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Ovarian Cancer, from Molecular Pathology to the
2014 WHO Classification: What You Need to Know
Valencia, Venezuela 2016
Anaís Malpica, M.D.
Professor
Department of Pathology
Contemporary Approach
to Ovarian Cancer
• Ovarian cancer is a heterogeneous
disease
• Each histotype represents a
different disease
• No universal grading can be
applied
Distribution of Ovarian Cancer Histotypes
by Stage
Köbel M, et al.
Int J Gynecol Pathol 2010
• The low grade serous carcinoma
was characterized by:
– Having a uniform, “boring”
appearance
– Protracted clinical course
– Periodically he was running into
additional specimens from
these cases
– Patients were not dead in spite
of large tumor volume
Low Grade Serous Carcinoma Emerged from Empirical
Observations
Dr. Elvio G. Silva created these terms in the
early 80’s when he realized that there were two
types of serous carcinoma
Serous Carcinoma
Binary System (MD Anderson system)
• User friendly
• Reproducible
• Two different groups with differences:
– Molecular level
– Pathogenesis
– Histology
– Immunohistochemistry
– Clinical level
Low Grade Serous Carcinoma
• Definition
– A serous carcinoma characterized by the
presence of uniform cells with mild to
moderate cytologic atypia and usually a low
mitotic index (≤ 12 mitoses per 10 high power
fields)
High Grade Serous Carcinoma
• Definition
– A serous carcinoma characterized by the
presence of pleomorphic cells with marked
nuclear atypia (≥3:1 variation in size and
shape), and a high mitotic index (>12 mitoses
per 10 high power fields)
The MD Anderson Binary System for
Grading Ovarian Serous Carcinoma
• Grade represents an independent prognostic
factor on multivariate analysis
• Good correlation with FIGO and Shimizu-
Silverberg grading systems
• Based on defined criteria
– User friendly
• It involves only two diagnostic categories
– It should provide better reproducibility
Low vs. High Grade Serous Carcinoma,
Reproducibility
• Nine pathologists from
academic centers and private
pathology laboratories
• Overall Kappa statistics: 0.909
• Interobserver Kappa:
• 1st
round: 0.717 to 1.000
• 2nd
round: 0.701 to 1.000
• Intraobserver Kappa:
• 8 pathologists: 0.775 to 1.000
(excellent)
• 1 pathologist: 0.725 (good)
Low vs. High Grade Serous Carcinoma,
Pathology Issues
• Cases with cytologic features difficult to assess
– Perhaps more than moderate atypia, but not sure
about severe atypia
– Check mitotic index
– Immunohistochemical studies
• Ki-67, p16 and p53
• Tumor heterogeneity
– Very rare, be careful with core biopsies
• Pathologist does not follow diagnostic criteria
• Cases with cytologic features difficult to
assess
– Perhaps more than moderate atypia, but not
sure about severe atypia
– Check mitotic index
– Immunohistochemical studies
• Ki-67, p16 and p53
Low vs. High Grade Serous Carcinoma,
Pathology Issues
Ascitic Fluid
Serous LMP with a Cribriform Pattern and
Atypia
Area of Invasion with Marked Atypia and no Mitosis
Ki-67
p53 p16p53
Diagnosis
Low grade serous carcinoma associated
with a serous tumor of LMP (borderline
serous tumor) with a cribriform pattern
Low vs. High Grade Serous Carcinoma
Tumor Heterogeneity
• Rare cases
• To be careful with the presence of
numerous mitoses or the presence of
difficult to assess cytologic atypia in
core biopsies
Low grade appearing areas
High grade carcinoma
Pathologist does not follow diagnostic criteria
High Grade Serous Ca Low Grade Serous Ca
Low vs. High Grade Ovarian Serous Carcinoma-
Histologic Appearance
Differences in :
• Incidence
• Pathogenesis
• Molecular Aspects
• Immunohistochemical
Features
• Clinical Features
• Genetic Risk
Low Grade
High Grade
Ovarian High Grade vs. Low Grade Serous
Carcinoma, Incidence
– High grade serous carcinoma is the most
common type of ovarian carcinoma
– Low grade serous carcinoma
• A rare tumor accounting for less than 10% of
ovarian carcinomas
• Recent review at MDACC (The American Journal
of Surgical Pathology 2015)
– 4.7% of cases (22/471 ovarian carcinoma cases with
primary surgery at MDACC, 1995-2005)
Ekene Okoye, M.D.
