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Presentation Pathology
bleeding
347191562.doc347191562.doc Proliferative pseudostratified glands w/
glandular
Dysfunctional uterine bleeding is abnormal uterine andsecondary
bleeding stromal breakdown (disordered
to ovulatory
and appear crowded due to stromal necrosis
dysfunction. Thus, specific pathologic processes such as polyps, carcinoma, exogenous
and collapse)
hormones, complications of pregnancy and postmenopausal bleeding are excluded.
Anovulation is the most common cause of dysfunctional bleeding.
Causes:
- Anovulatory Cycles:
o Follicles develop but ovulation does not occur; follicles continue to produce
estrogen (since no ovulation, no LH surge or progesterone)
Estrogen withdrawal (endometrium outgrows structural support)
Estrogen breakthrough (estrogen levels fall)
- Luteal Phase abnormalities (inadequate progesterone so you have an abnormally short
menstrual cycle)
o Luteal phase defect
o Persistent corpus luteum (irregular shedding)
Treatment
Diagnosis made w/ pelvic US and endometrial biopsy. This is a diagnosis of exlusion, thus
normal anatomy and normal endometrial biopsy.
Treat using IV conjugated estrogens, oral contraceptive pills, or MPA (medroxyprogesterone
acetate)
Endometritis
Presentation Pathology
Pelvic pain Acute PMNs
Bleeding Chronic plasma cells
3 types:
1. Acute endometritis seen in the context of spontaneous abortion, delivery or medical
instrumentation ; post-partum.
2. Chronic endometritis due to PID , intrauterine contraceptive devices/actinomyces,
retained products of conception, TB (see chronic inflammatory cells + granulomatous
inflammation)
3. Pyometra secondary to cervical stenosis (puss filling endometrium cavity), from tumor
or scarring from surgical treatment of the cervix.
Reproductive and Genetic Diseases
Endometriosis
Presentation Pathology
Pelvic pain, menorrhagia, dysmenorrhea Multiple chocolate cysts are present Can also
Infertility have unilocular cysts or inconspicuous
involvement
Endometrial glands and stroma in places they
should not be w/ hemosidderin laden
macrophages
Adenomyosis
Presentation Pathology
Abnormal bleeding and pain Gross markedly thickened (but not
nodular wall) w/ multiple tiny
hemorrhagic cysts
Histo -- glands and stroma extend deeply
into the myometirum
Adenomyosis is downgrowth of endometrial basalis into the myometrium
Occurs in 15-20% of uteri
Regresses after menopause
Reproductive and Genetic Diseases
Endometrial Polyp
Presentation Pathology
Abnormal bleeding (due to surface Most arise in the fundus; most are
ulceration or hemorrhagic infarction) solitary,
Histo core of polyp is composed of 1)
endometrial glands, usually cystically
dilated and hyperplasic 2) fibrous
stroma 3) thick-walled, coiled, dilated
bld vessels
Endometrial polyps are benign focal hyperplasia of the basalis. They occur in the
perimenopasual period and are virtually unknown prior to menarche. They are thought
to arsie from endometrial foci that are hypersensitive to estrogen stimulation or
unresponsive to progesterone.
They are not preneoplastic
Endometrial Hyperplasia
Presentation Pathology
Simple few dilated glands w/ non-
complex budding and no evidence of
crowding
Complex pseudostratified proliferative
appearance; more glands than stroma
Atypia cytologic atypia: epithelial cells
have round nuclei w/ nucleoli.
Endometrial hyperplasia refers to a spectrum that ranges from simple glandular crowding
to conspicuous proliferation of atypical glands, which are difficult to distinguish from
early carcinoma.
Usually are due to unopposed estrogen. May result from anovulatory cycles, polycystic
ovary syndrome, an estrogen producing tumor or obesity
Subtypes:
- simple hyperplasia w/out atypia: proportionate increase in glands and stroma
An
- complex hyperplasia w/out atypia: increase in glands greater than stroma
- atypical hyperplasia: simple or complex w/ cytologic atypia
Risk of progression to carcinoma:
- simple hyperplasia 1% over 10-15 years
Akfda
- complex hyperplasia - 3% over 10-15 years
- atypical hyperplasia 25-35% over 4-5 years
Reproductive and Genetic Diseases
Endometrial Adenocarcinoma
Presentation Pathology
In peri or postmenopausal women Gross ragged and thickened
Abnormal bleeding, (90%) endometrial lining.
Endometroid crowded, back to back
glands w/ cytological atypia. epithelium
have a proliferative appearance
Serous papillary w/ high grade
cytologic features. Nuclear
pleomorphism
Endometrial adenocarcinoma is the most common invasive cancer of the female genital
tract. 4th most common cancer in women. It accounts for 6% of all cancers in women.
Most paitents present at an early stage b/c of the warning sign of bleeding.
Histologic types:
- endometroid (most common, 80%)
- serous
o serous intraepithelial carcinoma is the in situ phase of serous carcinoma
which is rarely found prior to the development of invasive disease
o lymph invasion w/ serous carcinoma
- clear cell
Type 1 Type 2
Unopposed estrogen Present absent
Patient Younger and heavier Older and thinner
Menopausal status Pre and peri Post
Hyperplasia Present Absent (atrophy)
grade low high
Myometrial invasion Minimal (less Deep (more aggressive)
aggressive)
subtypes endometroid Serous and clear cell
Behavior Stable progresisve
genes MSI, ras, PTEN P53
Risk Factors:
- increasing age
- exogenous estrogen (unopposed estrogen increases risk 10 fold)
- menstrual factors (late menopause and early menarche)
- nulliparity (2x the risk; infertility, anovulation, high serum levels of androstenedione,
lack of monthly menses)
- polycystic ovary disease
- estrogen producing tumors
- endometrial hyperplasia
- tamoxifen
- obesity (results from adipose cells aromatase-mediated conversion of androstenedione
to estrone)
- diabetes
- genetic (DNA mismatch repair genes HNPCC)
Protective factors: OCPs smoking, multiparity, ovulation and progestin therapy
Reproductive and Genetic Diseases
Prognositc Factors
- stage (extent of disease) depth of myometrial invasion, +/- peritoneal washings,
nodal status, distant metastasis
- grade differentiaion
- histologic subtype endometroid (favorable), serous and clear cell (unfavorable)
- steroid receptors: tumor + for estrogen and progesterone receptors has a better
prognosis
Recurrence of endometrial cancer usually happens in the first 3 years. Most will be
symptomatic w/ abnormal bleeding. It is very rare to cure distant recurrences. 50% vaginal
recurrences cured .
The 5 year survival is good b/c most present at an early stage. However, if present at a late
stage then prognosis is not good.
Treatment Other
- Surgery Diagnosis is made via
o Total abdominal - endometrial biopsy
hysterectomy - D&C
o Bilateral salpingo- - Transvaginal US
oophorectomy
o Cytology (peritoneal Who needs a biopsy?
washings) - postmenopausal bleeding
o Lymph node dissection - postmenopausal pyometria (purulent
- radiation therapy (for stage I and II discharge from cervix b/c PID is
has no impact on distant mets!!) unlikely)
- chemotherapy - postmenopausal women w/
- hormonal therapy endometrial cells on pap
Likes to spread to pelvic and then peri- - perimenopasual intermenstrual
aortic lymph nodes bleeding
Surgical staging: - premenopausal abnormal bleeding
- stage I: uterus w/ history of anovulation
- stage II: cervix - thickened endometrial stripe
- stage III: abdomen (tubes, ovaries,
nodes) or vagina
Leiomyoma or fibroid
Presentation Pathology
Most occur in women older than 30, rare Gross well circumscribed white tan firm
before 20, and most regress after menopause mass w/ whorled appearance w/out capsule
Bleeding, pain (esp if undergo torsion) Histo bland smooth muscle
Can cause infertility
Leiomyoma is a benign tumor of smooth muscle in the uterus. It is the most common
neoplasm of the uterus affecting 25% of women of reproductive age.
it is hormonally responsive/dependent (estrogen promotes their growth) . Often multiple
Malignant transformation is rare or absent
They can be intramural (embedded in the myometrium), submucosal (close to the
endometrium), subserosal (beneath the serosa covering) or pedunculated.
