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Common Conditions: Ovarian Cancer

Colleen McCormick, MD, MPH
Gynecologic Oncologist
NW Cancer Specialists
NCNM Grand Rounds 10/19/09

OVARIAN CA
deadliest of gyne CA
usu not Dxd until stage 3-4
30-40% survival rate
no screening tests
hard to DX

survivors speaking first
survivor in turquoise does intro, she has peripheral neuropathy from lots of chemo

MARTHA'S STORY
Dx March 06
was business owner working 60-80 hours a week
did pilates, had two teens
had annual exam in May
in Aug while working out had sudden need to pee
was told it was normal
noticed it more on weekends when she was home with family
called again
said she felt pregnant
got annual, they told her she probably had fibroids
(fibroids are smoother, more mobile)
went for TVUS 4 days later, it was scheduled in office
7am Fri, scary news, need you to see specialist, word "cancer" not used
she got radiology report on fax at work
"strong possibility of bilateral ovarian malignancy"
got surgery within a week
gemsar and carboclatnum
worried about not enough chemo and taxol
did a year of taxol, 23 infusions
taxol can cause hives
acupx 2x/week, supps, changed eating habits
no recurrence

DIANE'S STORY
was social worker
early 90's was at friend's funeral
she'd died of ov ca at 34
trained to walk PDX marathon
walking partner pants were getting tight
she went to doc he said she was fat
she finished marathon
2 mo later dxed with stage 4 ca and had 20lb tumor removed
has died since
in 2002 Diane was at work, couldn't sit dt pain
got to doc, too tender for pelvic exam
she didn't think it was diverticulitis
was like ovulatory pain but worse
enlarged ovaries bilaterally
gyne said prob a cyst
repeated test, it had grown, scheduled for hysterectomy
after hysterectomy told it's all great
then got pathology report back on Valentine's day
you have ov ca, an early stage, advanced grade
6 rounds of carbo platinum taxol
had staging laparotomy, how they tell what stage

DIANE 2's STORY
hs counselor
free for a September 1st time ever
trained for cycle Oregon
told to eat and drink before need felt
needed to pee a lot on bike
then bowel changes: loose
then gas, bloating
her colonoscopy was clear
wrote it all off as postmenopausal sx
9/11/01 tenting in wilderness, had to pee 4x
ignored sx a few more months
Dec went to primary care doc who said IBS
no pelvic exam done, sent on vacation to Hawaii
bloating increased, felt worse
annual exam doc said fibroid size of grapefruit
prescribed TVUS same day
large septated growth on L ovary
appt with gynecologic oncologist on Mon
Thurs hysterectomy, debulking
stage 3 ov ca with mets around abdomen and in LNs
chemo, taxol carbo platinum, then taxol something else controversial
went to naturopath, used acupx, massage, yoga
naturopath limited diet based on EAV readout (corn, soy, sugar, etc) hives went away
naturopaths "not big in the east"

COLLEEN MCCORMICK
fast talker
just moved to PDX 2 mo ago
she's a smallish woman, curly blonde hair, glases, light skin
pink shirt, black/white small plaid suit, 1" heels on black shoes

CASE
62yo w/ abd pressure, bloating, ascites, pelvic mass
CT w/ "omental cake"/carcinomatosis
high CA-125
mass was adhered to transferse colon

OVERVIEW
21,650 new/year, 15,520 deaths/year
1/70 women get ov ca
2nd most common gyne ca, endometrial is more common but less deadly
lung, breast, CRC, top three overall

SYMPTOMS
my clothes are tight clothes
bloating, get full easy, pain like cramps
pain, pressure, girth, bowel change, urinary frequency
often attributed to other problems
primary peritoneal cancer mimicks ov ca, looks same, tx is same

DELAYS IN DX
pelvic exam very helpful in dx but many docs won't do it-->delay in dx
retrospective of 277pts showed 9mo to get first appt after sx
another 9mo to pelvic exam

PE
distended abdomen
fluid wave
omental mass
fixed pelvis**
must do pelvic exam, and rectal vaginal

WORKUP
imaging: US, CT
not easy to tell btw malig & b9 esp via US
bad prog: solid, septations, ascites
CA-125, poor sensitivity in early stage, poor specificity:
elevated in other dz incl abd ca, endometriosis, PID, renal dz, lupus, CHF
NO BIOPSIES!! COULD "UPSTAGE" PT
paracentesis of ascities is fine