Ovarian Low Grade Serous Carcinoma, Association
with Serous Tumor of Low Malignant Potential
• Association with Ovarian Serous
Tumor of Low Malignant Potential
– 60% of cases of low grade serous
carcinoma
Malpica A, et al. 2004
• In a series of 276 cases of ovarian
serous tumor of low malignant
potential and long term follow up (≥
5 years)
– 6.8% of the cases progressed to low
grade serous carcinoma
• Interval: 7 to 288 months (58% ≥ 60
months)
Longacre T, et al. 2005
Deavers MT, et al. 2002
99 cases of advanced stage ovarian serous tumor
of low malignant potential and long term follow up
18 cases
Serous LMP
with MP/CP
81 classic
Serous LMP
cases
14 (78%) cases with
progression or
recurrence
25 (31%) cases with
progression or
recurrence
11 (79%) cases
with low grade
serous carcinoma
17 (68%) cases with
low grade serous
carcinoma
Ovarian High Grade Serous Carcinoma, Association
with Serous Tumor of Low Malignant Potential
Malpica A, et al. 2004
1/50 (2%) case of ovarian high
grade serous carcinoma was
associated with a serous LMP
Low vs. High Grade Serous Carcinoma
Differences in Pathogenesis: Molecular Evidence
Ovarian Tumorigenesis Model
• Type I, tumors that arise in a stepwise manner from
borderline (low malignant potential) tumors
» Low grade serous carcinoma, prototypic type I tumor
» BRAF and KRAS mutations
• Type II (certain cases originate from the fallopian tube
fimbrial end)
» High grade serous carcinoma, prototypic type II tumor
» p53 mutation
Singer G, et al. 2002
Low vs. High Grade Serous Carcinoma
Differences in Pathogenesis: Molecular Evidence
– MDACC experience (Wong KK, et al. Am
J Path 2010)
• Low grade serous carcinoma, KRAS
mutation
• High grade serous carcinoma, p53
mutation
Current Proposals to Explain the Origin of High Grade Serous
Carcinoma
• The fallopian tube = site of
origin of ovarian carcinoma
• Proposed > 50 years
ago in an effort to
explain the presence of
serous tumors in the
ovary
• More recently, Dr. Crum
and his group have
worked extensively to
support this theory
Current Proposals to Explain the Origin of High
Grade Serous Carcinoma
• Multicentricity
• Stimulus (most likely hormonal) acts over
uncommited mesenchymal stem cells and
give origin to epithelial structures that
eventually will turn into a neoplasm
• Animal studies with guinea pigs (Silva EG, et al
1998)
• P53 immunoreactivity is not sufficiently specific
or sensitive to predict p53 mutations
• Low grade serous carcinoma
– Up to 8% can show p53 mutation
• High grade serous carcinoma
– Some cases lack aberrant expression of p53
by IHC (8%)
• Wild type p53 expression has been linked to worse
outcome
– Approximately 97 % of cases show p53
mutation
– Some cases that show no mutation arise in
the background of low grade serous carcinoma
Singer G, et al. 2005
Ahmed AA, et al. 2010
Mc Alpine JN, et al. 2012
P53 and Serous Carcinoma
Two distinct patterns of p53 expression
LG HG
High Grade Serous Carcinoma
 EGFR, p53, bcl-2, and c-Kit
Low Grade Serous Carcinoma
 Hormone receptors
 e-cadherin
Low vs. High Grade Serous Carcinoma
Immunohistochemical Differences
Brustmann H, 2008; O’Neill CJ, et al. 2005
Wong KK, et al. 2007
Low Grade vs. High Grade Ovarian Serous
Carcinoma : Genetic Risk
• BRCA1/2 mutations have been found in cases of
ovarian high grade serous carcinoma
• A rare case of ovarian low grade serous
carcinoma has been reported to have BRCA1
mutation
Maurac I, et al. 2012
Kobel M, et al. 2008
Low vs. High Grade Serous Carcinoma:
Differences in Biologic Behavior
– Patients with low grade serous carcinoma