Treatment they may require surgicical removal for bleeding or infertility
o Sarcoma
- Other
o Exogenous hormones
o Clotting disroders
Pelvic Inflammatory Disease (PID) is an ascending infection beginning in the vulva, vagina or
cervix that spreads upward to involve all structures of the female genital tract and potentially
other pelvic organs to varying degrees
Causes of PID:
- polymicorbial: most infections
- N gonorrhea: most common single agent, upward migration from mucinous glands to
eventually involve the tubo-ovarian region
- Other bacteria: E. coli, Staph, Strep, Clostridium: spread via lympahtics or vascular
channels following surgical procedures
- Chlamydia
- Mycoplasma
- Actinomyces (associated w/ IUDs)
Complications:
- infertility from tubal scarring
- ectopic pregnancy
- tubo-ovarian abscess
- peritonitis
- intestinal obstruction from adhesions
- bacteremia
Tubo-ovarian complex
Ectopic Pregnancy
Presentation Pathology
Pelvic pain w/ or w/out menstrual Resembles placenta increta or placenta
irregularity percreta of the uterus
Ectopic Pregnancy refers to implanation outside the endometrium. Over 95% occur in the
fallopian tube.
Pre-disposing factors: anything that alters the normal structure and function of the fallopian
tube: PID, prior pelvic surgery, endometriosis
Complications are rupture and hemorrhage
Treatment:
Surgery or chemotherapeutic intervention
Use of methotrexate terminates ectopic pregnancy and is used when the conceptus is
smaller than 4 cm.
Cystic lesions of the ovary are the most common cause of enlarged ovaries. Most airse from
ovarian follicles.
Follicle cysts are thin-walled, fluid filled structures that are lined internally by granulose cells
and externally by a layer of theca interna cells. lined by cuboidal epithelium w/out atypia
If the cyst persists, the hormonal output can cause precocious puberty in a child and menstrual
irregularities in an adult
Rupture of the cyst can lead to intraperitoneal bleeding
Surface epithelial inclusion cysts: small cysts formed from involution of surface epithelium
Functional cysts: follicular and corpus luteal cysts
Reproductive and Genetic Diseases
Diagnostic criteria:
- chronic anovulation, hyperandrogenism (acne, hirsutism, hyperandrogenemia),
Ultrasound (string of pearls) , and must exclude other related disorders such as non-
classical congenital adrenal hyperplasia.
Evaluation:
- testosterone (to exclude androgen producing neoplasm): if it is 200 ng/dl (androgen
producing neoplasm), then do a transvaginal US or adrenal CT/MRI
- 17 hydroxyprogesterone (to exclude nonclassical CAH): if it is 2 ng/ml then do an
ACTH stimulation test
- 24 hour urinary free cortisol (to exclude Cushings) : if signs and symptoms raise
significant suspicion.
Reproductive and Genetic Diseases
Treatment: wedge resection (remove the cysts and the theca cells) will restore normal menses
Ovary Neoplasms: 3 categories:
and fertility
Presentation Pathology
Most are asymptomatic in early stages
Urinary frequency or constipation as tumor
compresses pelvic structures, vaginal bleeding
Distention, bloating, pressure, pain, early satiety
as tumor/fluid fills abdomen
b/c ovarian cancer symptoms are common to so
many benign disease processes, by the time
ovarian cancer is diagnosed it it is usually at
an advanced stage!!!
Ovarian Cancer is 6% of all cancer mortalities in women leading cause of death from GYN
malignancy. It is a silent killer tends to present at high stage, thus is cause of of deaths
related to tumor of the female genital tract. 80% of ovarian tumors are benign
Risk Factors:
- Old age
- Nulliparity
- Family hx of ovarian or breast cancer
- Infertility
- Family history
- ovulation/ovulatory drugs and talc do not cause ovarian cancer
Protective Factors:
- Breast feeding
- Oral contraceptives (50% reduction in ovarian cancer in women to take the pill for 6+
years)
- Pregnancy
- Tubal ligation
Prognostic factors:
- Stage-extent of disease at presentation (most important)
o Carcinomas have tendency to implant in the peritoneal cavity and omentum
and spread by lymphatic dissemination to lymph nodes
- Histologic type of tumor
o Serous and clear cell are poor pronogis types
- Grade of tumordegree of differentiation
- Amount of residual tumor following surgical debulking
Molecular Origins of ovarian carcinoma
- Sporadic
o Activation of oncogenes: c-myc, K-ras, HER2/neu
o Inactivation of tumor suppressor genes: p53, p16
o Aneuploidy
- Hereditary
o 5-10% of ovarian cancers develop in women w/ a familial susceptibility to
ovarian and/or breast cancer
o Germline mutations in DNA repair genes
o BRCA 1 (chromosome 17) and BRCA (chromosome 13)
Reproductive and Genetic Diseases
Serous/endometrois --------Ca125
Mucinous --------------------CEA
Yolk sac tumor --------------AFP
Choriocarcinoma -------------hCG
Tumor markers ::
- CA125 is an antigenic determinant on a glycoprotein shed into the bloodstream by
malignant cells derived from coelomic epithelium. Serum levels of CA125 are
increased in about 80% of patients with epithelial ovarian cancers, more frequently in
patients with non-mucinous histologic types. Levels of CA125 are also increased in
patients with endometrial and pancreatic cancer.
- CA125 may be increased in patients with benign conditions, including endometriosis
and uterine leiomyoma; in patients with pelvic inflammatory disease (PID), in early
pregnancy, and with benign ovarian cysts; and in patients with cirrhosis and
pericarditis.
CA125 is most useful in monitoring response to therapy and detecting recurrent disease
Treatment Other
First line treatment: Debulking
surgery/staging chemo (platinum + taxol) Diagnosis:
every 3 wks for 6 cycles) second look - Pelvic exam
- Pelvic US
surgery
- CA-125 but there is really no good
Debulking surgery goal: optimal debulking
screening tests
of patient at primary surgery
o You can get False positive
- Optimal debulking: no residual tumor
in:
remaining 2 cm following surgery
Endometriosis
- Sub-optimal debulkin: residual tumor
Fibroids
remaining 2 cm following surgery
PID
Surgery options:
- Total abdominal hysterectomy Hepatitis
- Bilateral salpingo-oophorectomy CHF
- Peritoneal samping and washings Cirrhosis
- Omentectomy and nodal dissection
- Removal of all visible tumor
Second line treatment: ovarian cancer
recurrence other chemo? Hormonal tx?
Internal debulking surgery? Radiation?
Staging
- Stage I: ovaries
- Stage II: pelvic extension
- Stage III: abdominal implants or
lymph node spread
- Stage IV: distant mets
-
Reproductive and Genetic Diseases
sertoli/granulosa cells
Amenorrhea
If you have normal genitalia- then do a basic endocrine evaluation w/ TSH, FSH, and
prolactin
- TSH evaluation:
o High TSH with low Free T4 = hypothyroid, or normal free T4 = subclinical
hypothyroidism ---- both have thyroid auto-antibodies
o Low TSH and with high free T4 or normal T4 with high free T3 = hyperthyroid.
o If have low TSH and low free T4 get an MRI
o Normal TSH levels are euthyroid
- Prolactin evaluation
o High prolactin do hypothalamic-pit imaging. If it is normal then you have a
hypothalamic dysfunction. If it is abnormal then you either have
hypothalamic/pit tumor or empty sella syndrome
o Hyperprolactinemia
There is a strong association of high prolactin levels w/ menstrual
disorders b/c the high prolactin levels disrupt the pulsatile hypothalamic
GnRH release. Oligo/amenorrhea is the most common (common cause
of secondary amenorrhea or short luteal phase polymenorrhea)
Galactorrhea is only found in 1/3 w/ hyperprolactinemia b/c breast milk
production has numerous requirements, like estrogen.
Differential:
Prolactin secreting pituitary adenomas
Other pituitary/hypothalamic tumors
Drugs phenothiazines, reserpine, benzos, butyrophenones,
amphetamines, opiates, TCAs, metaclopramide
Hypothyroidism (high FSH levels stimulate prolactin secretion)
Exogenous estrogens (OCP)
Lung/renal tumors, renal failure
- FSH evaluation:
o High FSH ovarian failure
Premature ovarian failure most common
Due to early follicular depletion, genetic predisposition (sex
chromosome abnl or point mutation in FSH receptor gene),
radiation/chemo, autoimmune dz
Do a karyotype on 30 yrs or younger. If the karyotype is normal
then they have premature menopause and do an autoimmune
screen. If the karyotype is abnormal gonadal dysgenesis
o Karyotype excludes Y chromosome- risk for germ cell
tumors (30% w/ Y chrom will not virilize
o Exceptions to doing a karyotype is if you are over 30
(b/c tumors are virtually unknown so consider it
premature menopause) and if you have a hx of pelvic
radiation or chemo
Do autoimmune screen if karyotype is nl: Ca, P, TSH, free T4,
ANA, CBC, fasting glucose, 24 hr urinary free cortisol
Gonadal dysgenesis 1o amenorrhea
Single gonadotropin deficiency rare
Resistant ovary syndrome rare
Galactosemia rare
Reproductive and Genetic Diseases
Presentation Pathology
Oligomenorrhea: 35 days interval 6 mo Uterine abnl gross: enlarged (myomas),
Polymenorrhea: regular intervals 21 days irregular (myomas), soft (pregnancy or
Menorrhagia: regular intervals 7 days or adneomysosi) or tenderness (endometritisis)
80ml
Metrorraghia: irregular intervals 7 days or
80 ml in volume
Treatment:
- use cyclic progestin for anovulation, when no contraception is needed and when there
is no suspicion for anatomical abnormality
- use OCP for oligo-ovulation when contraception is needed
- for acute episodes of dysfunctional uterine bleeding do OCP taper
- for hypoestrogenism causing anovulation where there is a thin, inactive endoemtirum
do not give progestin. Make sure you give estrogen.
