Outline Tumor.pdf · Struma ovarii –teratoma composed entirely of mature thyroid tissue May be...
Transcript of Outline Tumor.pdf · Struma ovarii –teratoma composed entirely of mature thyroid tissue May be...
Outline
Ovarian tumors
Epithelial (Mullerian) tumors
Serous tumors
Mucinous tumors
Endometrioid ovarian tumors
Clear cell carcinoma
Transitional cell tumors
Outline
Germ cell tumors
Teratoma
Dysgerminoma
Yolk sac tumor (endodermal sinus tumor)
Choriocarcinoma
Sex cord stromal tumors
Granulosa cell tumor
Fibroma, thecoma, fibrothecoma
Sertoli-Leydig cell tumor
Ovarian tumors
Benign = 80%; 20-45 y/o
Borderline/low malignant potential = slightly older
females
Malignant = more common in older females, 45-65 y/o
Ovarian cancer:
3% of all female cancers
5th cause of female cancer deaths
Diagnosed at advanced stage hence higher
mortality – most have spread beyond the ovary at
time of diagnosis
Ovarian tumors
WHO classification based on tissue of origin:
Surface/FT epithelium & endometriosis
Germ cells (pluripotent cells that migrate to the ovary
from the yolk sac)
Stromal cells & sex cords (endocrine apparatus of
ovary)
Metastatic tumors to the ovary
Symptoms: abdominal pain & distention, urinary & GI
tract obstruction 2° tumor invasion, vaginal bleeding
Epithelial tumors
Histologic types:
Serous
Mucinous
Endometrioid
Each histologic type classified as:
Benign
Borderline/low malignant potential (LMP)
Malignant
Pathogenesis of ovarian epithelial tumors
Fallopian tube origin of
high-grade serous carcinoma
Observed in BRCA1/BRCA2 germline mutation
carriers
Risk-reducing salpingo-oophorectomy
Serous Tumors Benign, borderline, and malignant types account for about 30% of
all ovarian tumors and ~50% of ovarian epithelial tumors
About 70% are benign or borderline, 30% are malignant
Benign and borderline tumors – younger patients 20-45 yrs
Malignant tumors – later in life unless genetically susceptible (BRCA 1 and 2)
Risk factors for malignant serous tumors:
BRCA1/2 mutation – estimated risk 20-60% by the age of 70 years (these mutations are present in about 5% of women younger than 70 with ovarian cancer)
Nulliparity/low parity
Family history
Reduced risk
OCP use
Tubal ligation
Ovarian serous carcinoma
Low-grade serous carcinoma
(LGSC)
Arise in serous
borderline tumors
Mutation: KRAS, BRAF,
ERBB2
Wild type: TP53
High-grade serous carcinoma
(HGSC)
Arise from STIC or
inclusion cysts
Mutation: TP53
Wild type: KRAS, BRAF
Amplification of
oncogenes, deletions of
tumor suppressor genes
Present in BRCA1/2 pts
BRCA1/2 mutation rare
in sporadic HGSC
Serous tumors
Biologic behavior depends on degree of differentiation and peritoneal
involvement (tumor present on ovarian surface vs spread to peritoneum)
SBT & LGSC – slow progression even with peritoneal involvement, patient
may survive for relatively long periods
HGSC – often widely metastatic, rapid clinical deterioration
Malignant tumors:
5 yr survival if confined to ovary – 70%
5 yr survival if involving peritoneum – 25%
Borderline tumors:
5 yr survival if confined to ovary – 100% - but may recur after many
years
5 yr survival if involving peritoneum – 90%
Serous borderline tumor
Increased complexity of the
stromal papillae
Stratification of the
epithelium
Mild nuclear atypia, but
invasion of the stroma is not
seen
Micropapillary pattern –
papillae are long and thin
(“medusa head”)
Thought to be the precursor
to low-grade serous
carcinoma
Serous borderline tumor (low malignantpotential)Low-grade Serous Carcinoma
Low-grade invasive serous carcinomas
frequently merge with areas
morphologically consistent with SBT
Nuclei are uniform, round, or oval with
evenly distributed chromatin with or
without a prominent nucleolus
Typically shows papillary or micropapillary
patterns combined with areas of invasion
into stroma
Should be p53 wild-type/patchy staining
High-grade Serous Carcinoma
More frequently seen than low-grade
Demonstrates a wide range of
morphologic patterns
A consistent feature is enlarged nuclei,
usually with prominent nucleoli and
many mitoses, which are often
abnormal
Nuclei may demonstrate bizarre
morphology
p53 staining will be either strongly and
diffusely positive or completely
negative
Mucinous tumors
Mucinous tumors account for 20-25% of all ovarian neoplasms
Occur in middle adult life
Majority are benign or borderline tumors, most are unilateral