have a longer overall survival than patients
with high grade serous carcinoma
– Lesser response to conventional platinum
based therapy
– Patients with low grade serous carcinoma
are younger and have a better survival than
patients with high grade serous carcinoma
Gershenson DM, et al. 2006
Plaxe SC. 2008
• MEK inhibitors (GOG 0239)
• BRAF inhibitors
• mTOR/PI3K/AKT inhibitors
• Anti-angiogenesis agents
• IGF1R inhibitors
Targeted Agents
Endometrioid Carcinoma
Grade 1 : less than 5%
of solid component
Grade 2 : 6 to 50% of solid
component
Grade 3 : more than 50% of
solid component
Endometrioid Carcinoma
• Survival of patients with grade 1 and 2
tumors is better that the one for patients
with grade 3 tumors
Kline RC et al, 1990
Endometrioid Carcinoma
• Somatic mutations of the beta-catenin(CTNNB1)
and PTEN genes are the most common genetic
abnormalities in these tumors
• Compared with uterine endometrioid
carcinomas, they show similar frequency of
beta-catenin abnormalities but lower rate of
microsatellite instability and PTEN alterations
Endometrioid Carcinoma
• Beta-catenin mutations (seen in 38% to
50% of the cases) are associated with:
– squamous differentiation
– low tumor grade
– favorable outcome
Endometrioid Carcinoma
• Type of ovarian cancer with the most
favorable prognosis
– Lower grade
– Lower stage
– Responsiveness to chemotherapy
Clear Cell Carcinoma
Discrepancy between the degree of atypia and the mitotic index
Clear Cell Carcinoma
• 10% of ovarian cancers
• Up to 50 % of cases associated with
endometriosis
• Higher frequency of thromboembolic
complications and hypercalcemia (compared to
HGSCa)
• Low-stage outcome better than stage matched
HGSCa
• High-stage outcome worse than stage matched
HGSCa
Clear Cell Carcinoma
• Approximately 50% of the cases carry AR1D1A
mutations and lack BAF250 protein
• High rate of PIK3CA mutations
• Low rate of p53 mutations
• Low rate of KRAS, BRAF, PTEN mutations
• Immunohistochemical Studies
– HNF1-beta is positive in more than 90% of the cases
– Usually negative for WT-1, estrogen and
progesterone receptors
– P53 wild pattern
Glypican 3 HNF-1β
Clear Cell Carcinoma
Immunohistochemical Profile
Napsin-A
ER ER
p53 WT1
p16 PAX8
MLH1
Lynch Screening in the Ovary
• Clear cell
carcinoma
• Endometrioid
carcinoma
PMS2
MSH2MSH6
Microinvasive Mucinous Carcinoma
• Focus of invasion into
the stroma < 5mm in
greatest linear extent
• Marked cytologic
atypia within the
invasive focus
WHO 2014
Microinvasive
Carcinoma
Microinvasive Mucinous Carcinoma
• Experience is limited
• Rare cases have been reported with
recurrences cause of death
Nomura K, Aizawa S, Cancer 2000
Khunamornpong S. et al, Int J Gynecol Path 2011
WHO 2014
Mucinous Carcinoma
• Uncommon tumor
• Accounts for less than 5% of the
mucinous neoplasms of the ovary
• Frequently, metastatic mucinous
carcinomas to the ovary are diagnosed as
an ovarian primary
Mucinous Carcinoma
• Most cases are stage I
• Advanced stage cases have been
shown to have
– a lower response rate to platinum-based
chemotherapy
– a poorer prognosis
when compared with serous carcinoma
Mucinous Carcinoma
– Cases that grossly appear to be
confined to the ovary tend to have
negative lymph nodes
• This finding suggests that routine
lymphadenectomy may be omitted in
these patients
Schmeler K, et al. 2010
Mucinous Carcinoma
• Non-invasive (intraepithelial)
• Invasive
Non-invasive (Intraepithelial)
Mucinous Carcinoma
• Behavior
–Risk of recurrence for stage I cases:
5.8%
Invasive Mucinous
Carcinoma
• Expansive or Confluent