- If the biopsy yields minimal tissue or an attenuated endometrium (stripe 4 mm) then
give estrogen first and then progestin
- For breakthrough bleeding give OCP or supplemental estrogen. Or progestin
Menorrhagia
Differential diagnosis:
- uterine myomas
- endometrial polyps
- bleeding disorders
Treatment
- medical: evaluation reveals no cavitary lesion
o NSAIDS (reduces flow by 20%)
o OCP reduces volume/duration by inducing a decifualized, inactive
endometrium)
o Depot MPA 80% amenorrehiec by 1 year
o LNG-IUS (merina) reduces volume/duration in 75-90%
- surgical: cavitary lesions (submucous myoma, polyp) or failed medical
management
Evaluation:
- Uterine imaging via US or hysteroscopy
- Endometrial biopsy if older than 40
- Coagulopathy screen for adolescents, suspicious personal/family hx, or unexplained
menorrhagia
Reproductive and Genetic Diseases
Benign Breast diseases are a heterogenous group of lesions that may represent a palpable
mass, nonpalpable abnormality on imaging, or an incidental microscopic finding
two goals in the pathologic evaluation of a benign breast biopsy:
1. distinguish benign from insitu and invasive tumors
2. assess the risk of subsequent breast cancer associated with the lesion identified.
Components in the workup of a breast problem are the
- Hx of chief complaint onset, duration, changes over time, associated symptoms
such as pain, skin change, nipple inversion, discharge, fevers, trauma
- reproductive factors menarche, LMP, pregnancies/age of first live birth, OCP vs
HRT use
- associated factors family hx (1st degree relatives mom, sister, daughter), radiation
exposure (such as for tx of Hodgkins dz), prior breast biopsy, weight change, diet
(caffeine and high saturated fat, salty foods), past medical history for diabetes,
immunocompromised (lupus, fibromyalgia, HIV).
- imaging studies
- clinical breast exam.
Classification of benign dz is necessary to stratify for risk of future cancer:
1. Nonproliferative lesions no increased risk (unless family hx)
a. Cysts
b. Papillary apocrine change
c. Epithelial calcifications seen on radiograph
d. Mild hyperplasia usual type
2. Proliferative lesions w/out atypia risk is 1.5-2x
a. Moderate/florid hyperplasias
b. Intraductal papillomas (nipple discharge)
c. Sclerosing adenosis
d. Radial scar (radiographic finding)
e. Fibroadenomas
3. atypical hyperplasias risk is 3.3-5x. if have both then 6.8x defined as proliferative
lesions that possess some, but not all features of carcinoma insitu
a. Atypical ductal hyperplasia
b. Atypical lobular hyperplasia
Factors modifying breast cancer risk w/ women w/ benign dz:
- family history (first degree relatives)
- time since biopsy (if biopsy is benign and has been over 15 years than normal risk,
but if biopsy revealed ADH or ALH then its increased for many years)
- menopausal status
- laterality of risk
- consistency of histolofic classification (pathologists classify things differently by
looking at them)
Reproductive and Genetic Diseases
Treatment:
Medications bromocriptine, danzal, alleve
Supplements Vit E and B6
Solid Masses
False negative rate for mammography is 10-20% (mammography cannot catch everything)
Dominant noncystic masses under 40 is common. The incidence of breast cancer under 30 is
2.5% so it can happen if you feel something clinically and the mammogram and US are clear
DONT STOP- continue to monitor the patient b/c they can still have caner.
Imaging Studies for solid masses:
- Mammography
- Ultrasound used as an adjunct
- MRI of breast used in evaluating abnormal breast. Not helpful in benign cystic
changes.
Diagnostic Studies:
- core biopsy to determine histology not perfect b/c there is sampling error. Make sure
your results from the mammogram correlate w/ the results from the biopsy. If it does not
then do a surgical biopsy.
- followup management based on pathology
Fibroadenomas
Presentation: Pathology:
Mobile (not adherent to skin) , round, Gross: small, freely movable, round and
nonpainful encapsulated w/ grey-white cut surface
Shows menstrual variation Histo: glandular epithelial-lined spaces w/ a
Increased growth during pregnancy fibroblastic stroma. Network of ducts w/in a
proliferated, edematous stroma
Fibroadenomas are the most common benign solid masses. are pseudo-encapsulated
demarked, ovoid. They are mobile and multilobulated. They are present in women of
reproductive age, usually before 30 and may be related to increased estrogen sensitivity.
There are different kinds, such as:
- complex
- juvenile
- giant/phyllodes rapid growth can be malignant
If you leave fibroadenomas alone, they can infarct and become calcified
Imagining is based on age. You can do a core biopsy
Treatment
Surgical excision
Only remove if they are growing or over
3cm
Adenoma
Presentation
Nipple adenomas can present w/ bloody
discharge
Acute masitits
Fissures in nipples during early pregnancy or from skin disorders may predispose to bacterial
infection of the breast usually by Staph aureus or Strep. It is usually unilateral, with pus in the
ducts. Necrosis may also occur. Antibiotics and surgical drainage may be adequate therapy, but
necrosis and subsequent fibrosis of a localized area of breast tissue may occur.
Granulomatous Mastitis
Presentation: Pathology:
Firm, tender nodules Capsule formation, varying fibrosis and
inflammatory changes
Treatment:
Surgical excision
Reproductive and Genetic Diseases
Nipple Disorders
- Nipple inversion/retraction congenital vs acquired (duct ectasia, mastitis, CA, TB)
- Pagets disease vs spongiotic dermatitis: both present with scaly irritated nipple areolar.
Thus start off with a steroid cream and if no response after 1 week it is pagets dz and
do a skin punch biopsy
Nipple discharge:
- 95% benign etiology: hormonal papilloma
- Worrisome if unilateral, single duct, spontaneous or bloody
- Age of patient is an important distinguishing variable a predictor for malignancy. As
your age increases, higher likelihood it is malignant
- Management: do a QUIAC (to check for blood) NOT a cytology. Also, surgical duct
excision or meds/supplements
Infections:
- cellulitis w/ or w/out abscess formation
o at risk: overweight, large breasted, previous surgery, radiation, sebaceous cysts
o staph aureus is the most common
- Hyradenitis
o Involves distribution of sweat glands in axillae, inrammaotry folds, groins
o At risk: more common in smokers and AA women
o Symptoms: extensive, painful boils
o Management: chronic antibiotics, surgical excision, aggressive local hygiene
Nonlactional Infections:
- periareolar: younger women, smokers: 50% recurrence rate
- mammary duct fistula: most common after I&D, can be spontaneous
- peripheral nonlactional abscess: less common, associated w/ diabetes, RA, steroid RX,
trauma
- tuberculosis: rare in western cultures, presents as acute abscess w/ sinus tract from axilla.
Lactational infections:
- most common during first 6 months during breastfeeing
- symptoms: pain, swelling, tenderness, cracked nipple/abrasion, fever, chills
- manage w/ antiobiotics (dicloxillin, flucloaxillin, augmentin, erythromycin, clindamycine).
o Tetracycline, cipro, and chloremphenicol should NOT be used
- Continue breast feeding unless Post I&D w/ general anesthesia
Breast Cancer
Presentation:
Most present w/ local, early stage dz that is curable.
6% present w/ metastatic dz (and is more common in AA women than Caucasian) and
symptoms bone , lung, and chest wall/skin. HER2 + in brain
Breast carcinoma is the most common malignancy of women in the US. It is the second most
common cause of cancer mortality in women (after lung cancer). 1 in 8 will get breast cancer
and 1/3 of women w/ breast cancer will die. Regular risk is 8-10% (not if have history)
Risk factors for the development of breast cancer:
- Genetic
o Family hx of breast cancer esp in 1st degree relatives (mom, daughter, sister).