KRAS proto-oncogene mutation found in benign, borderline, &
malignant mucinous tumors
Pseudomyxoma peritonei:
Characterized by extensive mucinous ascites, cystic epithelial
implants on peritoneal surfaces, adhesions, and bilateral ovarian
involvement
Most cases are due to an appendiceal mucinous neoplasm (not
primary ovarian mucinous tumor), which is involving the bilateral
ovaries
Mucinous Borderline Tumor
Demonstrate epithelial
stratification, tufting, and/or
papillary intraglandular growth
Mucinous Carcinoma
Characterized by expansile
(confluent) or infiltrative
types
Expansile growth – back to
back glands and cysts with
little intervening stroma which
appear to be invading into
stroma across a broad,
demarcated front
Infiltrative growth - glands,
sheets, or single epithelial
cells haphazardly invade the
stroma
Mucinous Tumors
Approximate 10-yr survival rate for stage I invasive malignant
mucinous tumors is approximately 90%
Mucinous tumors that have spread beyond the ovary – usually
fatal
Need to distinguish from metastatic tumor to ovary
Endometrioid Ovarian Tumors
Less common than serous or mucinous ovarian tumor, but 10-15% of all
ovarian cancers
15-20% coexist with endometriosis
15-30% coexist with endometrial endometrioid carcinoma → thought to
represent 2 separate tumors rather than metastasis
Molecular profile similar to endometrial endometrioid carcinoma
PI3K/AKT pathway increased signaling through mutations in PTEN, PIK3CA,
ARID1A, and KRAS
Mismatch repair genes mutations
CTNNB1 (beta catenin)
Endometrioid Carcinoma
Cystic and solid tumors
40% are bilateral
Appearance is similar to endometrioid
carcinoma of endometrium, but can have
multiple different histologic patterns
5-year survival rate for Stage I tumors is 75%
Clear cell carcinoma
Presently thought to be variant of endometrioid carcinoma (a/wendometriosis or ovarian endometrioid carcinoma)
Molecular profile similar to endometrial endometrioidcarcinoma (PIK3CA, ARID1A, KRAS, PTEN, and TP53 mutations)
5-yr survival: Confined to the ovaries (about 40% of tumors) –90%, Advanced stage – poor prognosis (~20%)
Rarely, they may give rise to paraneoplastic hypercalcemia
Transitional cell tumors (Brenner tumors)
Usually benign
Neoplastic epithelium
resembles urothelium
About 10% of epithelial tumors -
often incidental finding
Can rarely be malignant
Can be associated with other
tumors in the ovary (mucinous
cystadenoma)
Microscopic: fibrous stroma
resembling ovarian stroma with
demarcated nests of bland,
transitional type epithelium
Clinical course, detection, & prevention
of ovarian epithelial tumors
Most women with ovarian carcinoma present with high-stage disease
Signs/symptoms: lower abdominal pain, abdominal enlargement, GI complaints,
urinary frequency, pelvic pressure
Ovarian capsular rupture → peritoneal seeding; tumor nodules on serosal surfaces →
ascites
Metastasis: regional lymph nodes, liver, lungs, GI tract
High stage at clinical presentation → poor prognosis
Tumor biochemical tests for early diagnosis still n/a
CA-125 serum marker → used in patients with known dz for disease monitoring
Germ Cell Tumors
Includes:
Teratoma
Dysgerminoma
Yolk Sac Tumor
Choriocarcinoma
Others
Germ Cell Tumors
25% of all ovarian tumors
All occur in premenopausal age
95% of germ cell tumors are benign cystic teratomas
(dermoid cysts)
5% are exactly like testicular counterpart
Testicular seminoma = Ovarian dysgerminoma
AFP, HCG tumor markers
Ovarian Teratoma Common benign ovarian tumor in young adult female
Contain tissues from 3 germ layers: ectoderm (predominant), mesoderm, endoderm
Rare fetiform teratoma (Homunculus)
Mostly cystic, benign, ectoderm dominant
Rarely benign, solid → “monodermal” (e.g. carcinoid tumor; struma ovarii[benign thyroid tissue])
May rarely be malignant:
1% will undergo malignant transformation of a component – squamous cell carcinoma most common
Immature (fetal) teratoma (like testicular teratoma)
Mixed with other malignant germ cell components
Teratomas
Ovary
Mostly benign
Mature tissue
Mostly cystic
Mostly pure tumor
46,XX most common
karyotype
Testis
Mostly malignant
Immature fetal tissue
Mostly solid
Mixed with other germ
cell tumors
Aneuploid
Mature Cystic Teratoma
Mature Cystic Teratoma
Monodermal Teratoma
Most common:
Struma ovarii – teratoma composed
entirely of mature thyroid tissue
May be functional and cause
hyperthyroidism