RISK FACTORS
age 45-70
nullip
early menarche, late menopause
family hx with 1st deg relative -->5x risk
hereditary CA syndromes: BRCA 1, 2 (autosomal dominant), cancer younger
with BRCA 1: 45% ov ca risk, 85% breast ca risk, chance of one of the two: 95%
**get screening for BRCA if premenopausal breast ca or more than one family member w/ female ca

PROTECTIVE
oral contraceptive use
bilateral tubal ligation
prophylactic oophorectomy

NO GOOD SCREENING
CX CA decreased by 74% since beginning pap smears
no such screening for ov ca
uncertain nature of early stage dz
low prevalence (as opposed to ov cysts which are common)
tests have low sensitivity & specificity
invasive procedure needed to eval positive screen
90% Dxd at stage 3C
9/10 exploratory surgeries don't find ov ca

SO I'M SUSPICIOUS MY PT HAS OV CA, WHAT NOW?
consider refer to gyn onco if
CA-125 over 35
ascites
comlpex, nodular and/or fixed pelvic mass
family hx
GYN ONCO does surgery, chemo, longterm management
significant survival advantage
WHAT THEY DO
exploratory laparotomy
TAH-BSO, omentectomy
collection of ascites, washings
palpate all intra-abdominal surfaces
remove macroscopic dz
pelvic/para-aortic LN dissection
GOAL: no visible dz, optimal if under 1cm, 5yr prog 50%
10 yr prog: another 50%, so 10yr survival 25%
if lesion above 2cm left: 5% survival
may incl bowel resection, splenectomy, etc
optimal cytoreduction-->sig survival advantage
TX cytoreductive surgery
chemo: carboplatinum taxol
"ov ca is uniformly fatal without chemo"

STAGING
stage 1 ovaries only
stage II pelvis only (first spread to omentum)
stage III upper abdomen and lymph nodes (next spread to lymph)
stage IV distant mets incl superclavicular LNs

HOW DO YOU BREAK THE BAD NEWS
the panel's stories are all the same that they weren't told at first that it was cancer
it was a shock
no doc wants to say "you have cancer" over the phone, pts would rather come in to office
"when you hear cancer you hear nothing else" but tone, something shuts down
can't process complex info: pt should bring someone who can hear: not spouse or mother
doc: keep the tone positive, stay calm when using word "cancer"
good sam support group has clinical psychologist says "you are each your own statistic"
give hope
explain the plan
you have a team
some pts want to be told what to do, "partner in your care" may not be a role they want

NATUROPATHIC CARE
don't get mad when other doc says what you want to give is unsubstantiated
pts need docs to work together
steroids-->high energy then emotional shredding, fear of death
schedule acupx for time when emotions decline
B12 shots before chemo
end anti-ox 3 days before chemo, start again 3-4 days after
shiatsu
supplements
emotional support: groups in person, online, peer support
cancer support group helps but the closer the type the better
"oh honey, we're all 3C" on the phone
risk of depression, use counseling, meds, whatever is needed
naturopathic tx needed for digestive issues, chemo flattens villi in intestines
"keep the treatment from killing the host"

SSL ON PATHOLOGY

What is the incidence of ovarian cancer?
--6% of all CA in women in US (excluding skin CA), ranking after cervical and endometrial CA
--numerous tumors of ovaries: 80% are benign and occur in women 20-45 years of age
--malignant more common in women 40-65

What is the mortality rate from ovarian cancer and why?
--Accounts for 1/2 of deaths from CA of the female reproductive tract, because there are few signs of an early ovarian cancer, they are rarely detected early. Many have spread before detection, seeding into the peritoneum or spreading by mets to all the usual places. Because early detection is rare and ovarian cancers "seed", the death rate if rather high.