Risk is greatest if the relative has bilateral dz or is affected at a young age.
o BRCA1 gene on 17q21 (breast/ovarian)
85% lifetime risk of breast cancer
By age 50, breast cancer has developed in and may be responsible for
up to of inherited breast cancers (10% of all cancers)
Increased risk of ovarian and colon cancers
o BRCA2 gene on 13q (breast women and men)
Responsible for up to 70% of inherited breast cancer not due to BRCA1
30-40% lifetime risk
o High penetration: BRCA1 and 2, p53, ATM, PTEN, NBS1, LKB1
o Low penetration: polymorphism
- Hormonal proliferation and/or differentiation of cycling breast epithelium
o Early menarche and late menopause (more time for estrogen)
o Nulliparity
o Late age at 1st term pregnancy
o OCP use and HRT
o High Mammographic breast density
o Lack of breast feeding
o Longer interval b/w births, longer interval b/w menarche and first birth
- Environmental
o Industrialized countries (USA and western countries) - (alcohol, high fat diet,
xenoestrogens, phytoestrogens, physical inactivity, decreased parity, parity at
later age, obesity post menopause, folate deficiency, night work, flavenoids,
deodarnt use, fertility drugs, smoking, pesticide exposure, PBBs, dairy
products?)
- Radiation
o Environmental radiation exposure or radiation exposure for Hodgkins dz in
young women ionizing radiation exposure in childhood
o Increased risk when exposure is at a young young but little increase in risk when
age is 40 indicates that the risk is greatest to the developing and hormonally
cycling breast
- proliferative fibrocystic change
o non-proliferative fibrocystic change NO increased risk
o proliferative fibrocystic change 1.5-2X increased risk
o proliferative fibrocystic change w/ atypia (ADH or ALH) 4-6X increased risk
o carcinoma in situ (ductal or lobular) 8-10X increased risk
- history of previous breast cancer
Reproductive and Genetic Diseases
Protective factors:
- oophorectomy age 35
- early age at first pregnancy, more children, breast feeding for extended time
- pre-menopausal obesity (obesity pre-menopause is protective but post-menopause is
harmful)
Epidemiology:
- The most commonly occurring cancer among women and the second as a cause of cancer
death in women
- over the last 2 decades, the annual incidence has been increasing in the US and
worldwide
- mortality rates have fallen world-wide, faster in developed countries (w/ greatest
decrease in women under 50)
- incidence rates are higher in developed countries and are higher in urban areas and higher
in NE
- for women over 40 it is higher in whites, but in women under 40 it is higher in blacks
- risk increases as you get older
- migrant studies have shown that first and second generation US Chinese women have
higher rates of incidence than Chinese women in china
Why these trends?
- Incidence trends - inherent genetic differences, differences in data completeness, lifestyle
factors, access to healthcare, screening and diagnosic services, access to better tx
- Mortality trends age distribution differences in populations, stage at diagnosis and
treatment
Prevention via exercise, diet, reproductive choices
Screening for Breast Cancer mammography has reduced breast cancer mortality as well as
allowed earlier more successful treatment
Does screening fit criteria for population screening?
- breast cancer is prevalent in the populaton
- it has an early detection phase
- it is acceptable (though not inexpensive)
- treatment is available for early detected cancers
- screening reduces mortality a 30% reduction in mortality for women 50-69 regularly
screened and a 10-20% reduction for women 40-49.
Start screening annually for women starting at age 40 yearly mammography + yearly
clinical breast exam. It does not detect all breast cancers but does reduce mortality. Lesions
detected early are more likely to be cured! It is more difficult in patients w/ denser breasts and
younger patients
MRI is used in high risk patients
Ultrasound is not a standard screening tool, but is useful to evaluate lumps and abnl on
mammogram.
- performance of mammorgraphy is equal in black and white women but the cancer
characteristics are different
o black women had higher grade, larger, more advanced tumors
o black women have a higher proportion of tumors that are ER and PR -
Reproductive and Genetic Diseases
Treatment
- determine the sentinel lymph node via radioactive technetium-labeled sulfur colloid and
isosulfan blue then submit it to path and immunohistocehmistry for cytokeratin. If the
SLN is negative, no further surgery required. If the SLN is positive then completion of
the axillary node dissection is performed: (complete removal of the axillary LN is not
longer the tx)
- Axillary lymph node dissection - causes arm edema, increased risk of infection, nerve
injury, winged scapula, rare is the development of angiosarcoma in the setting of long-
term lymphedema (high grade sarcoma w/ rapid spread and dismal prognosis)
- Metastatic work-up = CT scan of chest, ab, and pelvis + bone scan (not necessary if small
tumor and few/no + LN
- Brain CT or MRI only in symptomatic patients
- Most patients you do a conservative therapy of lumpetctomy + radiation =
mastectomy!
o Contraindications for breast conserving therapy: large tumor, multiple widely
separated tumors, skin involvement
o Radiation daily therapy of external beam x 5-r wks
SE- fatigue, skin changes/burns, potential damage to heart, lungs, bone
- Systemic therapy for early breast cancer
o Estimate risk of recurrence based on known prognostic factors: LN status***,
tumor size, lympathic vascular invasion, histologic grade hormone receptor
status, HER-2/neu status, patient age.
o Oncotype Dx evalutes the expression level of 17 genes in the tumor and
generates a recurrence score that predicts prognosis better than above and it can
help estimate the risk and decision for future therapy
Adjuvant treatment treatment to prevent relapse
- Hormonal ( 75% of breast cancers are hormone receptor +) only effective for cancers
that are either ER + or PR + or both; strongly + ER and PR benefit the most
o Tamoxifen (if ER+) reduces by 50%
Pre-menopausal women
Selective estrogen receptor modulator that blocks the effects of estrogen
at tumor estrogen receptors.
Acts like estrogen in bones (builds bones) and in uterus endometrium
(increase risk of uterine cancer), and lipids.
SE: hot flashes, nausea, fatigue, vaginal discharge, cataractsserious are
thromboembolism, stroke, uterine cancer
- Chemo
o Polycehmoterhapy reduces the risk of recurrence in early breast cancer by 30-
50%
o Combined tamoxifen + chemo is better than either alone!
o Benefit in ER/PR+ may be due to the indirect endocrine effect b/c chemo causes
ovarian suppression and induction of menopause
o In hormone receptor negative patients, chemo is the only means to reduce the
risk of recurrence!
Reproductive and Genetic Diseases
Metastatic Dz
- presents w/ symptoms and is incurable w/ a median survival of 2 years
- poor prognostic factors: age 50, ER - , HER2 +, presence of visceral dz, short dz free
interval from initial diagnosis and tx
- skeletal dz as 1st site of mets is more likely in ER+ and has better prognosis than
presentation w/ visceral dz.
- Tx:
o Goals are to improve survival and maintain QOL b/c incurable; use local therpay
only for pallation
o HR + - treat w/ hormone therapy first. Following progression ,then treat w/ other
hormonal therpay or chemo.
o HR and organ failure due to visceral dz treat w/ chemo first.
o HER2 + - treat w/ herceptin containing regimen
o Combo therapy yields higher response rates but no difference in survival.
o Use one drug at a time unless impending organ failure
o Bevacizumab (avastin) humanized monoclonal antibody against vascular
endothelial growth factor (VEGF)
o Bisphosphonates inhibit osteoclast acitivty leading to improved bone mass
and mineralization b/c many get bone mets that cause pain and fractures.
- CNS mets tx is palliative
o surgery or radiosurgery for few brain mets and whole brain radiation for multiple
brain mets. Efficacy is limited.
o Corticosteroids give short term palliation by decreasing vasogenic edema
o Leptomeningeal dz presents as HA, CN defects, - can respond to intrathecal
chemo
Ductal carcinoma in situ means that it is confined to the ductal tree (not invasive).
Thus, it does not show invasion through the myoepithelial layer and basement
membrane lining the ducts and lobules.
DCIS is the precursor lesion to invasive carcinoma! DICS usually originates in the
terminal duct lobular unit .
The likelihood of developing recurrent DCIS or an invasive carcinoma varies with the
- histologic subtype/grade of DCIS
- extent of disease (size)
- distance of tumor to the margins of excision
The most common method of detection is by suspicious calcifications on
mammography that are biopsied by stereotactic core biopsy or needle-localized
excisional biopsy.
There are two types of DCIS comedo (higher grade and more aggressive) and non-
comedo (many different patterns)
Presentation Pathology
Firm, palpable mass Gross: firm, pale gray/white, gritty, often stellate
Skin dimpling (from traction on Coopers Histo: infiltrating ducts w/in breast stroma.
ligament) or nipple retraction Variable degrees of differentiation (1-3) based on
Mammogram: stellate lesion +/- degree of tubule formation, nuclear grade, and
calcifications mitotic rate
Desmoplastic stromal response (reactive fibrosis)
Microcalcifications
Infiltrating ductal carcinoma (NOS) is the most common form of breast cancer. The
precursor lesion to it is DCIS. It is characterized by invasive malignant glands infiltrating
the breast stroma.
