity = better
 Her2/neu negativity = better
o Lymphovascular invasion
 Strongly associated with lymph node mets
o Proliferative rate-- mitotic figure numbers (less is better)
 Lower rate = better
o DNA content
 Diploid tumors= better
 Aneuploid tumors = worse
o Response to neoadjuvant therapy-- so if they had gotten chemo and it shrunk that's good
 Good response to pre-surgical chemotherapy
BREAST CANCER STAGING (AJCC)-- in breast the size of the tumor is what matters
o Stage I
 Invasive carcinoma ≤ 2 cm; no LN mets
 87% 5-year survival
o Stage II
 Invasive carcinoma > 2 cm; no LN mets
 Invasive carcinoma < 5 cm; 1-3 LN mets
 75% 5-year survival
o Stage III
 Invasive carcinoma >5 cm; 1-3 LN mets
 Invasive carcinoma, any size; ≥ 4 LN mets
 Invasive carcinoma involving chest wall or skin
 46% 5-year survival
o Stage IV
 Distant metastasis
 13% 5-year survival
METASTATIC PATTERNS
o Local extension: direct extension to the overlying skin or underlying chest wall
o Lymphatic spread
o Hematogenous spread
 Strong propensity of distant metastases through hematogenous route
 Occasionally present with symptoms and signs due to metastatic lesion and carcinoma of unknown
primary
o Sometimes you'll have a woman who presents and has carcinoma w/ no known primary—either she has pleural
effusion or liver lesion or bone lesion and the first question the pathologist asks is did you do a breast exam? Do a
breast exam and see when there last mammogram was! Most common tumor in women is breast cancer.
OTHER MALIGNANT BREAST TUMORS
o ANGIOSARCOMA
 Sarcoma arising from the blood vessels
 Sporadic cases seen in young women (average 35 yo)
 High grade, poor prognosis
 0.3% risk of sarcoma 5-10 yrs after radiation
 66% are angiosarcomas in the overlying skin
 May arise in an arm with chronic lymphedema secondary to prior mastectomy and lymph node dissection
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o

LYMPHOMA
 Burkitt lymphoma may present as massive bilateral breast enlargement during pregnancy or lactation
 Burkit's lymphoma can have prolactin receptors. So can present during lactation.
 All of a sudden their breasts triple in size after they gave birth b/c of the intense milk production
ANATOMICAL ORIGINS OF COMMON BREAST LESIONS
TUMORS ARISING FROM THE INTERLOBULAR STROMA
 FIBROADENOMA
o Most common benign breast tumor
 Most common condition of the breast is fibrocystic change!!!
 But if there is a mass this is usually what it is—most common benign breast tumor!!!
o Occurs at any age; most common in 20s and 30s
o Hormonally responsive
 May increase in size in late menstrual cycle due to proliferation under the
effects of estrogen & progesterone
 Increase in size due to lactational changes during pregnancy
o Grossly, well-circumscribed, with a lobulated, tan-white cut surface that bulges above
the surrounding breast parenchyma
 Freely movable
 Proliferation of stroma
 Proliferation of ducts and they are compressed
o Microscopically, benign proliferation of compressed slit-like glands and fibrous tissue
 more glands and fibrous tissue
o Generally, no increased risk for development of invasive carcinoma
 Increased risk (1.5-2X) for subsequent development of invasive carcinoma limited to complex
fibroadenomas
 Sclerosing adenosis, epithelial hyperplasia, papillary changes
 PHYLLODES TUMOR
o Older Women in the sixth decade
o Arises from intralobular stroma
o Histology
 Stroma: increased cellularity, increased mitotic rate ( mitotic figures), nuclear
pleomorphism, infiltrative borders (differentiates from fibroadenoma)
 Infiltrates the surrounding tissue
 Benign epithelium
 usually these are low grade
 Larger lesions have bulbous, “leaf-like” protrusions microscopically (phyllodes = Greek for leaflike)
o The low grade tumors may recur locally, while the high grade tumors, although less common, behave more
aggressively with local recurrences +/- distant hematogenous metastases
 Only stromal component metastasizes
 THESE HAVE A TENDENCY TO COME BACK!!!!