Ovarian carcinoid – carcinoid tumor
supposedly arising from intestinal
tissue in teratoma
May be functional and can produce
5-hydroxytryptamine sufficient
enough to cause carcinoid syndrome
Only about 2% of ovarian carcinoids
metastasize
Immature Malignant Teratomas
Rare, contain tissues resembling embryonal and
immature fetal tissue - immature
neuroectodermal epithelium
Usually in young patients (~18 yrs)
Dysgerminoma
Ovarian counterpart to testicular seminoma
Represent 2% of ovarian cancers and 50% of
malignant ovarian tumors
75% occur within the second and third decades
80-90% are unilateral
Gross: Can present as a large, fleshy tumor with
solid yellow-white cut surface
Micro: Composed of large vesicular cells with
clear cytoplasm, well-defined cell boundaries,
and centrally-placed, regular nuclei
Tumors grow in sheets separated by fibrous
stroma with mature lymphocytes
Dysgerminoma
All dysgerminomas are malignant
Responsive to chemotherapy if spread
outside of the ovary
Unilateral tumor confined to the ovary has
up to 96% cure rate after salpingo-
oophorectomy
YOLK SAC TUMOR. WITH ALFA FETOPROTEIN (PINK BLOBS)
AFP (pink blob)Yolk sac tumor(Endodermal sinus tumor)
Schiller-Duval body
Second most common malignant germ cell tumor
Derived from malignant germ cells that are differentiating along the extraembryonic yolk sac lineage
Tumors produce α-fetoprotein
Schiller-Duval body – glomerulus-like structure composed of a central blood vessel enveloped by tumor cells within a space that is also surrounded by tumor cells
Demonstrate intracellular and extracellular material, some of which stain for α-fetoprotein by immunohistochemistry
Choriocarcinoma
Aggressive malignancy – usually presents
with metastasis to lungs, liver, and bone
and other sites at the time of diagnosis.
Most exist in combination with other
tumors
Resemble cytotrophoblast and
syncitiotrophoblast cells from placenta
Tumors produce high levels of chorionic
gonadotrophins, which may be helpful in
establishing the diagnosis or detecting
recurrences
Choriocarcinoma arising primarily from
the ovary (an not arising in a placenta) –
unresponsive to chemotherapy and often
fatal
Other Germ Cell Tumors Embryonal Carcinoma – highly malignant tumor of primitive
embryonal elements
Polyembryoma – embryonal tumor containing predominately
embryoid bodies
Mixed germ cell tumors – contain various combinations of
teratoma, yolk sac, and choriocarcinoma
Sex Cord Stromal Tumors
Tumors derived from ovarian stroma, which is derived from the embryonic gonad
Undifferentiated gonadal mesenchyme produces –Sertoli and Leydig cells in males and granulosaand theca cells in female
Tumors produced from these cells are often functional, and can produce masculinizing and feminizing effects in the patient due to androgen and estrogen production
Granulosa cell tumor (GCT)
Tumor cells resembele granulosa cells of a developing ovarian follicle
Classified as Adult GCT (95% of GCTs) or Juvenile GCT based on age of
patient and histologic characteristics of tumor
2/3rds in postmenopausal women
Clinical importance:
Estrogenic →
Young pts: precocious puberty
Adult pts: proliferative breast disease, endometrial
hyperplasia, endometrial carcinoma
Act as a low grade/indolent malignancy →
5-25% risk of malignancy
Malignancy carries risk of relapses 10-20 years after removal
Granulosa Cell Tumor
Tumors are associated with
increased serum levels of inhibin –
which is also seen associated with
other sex cord stromal tumors
Up to 97% of adult granulosa cell
tumors have been shown to
demonstrate FOXL2 gene
mutations
FOXL2 encodes a factor
important in granulosa cell
development
,
COMBINED LEYDIG (L) AND SERTOLI CELL(S) TUMOR,OVARY
L
S
CRYSTALLOID OF REINKE (ARROW) IN LEYDIG CELL TUMOR
Sertoli-Leydig
Cell Tumors
Generally functional tumors,
can produce masculinization
or defeminization, rarely
estrogenic effects
Demonstrate cells resembling
sertoli and leydig cells, can
show Crystals of Reinke in
leydg cells
50% of tumors demonstrate
mutations in DICER1 gene – a
gene responsible for proper
processing of micro-RNAs
MUCIN POSITIVE (PINK) SIGNET RING CELLS IN
KRUCKENBERG TUMOR (MICRO)
Metastatic tumorsto ovary:
• Breast, Lungs• GI (mucinous)• Endometrial• Leukemia• Lymphoma (eg.Burkitt’s)
“Krukenberg tumor”Bilateral, solid, mucinousSignet ring cellsPrimary: often from stomach
References