A mammogram shows a stellate (speculated) density w/ or w/out calcifications
Reproductive and Genetic Diseases
Infiltrating Lobular Carcinoma is the second most common form of invasive breast
cancer. Because it does not create a reactive desmoplastic response in the tissue, it may
be clinically and mammographically occult. It also tends to be larger than clinically
estimated preoperatively.
It has an increased propensity to be multicenteric (involve more than one part of the
breast) and to be bilateral (affect both breasts). It also has the propensity to metastasize
to unusual sites, such as the gynecologic and GI tract.
It has the same prognosis (comparable survival) as infiltrating ductal carcinoma, when
matched, stage for stage!
It is usually ER+/PR+ , CerbB-2/HER2
It usually has single cells invading the stroma, thus it is hard to see on low power. You
can do a positive cytokertain stain to confirm the epithelial nature of the lobular
carcinoma.
Treatment
Inflammatory Carcinoma
Presentation Pathology:
Erythema and induration of the skin Inflammatory changes = Peau dorange: dimpling
of involved skin due to retraction caused by
lymphatic movt and obstruction
Histo dermal lymphatic spaces have tumor cells
Inflammatory Carcinoma is an invasive carcinoma involving superficial dermal lymphatic
spaces and is associated with characteristic skin changes. It has a very poor prognosis!
If you are unsure if you are dealing with inflammatory carcinoma or cellulites, then do a
punch biopsy and if you see tumor cells invading the lympathic spaces then you have
inflammatory carcinoma
Treatment:
Aggressive tx is necessary
No breast conservation
Pagets Disease
Presentation Pathology
Skin erythema, scaling, ulceration Malignant cells in small nests or singly w/
abundant pale cytoplasm and atypical
nuclei infiltrating the skin epidermis
Pagets disease is epidermal involvement of the nipple or areola by malignant cells, singly
or in small nests. It is almost always (95%) associated with an underlying in situ or
invasive carcinoma.
Treatment
Reproductive and Genetic Diseases
Phyllodes tumor is a biphasic (epithelial and stroma) tumor with risk for local
recurrence or metastasis.
The classification of grade (low vs high) reflects the probability of local recurrence and
metastasis:
- low grade: low ( 5%) risk of metastasis, but likely ( 25%) to locally recur if
not adequately excised
- high grade: high (25%) risk of metastasis, and high (25%) incidence of local
recurrence (behaves like a sarcoma)
Local recurrence is not required prior to metastaisis.
It mestatasis to the lungs, bone, heart (via vascular invasion-hematogenous spread)
Treatment
Complete exisicion to prevent local
recurrence
Intraductal Papilloma
Intraductal papilloma is a solitary lesion w/in a duct or cyust and is most common in
women 20-50 years of age. It may present w/ nipple discharge (serous or bloody), nipple
retraction, or a small subareolar mass.
Gross small lesion usually close to the nipple in major ducts. Sessile or peduncualted
Histo multiple papillae
A single intraductal papilloma are benign but multiple papillomas are associated w/ an
increased risk of cancer.
Reproductive and Genetic Diseases
Cervical Cancer
Presentation Pathology
Firm and bulky Gross: punctuation and mosaicism - vascular changes
Postcoital Histo: squamous (85-90%), adenocarcinoma, adenoaquamous (glassy
bleeding, cell)
intermitten Normal maturation: cell size increases and the cytoplasm volume and
spotting, watery density increases, the nucleus decreases and the chromatin goes from
vaginal discharge finely granular dark and pyknotic. The N/C ratio decreases
Intermitten Abnl: Koilocytes (Condyloma) HPV, clear cytplasic, well defined
painless vaginal vacuole w/ enlarged irregular and dark nucleus, binucleation is common
bleeding Squamous cell carcinoma in situ pap: 3D aggregates w/ high N/C
Invasive pap: keratinizing or non-keratinizing (irregular chromatin
clumping, prominent nucleoli, background is necrotic
Normal anatomy is that the ectocervix is lined with squamous epithelium and the endocervix
is lined with columar epithelium. Squamous metaplaisia occurs at adolescence and
pregancny. The transformation zone is the squamnocolumnar junction and is the site of
cervical dysplasia and carcinoma!! Thus, impt to sample this region while doing a pap and
visualize this zone during colposcopy.
Cervical cancer is caused by Human Papilloma Virus.
There are many types of HPV: (HPV is a small circular DNA virus 200 types identified bu
30 infect the anogential tract.
- low risk types: 6, 11, 42,43,44 ---- condylomatas
- high risk types: 16.18, 31, 33, 35, 39, 45, 51, 52, 56, 58 ---- HSIL, cancer.
o 16 = squamous cell 18 = endocervical glandular neoplasia adenocarcinoma
o HPV is best studied at molecular level b/c most infections are not microscopically
evident
HPV testing
- DIGENE HCII assay uses 2 RNA probes to differentiate b/w low and high risk HPV.
Can test this on the liquid based pap smear
HPV may produce a 1) transient/self limited infection or a 2) persistently expressed infection.
The vast majority of HPV infections spontaneously regress (intact immune system. Less than
of HPV infections persist for 24 months or more. A major factor in progression to cancer is
persistence of the HPV infection.
Most carcinomas are of squamous cell carcinoma (75-90%) and then adenocarcinoma (10-
20% and increasing) . precursor lesion to adenocarcinoma is adenocarcinoma in situ
Risk Factors for Cervical Cancer:
- prior affected partner gives new partner 2-3 X risk
- early initiation of intercourse
- multiple partners
- smoking (3-5X)
- high parity
- infection w/ high risk HPB subtypes (HPV 16, 18, 45, 31, 33)
- immunocompromised HIV, organ transplants, Hodgkins (b/c cannot clear the virus)
Reproductive and Genetic Diseases
Pap Smear Screening: - most effective prevention of cervical squamous carcinoma and detects
precursor lesions of SCC
- reasonably sensitivity and specificity, disease (CIN) has long latent periods, it is a
common disease, low morbidity of test, treatment and cure available, inexpensive, and
easy to perform .
- different guidelines: some say iniate at sexual activity or 18 years of age OR 3 years after
onset of vaginal intercourse but no later than 21 yrs
- you must sample entire transformation zone: use a spatula for the ectocervix and a brush
for the endocervix. In pregnant pts, use a broom.
- Includes palpation of the cervix.
- 90% effective in detecting precursor lesions
o Sampling and diagnostic errors failure to sample abnl cells, too few abnl cells
not diagnosed, failure to properly catecorgize cells,
False negative diagnostic errors too few abnl cells, smears w/ obscuring
o inflammation/blood limiting evaluation
o 3% real error rate in missing cervical SCC (60-90% due to inadequate screening
of population at risk the patient is not getting regular pap screening)
o If a lesions is suspicious clinically, it must be evaluated further irrespective of
negative pap smear results .
Treatment Other
Stage I simple hysterectomy Colposcopy:
Stage II radical hysterectomy - binocular microsopce of low mag (10X to
stage III/IV radiation/chemo 40X) w/ focal length 12-15cm
- clean cervix w/ 4% acetic acid
- Microinvasive stage Ia1 cervical - native squamous epithelium is gray
conization, simple hysterectomy - columnar epithelium is red, grapelike
- Advanced cancer: stage IIb-IV external - nl bld vessels branch like a tree
raidaiont and internal radiation and - acetowhtie changes are hallmark of
chemosensitization dysplasia
- early cancer: stage Ia2-IIa radial - must view all of transformation zone
hysterectomy, lymph node dissection
Surgical options: HPV vaccine:
- radical hysterectomy (hysterectomy - HPV 16 and 18 (66% of cervical cancers)
w/ radiacal resection of parametria - HPV 6 and 11 (90% of genital warts)
and upper vagina)
- lymph node dissection Tumor spreads from cervix to involve
- ovarian conservation possible in parametrial tissues and adj bladder/rectum.
young patient Mets to regional lymph nodes (illaic LN).
distantly to the aortic and mediastinal LN, lung
and bone
Cervicitis
Cervicitis is inflammation of the cervix. It can be from a non-infectious cause, such as a
chemical or mechanical in origin. Or, it can be from an infectious cause, such as a sexually
transmitted disease, or it may represent an endogenous flora. Endogenous flora of the cervix
are Staph and Group B strep. Other pathogens, such as Neisseria gonorrhea, Chlamydia
trachomatis, and Herpes are also agents.