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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If it looks really bad and it's a high grade tumor it can actually met and only the stromal portion mets—not
the grandular leaflike portion doesnt!
MALE BREAST
 Consists of a rudimentary duct system ending in terminal buds—so can get ductal carcinoma
o Lobules are not present
 GYNECOMASTIA
o Most common pathology in the male breast
o Proliferation of ducts and connective tissue, secondary to an imbalance between estrogens
and androgens
 Cirrhosis, aging, drugs ( estrogen metabolism)
 Need to r/o cancer tho
o Readily apparent on physical examination as unilateral or bilateral subareolar enlargement—man boobs
 CARCINOMA OF THE MALE BREAST
o Very rare occurrence with a frequency ratio to breast cancer in the female of less than 1:100
 Lifetime risk of 0.11% (versus 13% in women)
 incidence is 1% for every 100 female breast cancers there is 1 male breast cancers
o Same risk factors as female breast cancer: first degree relatives with breast cancer, decreased testicular function
(Klinefelter Syndrome), advanced age, obesity, BRCA mutation
 Or  estrogen or  E metabolism, and  androgens
o Due to the scant amount of breast substance, the tumor rapidly infiltrates the overlying skin or underlying thoracic
wall
 So little breast tissue so they get into the skin very quickly!!!
o Histology similar to that seen in female breast cancers
o These are unilateral or bilateral
o r/o invasive carcinoma
SUMMARY
 Clinical presentations of breast disease
o Pain, palpable mass, lumpiness, nipple discharge (bloody we're worried)
 Nonproliferative breast changes
o Cysts, apocrine metaplasia, fibrosis, adenosis
 Proliferative breast disease without atypia
o Fibrocystic change with epithelial hyperplasia
 Proliferative breast disease with atypia
o Fibrocystic change with ADH
 Clinical presentations of breast carcinoma
o Palpable mass in the UOQ (half are there!), peau d’orange, swollen erythemaous breast (inflammatory breast
cancer!)
 DCIS
o They are still in the duct but they can spread all the way up to the nipple
o Malignant ductal cells that have not invaded the basement membrane
o Low grade versus high grade
 LCIS
o Incidental finding
o Increased risk of cancer in either breast
 Invasive ductal carcinoma, NST
o Most common type
 best thing is to be ER pos and Her2 nega
o ER, PR, Her2-Neu status
 Invasive lobular carcinoma
o Older women
o Large, well differentiated tumor that is ER+
 Medullary carcinoma
o Younger patient or BRCA1 carrier
o Better prognosis despite aggressive histologic features-- really ugly high mitotic rate
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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Tubular carcinoma
o Well differentiated tumor with a favorable prognosis
o Summary
Prognostic factors for breast cancer
o Axillary lymph node status
o Size, inflammatory component, Invasion
Fibroadenoma
o Freely mobile, well-circumscribed mass in women in the 3rd and 4th decades-- microscopically looks infiltrative
o Most common benign breast tumor
o Benign proliferation of glands and stroma
Phyllodes tumor
o Freely mobile, well-circumscribed mass in women in the 6th decade
o Stromal component more pronounced and determines benign versus malignant
DISEASES OF PREGNANCY
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SPONTANEOUS ABORTION (MISCARRIAGE)
o Pregnancy loss before 20 weeks of gestation
 10-15% of pregnancies
 After 20 weeks its called an IUFD or stillborn
o Fetal causes: chromosomal anomalies
 Found in approximately 50% of cases
o Other 50% are
 Maternal causes: endocrine disorders, uterine defects (leiomyomas), systemic disorders (vasculature),
infections, trauma
 OR Unknown causes
ECTOPIC PREGNANCY