What's the pathogenesis of ovarian cancer?
?? the usual?
--RISK factors: (not as clear as for other genital cancers): nulliparity, low parity, FHx, gonadal dysgenesis, genetics
--BRCA 1 & 2 incr likelihood 20-60% by age 70-->mostly cystadenocarcinoma
--PROTECTIVE factors: OCP's and tubal ligation decr incidence in women 40-59
--GENETICS: 30% of Ov adenocarcinomas express high levels of Her2/neu oncogene
--Her2/neu correlates with poor prognosis
--p53 mutations found in 50% of ov CA

What's the overall frequency of the various types by cell of origin?
1) surface epithelium-stromal tumors: 65-70% of all tumors, 90% of malig, over age 20
2) germ cell tumors: 15-20% of all, 3-5% of malig, 0-25 years
3) sex-cord stromal tumors: 5-10% of all, 2-3% of malig
4) mets: 5% of all, 5% of malig, any age
5) malignant, defies classification

What are the categories of Mullerian types of ovarian cancer?
serous
endometroid
mucinous

What are psammoma bodies and where are they found?
concentric, laminar, circular, acellular, eosinophilic calficications
seen under a microscope
found in papillary carcinomas of the:
ovary, prostate, kidney, thyroid, endometrium, mesothelioma, meningioma
from Greek word psammos meaning "sand"
assoc with papillary histomorphology
thought to arise from infarction/calcification of papillae tips
OR from calcification intralymphatic tumor thrombi

What is pseudomyxoma peritonei?
ov tumor with extensive mucinous ascites, cystic epithelial implants on peritoneum, and adhesions, may result in intestinal obstruction and death

What is a Brenner tumor?
uncommon adeonfibroma in which epithelial component is nests of transitional cells
like bladder lining, sometimes cysts contain microcysts or gladular spaces lined by columnar, mucin-secreting cells, sometimes found in mucinous cystadenomas
MORPH: mb solid or cystic, usu unilateral, vary from small to massive
fibrous stroma looks normal, nests with mucinous glands in center
sometimes stroma has plump fibroblasts like thecal cells, may have hormonal activity

What is the clinical picture/course for Mullerian tumors?
most Brenner tumors are benign but some are borderline or malig
most often found incidentally, usu no problem

What are CA 125 and osteopontin and what do they tell you?
--CA-125 (high-MW glycoprotein) present in >80% of serous, endometrioid carcinomas.
--Newer marker – Osteopontin was only faintly mentioned in SSL's notes as a way to monitor the course of ovarian cancer. OSTEOPONTIN is a glycoprotein that was originally discovered in bone, linking osteoclasts to the mineral components, but has since been found to be involved in immune regulation (chemotaxis, apoptosis blocker), scar formation, tumors, and lots more. Works as anti-apoptotic factor sometimes. Provokes release of IL-17. Has lots of other names but OPN is most common. Involved in alcoholic liver disease, rhemuatoid arthritis, glomerulonephritis and tubulointerstitial nephritis, and is found found in atheromatous plaques within arteries. It is expressed in macrophages, neutrophils, dendritic cells, and T and B cells. Osteopontin is overexpressed in a variety of cancers: lung, breast, CRC, stomach, ov, melanoma, mesothelioma.

Which ovarian tumor may produce 5-hydroxytryptamine and a carcinoid syndrome?
a monodermal or specialized teratoma
(of the germ cell tumors, only mature teratoma and dysgerminoma will be on the final)

What is 5-hydroxytryptamine?
serotonin

What kind of ovarian tumor is most likely to be bilateral?
serous, in general
cystadenocarcinomas specifically (66%)

What are Schiller-Duval bodies?
glomerulus-like structure composed of a central BV in germ cell lined space

What kind of ovarian cancer has Schiller-Duval bodies under the microscope?
endodermal sinus or yolk sac tumor
2nd mc germ cell malignancy

Who gets yolk sac tumors?
children or young women who present with abdominal pain and rapidly growing mass

What fetal marker may be produced by yolk sac tumors?
α-fetoprotein

Which ovarian tumor is the counterpart of the seminoma in the testes?
dysgerminoma

What kind of ovarian tumor is most likely to be bilateral?
endothelial

Which kind of ovarian tumor is most likely to secrete hormones?
sex-cord stromal tumors
tumors secrete hormones assoc with the cell type, estrogens (theca), androgens (Leydig)

Why is endometrial carcinoma diagnosed earlier in the US than ovarian cancers?
because it causes DUB

Why is cervical cancer diagnosed earlier in the US than ovarian cancers?
because we get PAP smears