Infectious cervicitis is the initial site of infection in PID and may be associated w/ ascending
infections that complicate pregnancy (acute chroioamnitis)
Vagina
- lined by stratified squamous epithelium
- vaginitis is very common
o infectious: fungi (candida), bacteria (vaginosis-gardnerella), trichomonas
vaginalis
o atrophic: postmenopausal women, loss of estrogen
- DES exposure during pregnancy (used to prevent spontaneous abortions) has been
associated w/ a variety of non-neoplastic and neoplasic changes in the female genital tract
o Congenital anomalies of the cervix and/or vagina
o Vaginal adenosis
o Cervical ectropion
o Clear cell adenocarcinoma of the vagina and/or cervix rare
- Tumors primary tumors of the vagina are rare. Most tumors involving the vagina are the
result of either metastasis or direct extension from nearby malignaneis (cervix and
endometrium)
o Primary tumors:
Squamous cell carcinoma (95%) arise from dysplasia, termined
vaginal intraepithelial neoplasia (VAIN) and is graded VAIN 1-3, using
similar criteria as for the cervix
DES assocated clear cell adenocarcinoma
Sarcomas evaluating vaginal masses in kids (rhabdomyosarcoma)
Vulva
- covered by skin (keratinizing squamous epithelium). Thus any dermatologic condition may
involve the vulva
- vulvar dystrophies:
o lichen sclerosus painful, pale white plaques, cause unknown
o squamous hyperplasia pruritic and related to a wide variety of irritants
- Neoplasia
o Vulvar intraepithelial neoplasai (VIN 1-3) similar to cervix
o HPV infections of the vuvla are usually subtypes 6 and 11 resulting in
condyloma acuminatum (genital warts) papillomatosis, hyperkeratosis,
parakeratosis, and koilocytes
o Majority of invasive tumors of the vulva (85%) are squamous cell carcinoma
arising from VIN
- Pagets disease rare malignant tumors
o Glandular tumors cells w/in the epidermis and skin appendages. The tumor
cells stain for mucin indicative of their glandular origin. Most cases are NOT
associated w/ an underlying adenocarcinoma (thus not like the breast)
- Melanoma pathology similar to melanomas in other sites invasive or in situ
Reproductive and Genetic Diseases
Down Syndrome
Presentation
Typical facies round face, upslanting palpebral fissures, epicanthal folds, flat nasal bridges,
open mouth w/ protruding tongue secondary to hypotonia, short neck w/ excess nuchal skin,
small dysmorphic low set ears, microcephaly, brachycelphaly
Brushfield spots around iris margin
Short and broad hands w/ transverse crease and 5th finger clinodactylyl, wide gap b/w 1st and
2nd toes with furrow extending along length
Short stature, short fingers, hypotonia, single palmar crease
Heart defects (VSD, ASD, endocardial cushion defect) , GI atresia
Down Syndrome is the most common single, known cause of mental retardation (1/700
births).
Other characterisitics:
- mild-moderate MR (IQ: 30-60) need early intervention programs. IQ is about 50%
that of siblings
- hypotonia
- heart defects: AVSD, and VSD need newborn echo and cardiology eval
- GI: duodenal atresia, hirschprung, pyloric stenosis, TE fistula, omphalocele, annular
pancreas, imperforate anus
- Hearing loss
- Vision problems need ophthalmologist at 1 year
- Hip dislocation
- Endocrine: hypothyroidism need newborn thyroid screen (rpt @ 6mo, then
annually)
- Hematologic: leukemia (15X increase, but overall risk is 1%)
- Alzheimers disease in middle age
Inherritance pattern: chromosomal
Causes:
- 95% are due to nondisjunction trisomy 21 (most by maternal meiotic NDJ)
- 1-2% are due to mosaics w/ a normal cell line (mos46XX/47XX+21) a milder
phenotype but cannot predict on an individual basis. The mocaisim can be a result of
either 1) a normal conception followed post-zygotic non-disjunction or 2) trisomic
conception rescured by a nondisjunction or anaphase lag (more common).
- 3-4% are due to an unbalanced robertsonian translocation their phenotype is
indistinguishable from that associated w/ NDJ form of DS. (46XY, der (14:21)
(q10;q10), +21 ) -- most common
- Less common translocations: der(13:21); (15;21); and (21;22)
(21;21) risk for unbalanced offspring is 100% (50% eggs w/
der(21;21) DS and 50% eggs w/ nullisomic lethal monsomy 21)
- 40% of translocations are inherited from a carrier parent that is balanced.
Testing and Management
1
Lab tests karyotyping. Peripheral blood karyotype detects almost all cases, prenatal
diagnosis avl using cells from CVS or amniocentesis
Management echo and peds cardiology eval for newbornd, newborn thyroid screen (repeat
at 6 months and annually), monitor hearing, check vision (opthamlogist @ 1 yr), track growth,
obesity may be a problem in late childhood. C-spine Xrays b/w 3-5 to assess for atlantoaxial
instability or subluxation.
Reproductive and Genetic Diseases
Genetic Counseling:
The recurrence risk of having a second child w/ DS secondary to nondisjunction is related to
maternal age but remains low:
- 30 yrs old = 8X in age related risk (1%)
- 30 yrs old = 2X in age related
The increased recurrence risk seen in young women w/ a previous child w/ trisomy 21 may be
explained by gonadal (germline) mosaicism (results in the same trisomy) or an increased
predisposition to meiotic error (results in the same or a different trisomy). The increased
recurrence in older women is a function of her age!
You should offer prenatal diagnosis for all future pregnancies.
Parental karyotyping is NOT needed the abnormal meiotic events that produce numerical
abnormalities are sporadic events.
An individual w/ DS (secondary to nondisjunctioN) is at a 50% risk of having a child w/ DS.
There is no significant risks for other relatives!
For DS due to mosaicism counseling should proceed as if the child has standard NDH form
of DS (this will result in an overestimation of risk for parents in which NDJ occurred during
mitosis)
Those DS resulting from an unbalanced robertsonian translocation have a substantial
recurrence risk. 40-50% of the time robertsonian translocations are inherited from a balanced
carrier parent. It is necessary to karyotype the parents
- For a de novo robertsonian, a reuccorence risk of 1% is given and a prenatal dx is
offered.
- For a carrier parent the recurrence risk will be higher
- 80% of DS conceptions die in utero only 20% survive to birth. The theoretical
recurrence risk for live born DS is 33% and the empiric recurrence risk is 3-5% for
male and 10-15% for female carriers.
For genetics counseling for robertsonian translocations discuss carriers risk for miscarriages,
infertility and live born child w/ unbalanced (+13 or +21) karyotypes. Offer prenatal testing,
and recommend parental karyotypes to assess risk of relatives and other children of
Reproductive and Genetic Diseases
Trisomy 13, or Patau Syndrome occurs in 1/12, 000 births. It is a cause of severe mental
retardation. The mean life expectany is only 130 days (86% die during year 1)
Inheritance is chromosomal
Causes:
- 75% is due to trisomy 13 due to nondisjucntion.
o Recurrence risk is low (1%) for live birth
- 5% due to mosaic (47X_+14/46X_)
- 20% due to translocations
o All are robertosonians and are mostly 13;14
Most common translocation in man - 1/1,100 individuals
50% of 13;14 are inherited from parent
Balanced 13;14 rob carrier has 1% risk of unbalanced offspring
Presentation
Mental retardation, failure to thrive, severe heart malformations, hypotonia, clenched fists
Trisomy
(2nd and 518
th Edwards Syndrome
digits overlap 3rd and 4th), rocker bottom feet, prominent heel bone,
Prominent occiput, receding jaw, low-set and malformed ears
Trisomy 18 ,or Georges syndrome, occurs in 1/7,500 births. It also cuases mental retardation.
Less than 10% survive beyond 1st year. The median survival is only 5 days!!!
Inheritance: chromosomal
Caused by
- 80% are due to trisomy 18 (NDJ) the recurrence risk is low ( 1%)
- Some mosaics
- 20% w/ translocations most w/ partial trisomy 18
Reproductive and Genetic Diseases
Turners Syndrome
Presentation
Prenatally increased nuchal thickness, lymphadema, cystic hygroma, hydrops fetalis and
high risk of fetal demis w/ a 45 X karytoype
Newbon lymphadema, webbed neck, cardiac abnl 50% have coartaction of the aorta ,
usually normal linear growth until 2-3 years.
Childhood low posterior hairline, cubitus valgus, short 4th metacarpals, short stature
(progressive decline in growth velocity), disproportanitly short legs, broad chest, prominent
ears, pigmented nevi, scoliosis, micrognathia
Adolescence short stature and delayed puberty, delayed epiphyseal fusion. nipples are
widely spaced, increased carrying angle
Adults infertility/anovulation
Increased risk of LD involving spatial perception NO mental retardation.
Infertile w/ streak ovaries. Most will not develop secondary sex characteristics w/out hormone
replacement. Renal abl are common. Phenotypic and karyotypic variability
Turner Syndrome is in 1/ 4-5000 female births. 1-2% of all conceptions, 6-7% o all SABs.