o DON'T send a women home whose around 6-8 weeks after her LMP and she comes in with pain. Do an ultrasound
and a -HCG
o Implantation of the fetus in any site other than the uterus
 90% within fallopian tube
 Ovary, abdominal cavity and intrauterine portion of the fallopian tube (cornu)
o 1 out of 150 pregnancies
 35-50% of patients have history of PID
 Long term complication of PID involves scarring of the cilia in the fallopian tube and adhesions
 PID is usually caused by Chlamydia or Gonorrhea or polymicrobial infections
o Most common cause of hematosalpinx
o Severe abdominal pain, usually 6 weeks after last normal menstrual period, when ruptured tube leads to pelvic
hemorrhage
 Medical emergency
DISORDERS OF LATE PREGNANCY
o Interruption of blood flow through the umbilical cord
 Knots or cord compression--can be due to position
o Infections
o Hemorrhage
 Abruptio placentae (Abruption: hemorrhage where the
placenta and myometrium meet), intervillous
hemorrhage (hemorrhage between the chorionic villi),
placenta previa, placenta accreta
o Utero-placental malperfusion
 Thrombosis, infarction
 Abnormal placental implantation or development
TWIN PLACENTATION
o Monochorionic twins are always monozygotic
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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The time of splitting determines whether one or two amnions are present
 Sharing a chorion every time it’s monochorionic- whether or not there are 2 amnions
 Twin-twin transfusion syndrome possible complication
 There will always be a blood exchange between the 2 fetuses
 Donor twin: pale anemia and smaller than the recipient
 As soon as the 1 dies the other will as well: fatal for both fetuses
o Dichorionic twins may be monozygotic or dizygotic
ABNORMALITIES OF PLACENTAL IMPLANTATION
 PLACENTA PREVIA
o Implantation in lower uterine segment or cervix
o Will cause 3rd trimester bleeding
 A lot of times you don't even know this until you're in the 3rd trimester and then you see the cord and
placenta is covering the internal os
o When covering the internal os, requires cesarean section to prevent placental rupture and maternal hemorrhage
o These babies need a C section
 PLACENTA ACCRETA
o Absent decidua (Interface between the placenta and the uterus) with adherence of placenta to myometrium →
failure of placental separation at birth → postpartum hemorrhage
 In this case it was implanted right in the myometrium so you're going to have a poorly separating placenta
and the mom will get a hemorrhage-- they will not have any symptoms before that. 3rd trimester bleeding.
One of the reasons you do ultrasounds late.
o Associated with placenta previa and previous cesarean sections
 PLACENTAL INFECTIONS
o Ascending infection (coming from vagina, vulva and cervix)
 More common
 Usually bacterial
o Hematogenous (transplacental)
 TORCH
 T – Toxoplasmosis / Toxoplasma gondii
 O – Other infections (see below)
o Syphilis, Tb, Listeria
 R – Rubella
 C – Cytomegalovirus
 H – Herpes simplex virus-2
o Chorioamnionitis
 Inflammation of chorion and the amnion
o Funisitis
 inflammation of the umbilical cord
o Placentitis or villitis
 PREECLAMPSIA
o Systemic syndrome with widespread maternal endothelial dysfunction
 Hypertension, edema and proteinuria
 Less common are Hypercoaguability, ARF (acute renal failure), pulmonary edema
o 3-5% of pregnancies, during 3rd trimester (8.5 months)
o Typically starts at 34 weeks gestation (doc will check your BP and ankle swelling)
 Earlier with hydatidiform mole or preexisting kidney disease, hypertension or coagulopathies
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o ECLAMPSIA
 More severe form with convulsions/seizures, DIC and organ damage
 You just treat by preventing seizures and delivering as soon as possible
 They aren't really sure how it happens. (can happen 48hrs after delivery as well!)