Type
• Confluent glandular
growth measuring
more than 5 mm
(Hopkins) or more
than 10 mm2
(WHO)
Invasive Mucinous
Carcinoma
– Infiltrative Type
• Small glands, cells
clusters or individual
cells in the stroma
measuring more than 5
mm (Hopkins) or more
than 10 mm2
(WHO)
Ker20 Ker7 SATB2
Mucinous carcinoma of the ovary:
keratin 7 +++, keratin 20 ++, PAX-8 +/-, CDX2 +, HR -
Metastatic colorectal adenocarcinoma to the ovary
Mucinous Carcinoma
–Invasive Carcinoma
• 5 year survival = 91% for stage I cases
– Advanced stage disease cases, all die of
disease (Riopel MA, et al. 1999)
• Infiltrative invasion appears to be more
aggressive than the expansile type
(Lee KR, and Scully RE. 2000;
Rodriguez IM, and Prat J. 2002)
Molecular Alterations in
Ovarian Mucinous Carcinoma
Molecular Alteration Ovarian Mucinous Carcinoma
MSI-H 22%
KRAS mutation 43%
BRAF mutation 0%
HER2 amplification 18%
APC or CTNNB1 mutations 9%
TP53 mutations 26%
Kelemen LE, Köbel M. 2011
Histotyping Pitfalls
• Endometrioid carcinoma with mucinous
metaplasia is the tumor usually seen in
the context of a seromucinous borderline
tumor
• Seromucinous carcinoma arising in an
endocervical type (seromucinous)
borderline ovarian tumor is an extremely
rare tumor
Endometrioid Carcinoma with Mucinous Metaplasia
Seromucinous Carcinoma
Arising in a Mucinous LMP,
Endocervical Type is an
Extremely rare tumor
Transitional Cell Pattern
• It can be seen in serous or
endometrioid carcinomas
• It was originally described as a
pattern related to a better response
to chemotherapy
• More recently associated with tumors
detected in patient with BRCA
mutations
FIGURE. Transitional cell carcinoma
of the ovary is composed of
multilayered papillae (A). High-grade
cytologic features can be seen on
higher power (B) as well as foci of
necrosis. ER (C) and WT1 (D)
immunostains are both positive.
FIGURE 1. Ribbon-like
growth patterns simulating
TCC, arising from cyst wall
(A); showing fusion (B),
interanastomoses (C),
glandular architecture (D).
Malignant Brenner Tumor
Gertrude Goldschmidt
(1912 –1994) also known as Gego

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Malpica ovarian cancer, Venezuela 2016

  • 1. Ovarian Cancer, from Molecular Pathology to the 2014 WHO Classification: What You Need to Know Valencia, Venezuela 2016 Anaís Malpica, M.D. Professor Department of Pathology
  • 2.
  • 3. Contemporary Approach to Ovarian Cancer • Ovarian cancer is a heterogeneous disease • Each histotype represents a different disease • No universal grading can be applied
  • 4. Distribution of Ovarian Cancer Histotypes by Stage Köbel M, et al. Int J Gynecol Pathol 2010
  • 5. • The low grade serous carcinoma was characterized by: – Having a uniform, “boring” appearance – Protracted clinical course – Periodically he was running into additional specimens from these cases – Patients were not dead in spite of large tumor volume Low Grade Serous Carcinoma Emerged from Empirical Observations Dr. Elvio G. Silva created these terms in the early 80’s when he realized that there were two types of serous carcinoma
  • 6. Serous Carcinoma Binary System (MD Anderson system) • User friendly • Reproducible • Two different groups with differences: – Molecular level – Pathogenesis – Histology – Immunohistochemistry – Clinical level
  • 7. Low Grade Serous Carcinoma • Definition – A serous carcinoma characterized by the presence of uniform cells with mild to moderate cytologic atypia and usually a low mitotic index (≤ 12 mitoses per 10 high power fields)
  • 8.