Other features:
- cardiac abnormalities (bicuspid aortic valve, aortic dissection, coarctation of the aorta)
need a cardiac evaluation and ECHO
- renal abnormalities (horseshoe kidneys, unilateral renal agenesis) need a renal US
- short stature avg height is 4;7 need endocrine and growth hormone tx
- delayed puberty - secondary sex characteristics need hormone replacement
- hearing impairment
- learning disabilities spatial perception need intervention programs
Caused by:
- 50% are due to 45X paternal sex chromosome preferentially lost
- The remainder contain other sex chrom abnormalities
o Structurally abnl sex chromosome (X or Y) isochromosomes, deletions, rings,
duplications, etc
o Mosaicism for a normal or abnormal cell line - most common are 46XX, 46XY,
and/or 47XXX cell lines.
- There is a risk of gonadoblastoma if Y bearing cell line is present thus do a
prophylactic gonad removal
Testing and Management
Lab tests karyotying. Peripheral blood karyotype, extended analysis may be needed to
detect mosaicisms
Management issues ped cardiology evalulation, ECHO and renal US. Increased risk for
chronic otitis (and hearing loss), hip dysplasia, strabismus, HTN, sciolosis, and
hypothyroidism. Use TS growth charts at age 2, evaluated speech and development. Referral
to ped endocrinologist for growth and sex hormone replacement therapy!
Genetic Counseling
- there is no need for parental karyotyping b/c the sex chromosome is loss due to a
sporadic error during cell division.
- The recurrence risk is 1%
- The risk for a female w/ TS to have a clinically abnl child most TS patients are
infertile/ 1% have unassisted pregnancies (mosaics w/ nl cell line) thus assisted
reproduction techniques are possible. You need to offer prenatal diagnosis (increased
incidence congenital and chromosomal abnl)
o 5-10% may begin puberty, 1% may have periods
Reproductive and Genetic Diseases
DiGeorge Syndrome
Genetic Counseling
Parental karyotyping is recommended
- 94% of deletions are de novo
o Small recurrence risk (less than 1%)
o Risk for germline mosaicism is unknown
- 6% of deletions are inherited
o Recurrence risk is 50%
o Prenatal FISH is avl
o Consider gentics evaluation and/or FISH to relevant family members
Complementatary duplications and deletions can occur secondary to unequal crossing over
(nonallelic homologous recombination)
Crytpic duplication involving the DiGeroge cirtical region detected prenatally
Reproductive and Genetic Diseases
Cystic Fibrosis:
Presentaiton: (lung dz, liver dz, meconium ileus, sweat cl, pancreatic dz, male infertility)
Chronic congestive lung dz + high levels of salt in sweat. 85% have pancreatic insufficiency
(bulky foul smelling stools), 10-20% have meconium ileus at birth
Poor weight gain, recurrent lung infections, diabetes in 10-15%, severe lung dz in 5%. 95%
of males are infertile (CBAVD). Males can also have isolated congenital bilateral absence of
vas deferens (w/out other symptoms of CF) and have 2 mutations in the CF gene.
Cystic Fibrosis is a genetic condition that affects 1 in 2500 to 1 in 3200 N european and
ashkenzai jews, and 1 in 1500 AA. Carrier frequency is 1/25 to 1/150. The mean survivial of
a person w/ CF is 31. Death is usually secondary to pulmonary complications. Diagnosis is
made by age 3 (although some have milder symptoms)
Classic CF severe lung dz, pancreatic insufficiency, sweat Cl, liver dz, CBAVD
Moderate CD moderate lung dz, pancreatic insuff, sweat Cl, CBAVD
Mild CF mild lung dz, pancreatic insuff, normal/borderline sweat CL, CBAVD
Non-classic CF isolated CBAVD, idiopathic pancreatitis, atypical sinopulmonary
dz/sinusisits/nasal polyps
The inheritance pattern is autosomal recessive w/ variable expression
Mutations: allelic heterogeneity more than 1400 different mutations on the CFTR gene
(cystic fibrosis conductance regulator) on chromosome 7q31.2. Most common mutation is
the deltaF508, a 3 base pair deletion accounting for 70% of mutations.
There is some genotype/phenotype correlation. Six mutations account for 98% of those in
Ashkenazi Jews.
Genetic Counseling
Recurrence risk is 25% when both parents are carriers and it is 2% if someone has CF has a
partner from the general population.
Offer carrier testing to siblings and other relatives.
For CF carrier screening in the general population, false negative rate of carrier testing should
be explained. Do not test asymptomatic children.
Reproductive and Genetic Diseases
Fragile X Syndrome
Presentation variable but becomes more pronounced w/ age
Physical prominent forehead, long, thin face w/ prominent jaw, large protuberant ears,
post-pubertal macroorchidism (enlarged testes)
Cognitive mild to severe developmental delay. (males worse than females, 50% of females
w/ full mutation have normal intellect)
Behavior hyperactivity, lack of eye contact, repetitive behaviors, preservative speech,
autistic like behaviors, social shyness, low self-esteem
Fragile X syndrome is a common hereditary cause of mental retardation. The incidence is
1/4000 males and 1/8000 females. (down syndrome is most common cause)
People w/ fragile X are at an increased risk for strabismus, cleft-palate, joint laxity, dislocated
hips, seizures, mitral valve prolapse .
The inheritance pattern is X-linked w/ anticipation due to trinucleotide repeat expansion.
The expansion of CGG trinucleotide repeat is in the first exon of FMR1 gene on Xq27.
Repeat sizes: normal is 5-44, intermediate is 45-58, permutation is 59-200 and full mutation is
over 200 and highly methylated.
Premutations expand into full mutations ONLY when inherited from a permutation carrier
female. Permutation carriers are not clinically affected. The daughters of males w/ a
permutation are obligate carriers but are intellectually normal.
Due to the increasing size of permutations through generations, the risk of an affected child is
greater in later generations = anticipation (the progressively earlier onset and increased
severity of certain diseases in successive generations of a family) However, no correlation b/c
age of onset and severity with repeat numbers instead the more repeats you have the more
likely you are to be affected and once you have the mutation you have it
CpG island a region of genome containing an unusually high concentration of 5-CG-3
and the Cs are susceptible to methylation. A high level of methylation in a promoter can lead
to transcriptional inactivation of a gene. When the CGs of Fragile X is over 200 it gets
mehtylated and the gene turns off and get a loss of function mutation so that the gene product
is not made.
Lab testing and management
Lab testing: Southern Blot detects presence of full and permutations, approximation of
repeat number, and methylation status.
PCR yields accurate estimates of normal and small permutation alleles.
Diagnositc and carrier testing is very accurate; prenatal testing is avl
Management ophthalmologic (strabismus, myopia, nystagmus), audiology (recurrent
serous otitis), orthopedic (flat feet, scoliosis), and neurologic (seizures). Developmental
evaluation, review school placement, assess needs for PT, OT, and speech and hyperactivity
management.
Genetic Counseling
Young asymptomatic kids may not benefit from carrier testing.
Permutation carrier females have 20% risk of premature ovarian failure w/ premature
menopause
Premutation males have a high risk of late-onset ataxia/tremor syndrome : intention tremor,
ataxia, cognitive decline, eventual brain atrophy.
Reproductive and Genetic Diseases
Side note: CAG repeat disorders are different CAG repeat disorders result from much smaller
expansion and methylation is not involved in expression of the genes, and expansion can occur in
both sexes but they tend to be larger when the expanded allele is inherited from the father!
Huntingtons Disease
Presentation
67% present w/ neurologic features incoordination, jerks, 33% have pyschatiric changes
(depression, irritability)
Mean age of onset is 35-44.
25% have onset after 50
10% have juvenile onset before 20 - seizures and rapid decline
Progressive chorea (not repetitive), dysarhria/dysphagia, outbursts of aggressive behavior,
social disinhibition, paranoid delusions.
72% have signiifiacnt personality changes.
Late stages: weight loss ,total dependence, no speech
Huntingtons Disease is a progressive disorder of cognition, motor and psychiatric disturbance.
It includes voluntary and involuntary movements, cognitive decline and/or personality
changes. Involuntary, spasmodic movements (chorea) w/ progressive dementia. The median
survival after time of onset is 15-18 hears. The average age of death is 55 years and suicide is
12%. It is a degenerative brain disease resulting from loss of cells in the basal ganglia.
The incidence is 3-7/100000 in Western Europe descent and less in Asia and Africa
The inheritance pattern is dominant. Most will have an affected parent. New mutations rae
very rare. HD shows decreased penetrance and anticipation
The mutation in HD is a CAG triplet repeat expansion w/in the HD gene on chromosome 4p.
There is an inverse correltion b/w number of repeats and age of onset.
Repeat sizes: normal is less than 26, intermediate that confers no increased risk for individual
but can expand to offspring who can become affected is 27-35, reduced penetrance alleles
which causes symptmoms in some but not all is 36-39. adult onset is 40-59 repeats and
juvenile onset is above 60 repeats.