o HELLP SYNDROME
 10% of women with severe preeclampsia
 Preeclampsia PLUS Hemolysis, Elevated Liver enzymes, Low Platelets
o PATHOGENESIS OF PREECLAMPSIA
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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Exact mechanism unknown, but symptoms disappear after delivery of placenta
 Management depends on gestational age and severity of disease
 Inducing delivery depending-- treatment is getting the placenta out
 Diffuse endothelial dysfunction, vasoconstriction and increased vascular permeability
 This comes from Abnormal placental vasculature
 Decidual spiral arteries are not converted to large capacity vessels →poor placental blood flow →
placental ischemia
o Supposed to have nice big BV that allow the placenta to get blood but the placenta gets
ischemic and the endothelium releases vasoconstrictors (leading to HTN) and decreases
angiogenesis earlier than normal
 Endothelial dysfunction
 Placental ischemia → release of vasoconstrictors and factors that decrease angiogenesis earlier
than normal
 Coagulation abnormalities
 Decreased production of anti-thrombotic factors & increased release of coagulation factors →
hypercoaguable state
 Places that get a lot of blood (pituitary, kidney, brain) you'll see thrombi and infarcts in those
areas
UTERINE SPIRAL ARTERIES
o
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Cytotrophoblasts make a column and the BV lose their media and get nice and big and there is a lot of
blood flow that can go through there.
With pre-ecmapsia you don't get the change to the large capacity vessels and the vessels don't open; you
still have the spiral artery w/ nice thick tunica media but the cytotrophoblasts for some reason don't come
and open up the BV’s to  BF-- no large capacity vessels placenta is crying out for blood
PREECLAMPSIA
o Placenta
 Ischemic infarctions
 Hematomas
 Fibrinoid necrosis and lipid deposits in vessels
 Acute atherosis
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Acute atherosis of uterine vessels
o Liver, brain, heart, anterior pituitary
 Hemorrhages
 Fibrin thrombi in vessels
o Kidney
 Fibrin deposition
o THIS IS A CLINICAL DIAGNOSIS.
 20% develop HTN and microalbuminemia and
some kidney function in the next 7-10 years and
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
we don't know why that occurs. So some patients have long term sequelae after having this. Symptoms
are treated at that time.
GESTATIONAL TROPHOBLASTIC DISEASES:
 HYDATIDIFORM MOLE
o Cystic swelling of the chorionic villi with trophoblastic proliferation
 Grossly appears as clusters of grapes (swelling of the chorionic villi and trophoblast proliferation)
o 1/1,000 pregnancies
 Teens or 40-50 yrs
o Earlier diagnosis than in past
 Vaginal bleeding, enlarged uterus before it should
be and high HCG for what it should be
o Associated with increased risk of invasive mole or
choriocarcinoma (esp complete mole)
 10% of moles develop into persistent or invasive
moles
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o COMPLETE MOLE
 Fertilization of egg without chromosomes “empty ovum)
 All genetic material in that mole is from
sperm (dad)—either 1 sperm fertilizing
and empty ovum or you have 2 sperm
fertilizing and empty ovum
 Most or all villi enlarged and edematous
 Lack of vessels
 edematous: nuclei should be closer together and very blue; there are no BV in there
 Diffuse trophoblast hyperplasia
 Syncytiotrophoblasts and cytotrophoblats are all proliferating
 No fetal parts
 Increased risk of invasive mole or choriocarcinoma
 they get a section curettage and if its big enough they can get a hysterectomy and monitor the
HCG
o
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PARTIAL MOLE
 Fertilization of egg with 2 sperm
 Maternal and paternal genetic material
o You do see some fetal genome material; has some mom's (paternal imprinted--so only
maternally expressed) = p57—maternally expressed;
 Some villi enlarged and edematous
 Lower degree of trophoblast hyperplasia/proliferation
 Fetal parts more common
 Rarely followed by choriocarcinoma
 p57 cell cycle inhibitor expressed
 You can do with the brown stain so you know that it's from the egg so you know it has to be a
partial mole. If you do a p57 then there is no genetic material from the egg then you know it's a
complete mole (important to differentiate partial and complete b/c of risk for choriocarcinoma)
INVASIVE MOLE
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REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
o
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UNLIKE CHORIOCARCINOMA:
 villi associated with it and even though it embolises it can't survive there and it just regresses (so doesn't
metastasize)
o Invasion of myometrium by hydropic chorionic villi
 May perforate uterus
 May invade surrounding tissues
 May embolize to lungs and brain
 No growth; eventually regress
o Presents as vaginal bleed and uterine enlargement with persistently elevated HCG
o Treated with chemotherapy
CHORIOCARCINOMA
o THIS IS THE WORST
 The trophoblasts become malignant and become invasive and mets all over the place
(the vagina, lungs, liver, kidneys) and they can get into the bloodstream. NO villi
associated with it!—just the trophoblasts.