  • 9.
  • 10. High Grade Serous Carcinoma • Definition – A serous carcinoma characterized by the presence of pleomorphic cells with marked nuclear atypia (≥3:1 variation in size and shape), and a high mitotic index (>12 mitoses per 10 high power fields)
  • 11.
  • 12.
  • 13.
  • 14. The MD Anderson Binary System for Grading Ovarian Serous Carcinoma • Grade represents an independent prognostic factor on multivariate analysis • Good correlation with FIGO and Shimizu- Silverberg grading systems • Based on defined criteria – User friendly • It involves only two diagnostic categories – It should provide better reproducibility
  • 15. Low vs. High Grade Serous Carcinoma, Reproducibility • Nine pathologists from academic centers and private pathology laboratories • Overall Kappa statistics: 0.909 • Interobserver Kappa: • 1st round: 0.717 to 1.000 • 2nd round: 0.701 to 1.000 • Intraobserver Kappa: • 8 pathologists: 0.775 to 1.000 (excellent) • 1 pathologist: 0.725 (good)
  • 16. Low vs. High Grade Serous Carcinoma, Pathology Issues • Cases with cytologic features difficult to assess – Perhaps more than moderate atypia, but not sure about severe atypia – Check mitotic index – Immunohistochemical studies • Ki-67, p16 and p53 • Tumor heterogeneity – Very rare, be careful with core biopsies • Pathologist does not follow diagnostic criteria
  • 17. • Cases with cytologic features difficult to assess – Perhaps more than moderate atypia, but not sure about severe atypia – Check mitotic index – Immunohistochemical studies • Ki-67, p16 and p53 Low vs. High Grade Serous Carcinoma, Pathology Issues
  • 19. Serous LMP with a Cribriform Pattern and Atypia
  • 20. Area of Invasion with Marked Atypia and no Mitosis
  • 21. Ki-67
  • 23. Diagnosis Low grade serous carcinoma associated with a serous tumor of LMP (borderline serous tumor) with a cribriform pattern
  • 24. Low vs. High Grade Serous Carcinoma Tumor Heterogeneity • Rare cases • To be careful with the presence of numerous mitoses or the presence of difficult to assess cytologic atypia in core biopsies
  • 27. Pathologist does not follow diagnostic criteria High Grade Serous Ca Low Grade Serous Ca
  • 28. Low vs. High Grade Ovarian Serous Carcinoma- Histologic Appearance Differences in : • Incidence • Pathogenesis • Molecular Aspects • Immunohistochemical Features • Clinical Features • Genetic Risk Low Grade High Grade
  • 29. Ovarian High Grade vs. Low Grade Serous Carcinoma, Incidence – High grade serous carcinoma is the most common type of ovarian carcinoma – Low grade serous carcinoma • A rare tumor accounting for less than 10% of ovarian carcinomas • Recent review at MDACC (The American Journal of Surgical Pathology 2015) – 4.7% of cases (22/471 ovarian carcinoma cases with primary surgery at MDACC, 1995-2005) Ekene Okoye, M.D.