What hormone might be produced by a dysgerminoma?
chorionic gonadotropin

What's the overall survival rate for dysgerminoma?
over 80%

What is the most common ovarian malignancy?
serous cystaenocarcinomas 40% of all OvCa, occur age 40-60

What ovarian cancer has the worst prognosis of all?
not sure of exact answer, what do you say?
notes:
90% of malignant ovarian CA comes from surface epithelium-stromal tumors
(from coelomic or ectopic endometrial epithel)
Her2/neu gene correlates with poor prognosis
PSEUDOMYXOMA PERITONEI is pretty bad, means seeding into peritoneum
clear cell adenoma pts rarely survive to 5 years if CA has spread past ovary
**choriocarcinoma usu unresponsive to chemotherapy and are often fatal (this may be the one)
rapid proliferation of trophoblastic cells (chemo very effective)

What kind of epithelium precedes mullerian?
coelomic
(coelomic epithelium-->mullerian epithel-->fallopian tubes, endometrium, endocervical glands)

What percentage of women with irregular periods have ovarian cysts?
50%

What sex cord tumor may produce large amounts of estrogen in a postmenopausal woman?
Granulosa-Theca Cell Tumor
5% of all ov CA
2/3 in postmenopausal women

What other hormones may be produced by granulosa-theca cell tumors?
androgens, or inhibin

What color are the areas of hormonal functionality in a G-T tumor?
bright yellow

What hormone is elevated in the serum of women carrying Down's syndrome fetuses?
(2nd trimester)
inhibin from thecal cells
also produced by sertoli cells in male

What ovarian cancer sends mets to lung, bone, vagina, brain, liver and kidney?
choriocarcinoma

MORE SSL


OVARIAN TUMORS
--common neoplasia in women
--6% of all CA in women in US (excluding skin CA), ranking after cervical and endometrial CA
--usu not detected early so often fatal: accounts for 1/2 of deaths from CA of female tract
--numerous tumors of ovaries: 80% are benign and occur in women 20-45 years of age
--malignant more common in women 40-65
--RISK factors: (not as clear as for other genital cancers): nulliparity, low parity, FHx, gonadal dysgenesis, genetics
--BRCA 1 & 2 incr likelihood 20-60% by age 70-->mostly cystadenocarcinoma
--PROTECTIVE factors: OCP's and tubal ligation decr incidence in women 40-59
--GENETICS: 30% of Ov adenocarcinomas express high levels of Her2/neu oncogene
--Her2/neu correlates with poor prognosis
--p53 mutations found in 50% of ov CA
--tumors from four sources:
1) surface epithelium--mullerian epithelium (90% of malig),
2) germ cell tumors (from yolk sac, totipotential)
3) sex-cord stromal tumors
4) mets
--type 1) from mullerian epithelium which is incorporated into the ovarian cortex to form mesothelial inclusion cysts, origin of mucinous tumors is unclear, mb assoc w/ teratomas too
--most are nonfunctional and produce mild sx until they are HUGE
--epithelial tumors tend to be bilateral

OVARIAN CANCER ORIGINS (from text page 1093)

1) surface epithelium-stromal tumors (from coelomic or ectopic endometrial epithel)
(coelomic epithelium-->mullerian epithel-->fallopian tubes, endometrium, endocervical glands)
most primary cancers of ov are this type
(90% of malig)
three major groups: serous (tubal), mucinous (cervix), endometrioid (endometrial)
incr risk of malig w/ more discernible solid epithelial growth
MORPH: papilli, thickened tumor lining cyst spaces, or solid necrotic friable tissue
65-70% of all tumors, over age 20
these tumors occur predominantly in ovaries b/c this epithelium is incorporated into the ovarian cortex to form mesothelial inclusion cysts
in the endometroid category: clear cell, brenner tumor
cystadenofibroma = b9 (most endometrioid tumors are carcinomas)
epithelial tumors tend to be bilateral
Sx: abd pain, distention, urinary & GI sx dt compression or invasion, abd or vaginal bleeding
may be small or large

2) germ cell tumors
(germ cells migrate from yolk sac to ovary and are totipotential)
15-20% of all, 3-5% of malig
0-25 years
most are benign teratomas, the rest are found in kids/youth and are more malig
types: teratoma, dysgerminoma, endodermal sinus tumor, yolk sac tumor, mixed germ cell tumor,
choriocarcinoma
teratomas: mature are benign, immature are malig, monodermal are specialized and benign