 Usually follow with an abnormal pregnancy (usually after a complete mole)
o Malignant tumor of villous trophoblastic cells following normal or abnormal pregnancy
 1/20,000 pregnancies
 50% from moles, 25% from abortions, 22% from normal pregnancies, 3% ectopic
pregnancies
o Irregular vaginal discharge with high HCG
 6 weeks expected to bleed but she's still bleeding 10-12 weeks later check this out!
 hCG positive!
o Rapidly invasive with widespread metastases to lungs, vagina, brain, liver and kidneys
o Proliferation of malignant syncytiotrophoblasts and cytotrophoblasts without chorionic villi
o Treated with chemotherapy
 The ones associated with the placenta have good remission rate and good with chemo
 But if this arises in the ovary or in male with the germ cell tumors the prognosis for those is worse
PLACENTAL-SITE TROPHOBLASTIC TUMOR
o These arise from the trophoblasts NOT associated w/the villi (these are found at the implantation site and the
parenchyma of the placenta on the chorion and in the placental membranes)
 These are the INTERMEDIATE trophoblasts (different than cytotrophoblasts and syncytiotrophoblasts).
These lead to placental-site trophoblastic tumor (PSTT) and not a choriocarcinoma.
 You get a mass into the myometrium
o Malignant transformation of intermediate trophoblasts that normally populate nonvillous
tissues
 Implantation site, placental parenchyma, chorionic plate, placental membranes
o Uterine mass with increased HCG and abnormal bleed or amenorrhea
o Follows normal pregnancy (50%), spontaneous abortion (15%) or molar pregnancy (20%)
o Tumors < 2yr post pregnancy or localized have good prognosis
o Tumors arising > 4yr post pregnancy or advanced stage have poor prognosis
SUMMARY
 Ectopic pregnancy
o Implantation site other than uterus-- usually the fallopian tube
o Hematosalpinx—On transvaginal ultrasound nothing in the endometrium cavity but see bleeding in the fallopian
tubes
 Twin placentas
o Dichorionic diamnionic, monochorionic diamnionic, monochorionic monoamnionic
 Placenta previa
o Painless vaginal bleeding
 Placenta accreta
o Profuse, life-threatening hemorrhage that occurs at the time of attempted manual placental separation
 Placental infections
REPRODUCTIVE PATHOLOGY PART 2 LECTURE OUTLINES—Elisa Furay
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o Ascending, hematogenous, chorioamnionitis
Preeclampsia and eclampsia
o New onset hypertension and proteinuria, grand mal seizures
Hydatidiform mole
o Evacuation is indicated for pathologic confirmation, symptom relief, and to prevent complications
o Partial versus complete
Choriocarcinoma
o Postpartum bleeding beyond 6 to 8 weeks or postpartum hemorrhage
o Malignant tumor of villous trophoblastic cells
o High HCG
Placental-site trophoblastic tumor
o Irregular vaginal bleeding and an enlarged uterus months to years following a term pregnancy
o Malignant tumor of non-villous trophoblastic cells