Expansions are more likely to occur during paternal gametogenesis, w/ juvenile onset HD
almost exlusively inherted through affected fathers. For adult onset, repeat size is not
correlated w/ appearance of clinical features or w/ rate of progression
Genetic Counseling
Genetic testing of asymptomatic individuals is predictive (increases or decreases prior risk)
but is NOT diagnostic. Age-related penetrance figures are avl.
Does the individual at risk really want to know what s/he will die of and when? How will the
individual cope w/ results? Confidentiality, possible genetic discrimination.
Reproductive and Genetic Diseases
- all autosomal dominant repeat expansion disorders show anticiatpion and most show
parental bias in transmission of larger expansions to offspring. CAG repeats are
moderately unstable, whereas other repeats are prone to very large expansions. CAG
repeats in coding regions leads to toxic proteins.
- Expanded Repeats in DM1 and DM2 result in toxic mRNA.
- Other expansions can lead to loss of function
Phenylketonuria (PKU)
Presentation
Untreated children severe mental retardation, seizures, increased irritability, musty odor and
eczema. They are NOT dysmorphic
Elevated levels of phe in older kids and adults w/ PKU put them at risk for behavioral and
learning problems, regardless of good early treatment
(kids have progressive developmental delay/MR, autistic like behavior, hyperactivity)
PKU is an inborn error of metabolism caused by significant decreased activity of the liver
enzyme phenylalanine hydroxylase, resulting in increased blood levels of the amino acid
phenylalanine.
1-2% of individuals w/ hyperphenylalanemia will have impaired synthesis or recycling of
tetrahydrobiopterin (BH4), a necessary cofactor for phenylalanine hydroxylase.
The incidence is 1/15000 to 1/20000 newborns in the general US population. More common
in those of N European ancestry. In that population, carrier frequency is 1/50.
The inheritance pattern is autosomal recessive w/ variable expression due to varying levels of
enzyme activity and other epigenic effects which may modulate the phenylalanine such as
absorption during the digestive process or its transport across the BBB.
PKU displays allelic heterogeneity, w/ over 400 mutations in the phenylalanine hydroxylase
gene on chromosome 12q. most affected individuals are compound heterozygotes (2 different
mutations w/in the gene)
Lab Testing and Management
Lab testing screening lab measures blood Phe levels from samples taken in the newborn
nursery and spotted on filter paper (every state). This is accurate when performed on blood of
infants older than 24 hours.
Carrier testing is accurately detected by molecular analysis when the mutations have already
been identified in the proband.
Prenatal diagnosis is possible if mutations in the family are known.
Screening for BH4 deficiency should be completed in all neonates w/ persistent
hyperphenylalanemia
Management MR can be prevented if tx is initiated before 4 wks of age w/ a special
individualized diet low in Phe. A life-long diet consisting of a metabolic formula w/out Phe,
and includes measured amts of fruits, veggies, limited grains, and specially processed low-
protein foods.
Blood levels of Phe are obtained weekly: want it to be b/w 120-180 micromoles/L.
Adjustments on phe intake are needed based on individuals growh, intercurrent illness, and
phe tolerance.
Indiviuals who are hyperphenylalanemia due to BH4 deficiency require biopterin replacement
therapy and NT replacement terappy. They are typically not on a low Phe diet.
Reproductive and Genetic Diseases
Genetic Counseling
Children born to women w/ PKU are at increased risk of birth defects and MR b/c of the
teratogenic effects of Phe. Thus, keep maternal Phe levels at 120-360 micromoles/L prior to
conception and throughout pregnancy.
If maternal blood levels are 1200 micromoles/L during prenangy high risk of IUGR,
microcephaly and MR and a moderate risk for specific dysmoprhic features (bypertelorism,
epicanthal folds, upturned nose, long philtrum, high arched palate) and congenital heart
defects and spontaneous abortions.
Galactosemia
Presentation
Presents w/in the first 2 weeks of life w/ jaundice (due to conjugated hyperbilirubinemia),
lethargy, cataracts, hepatomegaly, and FTT, an rapidly processed to death if untreated
Treatment
Any infant suspected of having galactosemia should be on a galactose-free diet (soy formula)
Life-long restriction of galactose and lactose-containing products is essential.
**short stature, ovarian failure, and visual-preceptual speech and learning disabilities are
common in patients treated from birth (different from PKU where you can prevent symptoms)
Hyperammonemia
Presentation
The chronic episodeic hypoglycemia results in Hepatomegaly, poor growth, lactic acdisosi,
hyperlipidemia, easy bruising, and if severe and untreated, life threatening hypoglycemic
seizures.
Reproductive and Genetic Diseases
GSD type 1 = Glucose 6 phosphatase defieeincy (cant move glucose out of the liver) is
characterized by hypoglycemia occurring 2-3 hours after eating.
The hypoglycemia is secondary to an inability to release glucose from the liver
Treatment
Frequent feedings w/ glucose or glucse polymers
Raw cornstarch, a slowly digested glucose polymer, can act as a time-release source of
glucose and can be very helpful in mainitng glucose levels when taken orally every 4-6 hours.
Biotinidase Deficiency
Presentation
Seizures, ataxia, hypotonia, developmental delay, skin rash, alopecia
Biotinidase cleaves the biotin from biocytin and biotinyl peptides released during proteolytic
degradation. Thus do not have biotin.
Treatment
5 and 20 mg oral biotin (in the free, unbound form) per day
Reproductive and Genetic Diseases
Presentation
Newborn: severe central hypotonia and feeding difficulties
12 months 6 yrs: excessive eating and development of morbid obesity (esp b/w 2-4yrs).
Food seeking behaviors such as hoarding or foraging for food, eating of inedibles, and stealing
of food
Short stature, facial features such as bitemporal narrowing, almond-shaped paleprebal
fissures, down-turned mouth, small hands and feet, hypogonadism, thick saliva, strabismus,
scoliosis, reduced growth hormone secretion,
developmental delay and cognitive impairment (mild range of mental retardation)
behavioral concerns temper tantrums, obsessive-compulsive behavrior, stubbornness,
rigidity, stealing, lying, manipulative behavior, skin picking
Marfan Syndrome
Presentation affects cardiovascular, ocular, and skeletal systems!
Cardiovascular aortic root dilation, dissecting aortic aneurysm, mitral valve
prolapse/regurg, dilation of pulmonary artery or descending aorta
Ocular dislocated lenses (ectopia lentis), detached retina, myopia
Skeletal tall stature, relatively long arms and legs compared to trunk, arachnodacytly (long
thin spider-like digits), dolichostenomelia (long thin extremetieis), limitation of elbow
extension, joint laxity, scoilisosi, pectus excavatum or carinatum, flat feet (pes planus),
protrusion acetrabulae)
Other dural ectasia, recurrent or incisional hernias, stretch marks (striae), spontaneous
pneumothorax, apical blebs, high-arched palate, dental crowding, typical facies
(dolichocephaly, malar hypoplasia, enopthalamos, retrognathia, downslanting palpebral
fissures)
Marfan Syndrome the incidence is 1/10,000
25% of cases are due to new mutations
It is autosomal dominant with variable expression. It also shows allelic heterogeneity with
various mutations within the FBN1 gene on chromosome 15q21 protein is fibrillin
Neurofibromatosis Type I
Presentation
At least 2 of the following:
- 6 or more caf au lait spots (CLS) 15 mm postpubertal or 5mm prepubertal
- 2 or more neurofibromas of any type or 1 plexiform neurofibroma
- Axillary or groin freckling (small CLS macules 5mm)
- Optic glioma
- 2 or more Lisch nodules (benign, raised iris hamartomas seen by slit lamp exam)
- A distinctive bony lesion (Dysplasia of sphenoid bone, thinning of long bone cortex)
- A 1st degree relative w/ NFI by independent diagnostic criteria
NF type I progresses w/ age, and some features are age-dependent. Children may only have
CLS. Lisch nodules and cutaneous fibromas usually develop in late childhood to adulthood.
Plexiform neurofibromas often appear to be congenital. There are increased risk for learning
problems (40-60%), seizures, HTN (due to rental artery stenosis or rarely pheocromocytoma)
and malignant neoplasms
NF type I has an incidence of 1/3000.
50% are due to new mutations!!!!
It is autosomal dominant with variable expression and nearly complete penetrance.
It also shows allelic heterogeneity o the NF1 gene chromosome 17q, protein is neurofibromin.
Genetic Counseling
50% have mild manifestations and 30% have severe complications.
Intrafamilial variability is common.
First degree relatives need examination
Prenatal genetic diagnosis is feasible but cannot predict severity!
Puberty and pregnancy associated w/ increase in size and number of neurofibromas in some
women.
Reproductive and Genetic Diseases
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