3) sex-cord stromal tumors
tumor derived from ovarian stroma
(stroma of ovary contains sex cords of embryonic gonad, forerunners of endocrine apparatus)
5-10% of all, 2-3% of malig
all ages
types: granulosa-stromal cell tumors, fibroma, granulosa-theca cell tumor,
sertoli-leydig cell tumor
tumors secrete hormones assoc with the cell type, estrogens (theca), androgens (Leydig)
tumors mb feminizing (granulosa-theca cell tumors) or masculinizing (Leydig cell tumors)

4) mets
5% of all, 5% malig, any age

5) malignant, can't tell cell of origin
(defies classification)

SEROUS TUMORS
common cystic neoplasms
MORPH:
lined by tall, columnar ciliated epithelial cells
filled with clear serous fluid
accounts for about 30% of all ov tumors
75% of benign or borderline (age 20-50)
25% malig
serous cystaenocarcinomas 40% of all OvCa, are MOST COMMON MALIG, occur age 40-60
benign & borderline malignant occur most often in women 20-50 yo.
MORPH: 2 main types:
1) cystic lesion w/ intracystic papillary epithelium in fibrous walled cyst or
2)projecting from ov wall
bilaterality is common: 20% of b9 cystadenomas, 30% of borderline, 66% of cystadenocarcinomas
lining columnar epithelium with abundant cilia in b9!! microscopic papillae mb found
cystadenoma: solid tumor, complex growth, atypical, psammoma bodies
PSAMMOMMA BODIES = concentric calcium concretions in SEROUS tumors, also in prostate
Borderline tumors may arise from or extend to peritoneal sfcs as noninvasive implants
5 year survival for borderline and malig tumors confined within ov is 100% and 70% respectively
5 year survival if peritoneium is involved is 90% and 25% respectively
after 5 years many borderline tumors recur

MUCINOUS TUMORS
resemble serous
less common
25% of all ov neoplasms
usu in midlife, rare before puberty or after menopause
80% are B9 or borderline, approx 15% are malig
mucinous cystadenomcarcinoams are uncommon, only 10% of ovCa
MORPH: more cysts of variable size and rare sfc involvement
less bilateral (only 5%)
make larger cystic masses, weights can surpass 25kg
gross: multiloculated tumors filled with gelatinous fluid
HISTOL: tall columnar epithelial cells with apical mucin and no cilia
akin to B9 cervical or intestinal epithelia
endometriosis type: "mullerian mucinous" cystadenoma, uncommonly malig
more common: abundant gland-like or papillary growth with nuclear atypia and stratification
sim to tubular or villous adenomas of intestine,
mb precursor of cystadenocarcinoma
PSEUDOMYXOMA PERITONEI is ov tumor with extensive mucinous ascites, cystic epithelial implants on peritoneum, and adhesions, may result in intestinal obstruction and death

ENDOMETRIOID TUMORS
20% of all ov CA excluding endometriosis which is considered non-neoplastic
most are carcinoams
less common benign forms are cystadenofibromas
both: can tell from mucinous by the tubular glands, have solid and cystic areas
15% coexist with endometriosis

CLEAR CELL ADENOMA
uncommon pattern of sfc epithelial tumor of ov
characterized by large epithel cells with abundant clear cytoplasm
sometimes in assoc with endometriosis or endometrioid carcinoma of the ov
now thought to be of mullerian duct origin and variants of endometrioid adenocarcinoma
can be predominantly solid or cystic
if solid, arranted in sheets or tubules
if cystic, neoplastic cells line the spaces
5 year survival is 65% when confined to ovaries
with spread beyond ovary rare to live 5 years

CYSTADENOFIBROMA
variant with more pronounced prolif of fibrous stroma under columnar epithelium
benign
usu small and multilocular
small papillary processes that don't get as complicated and branching as ordinary cystadenoma
mb composed of mucinous, serous, endometrioid or transitional (Brenner) epithelium
mets are rare

BRENNER TUMOR
uncommon adeonfibromas in which epithelial component is nests of transitional cells
like bladder lining
sometimes cysts contain microcysts or gladular spaces lined by columnar, mucin-secreting cells
Brenner tumors sometimes found in mucinous cystadenomas
MORPH: mb solid or cystic, usu unilateral, vary from small to massive
fibrous stroma looks normal, nests with mucinous glands in center
sometimes stroma has plump fibroblasts like thecal cells, may have hormonal activity
most brenner tumors are benign but some are borderline or malig

OVARIAN CARCINOMA COURSE, DETECTION AND PREVENTION
--CA-125 (high-MW glycoprotein) present in >80% of serous, endometrioid carcinomas.
--Newer marker – osteopontin
--Tubal ligation & OC’s – assoc with sig. ↓ in risk
--Long term OC use for women with a FHX of OvCa confers 50% ↓ risk
--Tubal ligation confers >50% ↓ risk & mb effective in women with BRCA & FHX
--prophylactic oophorectomy in BRCA + women is standard allopathic care

TERATOMAS
Mature (Benign) mostly cystic, "dermoid cysts"
derived from the ectodermal differentiation of totipotential cells
usu in young women during reproductive yrs.
karyotype of all benign teratomas is 46,XX.
tumors probably arise from an ovum after the first meiotic division
MORPH: bilateral 10%-15% of cases
unilocular cyst containing hair & cheesy sebaceous material
may find teeth and other areas of calcification
HISTOL: cyst wall is stratified squamous epithelium with underlying sebaceous glands,
hair shafts, & other skin adnexal structures
other germ layers also present: cartilage, bone, thyroid tissue
~1% of dermoids-->malig-->thyroid carcinoma, melanoma, squamous cell carcinoma (most common)

Immature Malignant Teratomas
rare
component tissue resembles fetus or embryo rather than adult
usu in prepubertal adolescents & young women – mean age is 18 yo
grow rapidly & freq penetrate the capsule with local spread or mets
PROG: excellent at stage I
higher grade tumors confined to ovary txd with prophylactic chemo
most recurrences within 2 yrs, absence of dz beyond this time confers excellent prognosis
MORPH: bulky tumor with smooth external surface, solid structure,
areas of necrosis & hemorrhage present
hair, grumous material, cartilage, bone, & calcification mb present
primitive neuroepithelium
risk of spread outside ov incr in higher grades

What is grumous material?
coagulated blood

Monodermal or Specialized Teratomas
rare, most common being struma ovarii & carcinoid
unilateral
Struma ovarii is composed of entirely mature thyroid tissue may-->hyperthyroidism
Ovarian carcinoid arises from intestinal epithelium in a teratoma
mb fxning esp in lg tumors (>7 cm) producing 5-hydroxytryptamine & the carcinoid syndrome Primary carcinoids are malignant <2%

What is 5-hydroxytryptamine?
5-HTP = serotonin
a monoamine neurotransmitter
found extensively in the GI tract of animals
80-90% of human serotonin is found in the enterochromaffin cells in the gut
used to regulate intestinal movements
the rest is synthesized in serotonergic neurons in the central nervous system (CNS)
controls appetite, mood and anger
also found in many mushrooms and plants, including fruits and vegetables

SOURCES
http://liveonearth.livejournal.com/537333.html major pathology post

Comments

( 2 comments — Leave a comment )
neptunia67
Oct. 19th, 2009 05:15 pm (UTC)
F**K! You see, this is why I get so concerned when I have "lower GI" pain. Last week I had another bout that felt exactly like before I had my ovary removed. Steady, sharp pain for a week. I need to see my gyn, but am not sure if I should just wait until annual exam next April, or go now.

I have an LJ friend who had a 40+ pound tumor removed and survived stage 3 or 4 ovarian cancer - has been cancer-free for at least a year now. She knew it was there but was in denial. Amazing story.
liveonearth
Oct. 19th, 2009 07:30 pm (UTC)
Yeah, I had no idea that 1/70 women get this in the US....thought it was much less common. I'm hoping you have nothing of the sort, but a skilled physical exam by a gynecologist, and a transvaginal ultrasound, is what you want to go for if you think you have a mass or other symptoms. Sounds like the CA-125 blood test is not accurate, but it wouldn't hurt to have that done.
( 2 comments — Leave a comment )

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