  • 30. Ovarian Low Grade Serous Carcinoma, Association with Serous Tumor of Low Malignant Potential • Association with Ovarian Serous Tumor of Low Malignant Potential – 60% of cases of low grade serous carcinoma Malpica A, et al. 2004 • In a series of 276 cases of ovarian serous tumor of low malignant potential and long term follow up (≥ 5 years) – 6.8% of the cases progressed to low grade serous carcinoma • Interval: 7 to 288 months (58% ≥ 60 months) Longacre T, et al. 2005
  • 31. Deavers MT, et al. 2002 99 cases of advanced stage ovarian serous tumor of low malignant potential and long term follow up 18 cases Serous LMP with MP/CP 81 classic Serous LMP cases 14 (78%) cases with progression or recurrence 25 (31%) cases with progression or recurrence 11 (79%) cases with low grade serous carcinoma 17 (68%) cases with low grade serous carcinoma
  • 32. Ovarian High Grade Serous Carcinoma, Association with Serous Tumor of Low Malignant Potential Malpica A, et al. 2004 1/50 (2%) case of ovarian high grade serous carcinoma was associated with a serous LMP
  • 33. Low vs. High Grade Serous Carcinoma Differences in Pathogenesis: Molecular Evidence Ovarian Tumorigenesis Model • Type I, tumors that arise in a stepwise manner from borderline (low malignant potential) tumors » Low grade serous carcinoma, prototypic type I tumor » BRAF and KRAS mutations • Type II (certain cases originate from the fallopian tube fimbrial end) » High grade serous carcinoma, prototypic type II tumor » p53 mutation Singer G, et al. 2002
  • 34. Low vs. High Grade Serous Carcinoma Differences in Pathogenesis: Molecular Evidence – MDACC experience (Wong KK, et al. Am J Path 2010) • Low grade serous carcinoma, KRAS mutation • High grade serous carcinoma, p53 mutation
  • 35. Current Proposals to Explain the Origin of High Grade Serous Carcinoma • The fallopian tube = site of origin of ovarian carcinoma • Proposed > 50 years ago in an effort to explain the presence of serous tumors in the ovary • More recently, Dr. Crum and his group have worked extensively to support this theory
  • 36. Current Proposals to Explain the Origin of High Grade Serous Carcinoma • Multicentricity • Stimulus (most likely hormonal) acts over uncommited mesenchymal stem cells and give origin to epithelial structures that eventually will turn into a neoplasm • Animal studies with guinea pigs (Silva EG, et al 1998)
  • 37. • P53 immunoreactivity is not sufficiently specific or sensitive to predict p53 mutations • Low grade serous carcinoma – Up to 8% can show p53 mutation • High grade serous carcinoma – Some cases lack aberrant expression of p53 by IHC (8%) • Wild type p53 expression has been linked to worse outcome – Approximately 97 % of cases show p53 mutation – Some cases that show no mutation arise in the background of low grade serous carcinoma Singer G, et al. 2005 Ahmed AA, et al. 2010 Mc Alpine JN, et al. 2012 P53 and Serous Carcinoma
  • 38. Two distinct patterns of p53 expression LG HG
  • 39. High Grade Serous Carcinoma  EGFR, p53, bcl-2, and c-Kit Low Grade Serous Carcinoma  Hormone receptors  e-cadherin Low vs. High Grade Serous Carcinoma Immunohistochemical Differences Brustmann H, 2008; O’Neill CJ, et al. 2005 Wong KK, et al. 2007
  • 40.
  • 41. Low Grade vs. High Grade Ovarian Serous Carcinoma : Genetic Risk • BRCA1/2 mutations have been found in cases of ovarian high grade serous carcinoma • A rare case of ovarian low grade serous carcinoma has been reported to have BRCA1 mutation Maurac I, et al. 2012 Kobel M, et al. 2008
  • 42. Low vs. High Grade Serous Carcinoma: Differences in Biologic Behavior – Patients with low grade serous carcinoma have a longer overall survival than patients with high grade serous carcinoma – Lesser response to conventional platinum based therapy – Patients with low grade serous carcinoma are younger and have a better survival than patients with high grade serous carcinoma Gershenson DM, et al. 2006 Plaxe SC. 2008
  • 43. • MEK inhibitors (GOG 0239) • BRAF inhibitors • mTOR/PI3K/AKT inhibitors • Anti-angiogenesis agents • IGF1R inhibitors Targeted Agents
  • 44. Endometrioid Carcinoma Grade 1 : less than 5% of solid component Grade 2 : 6 to 50% of solid component Grade 3 : more than 50% of solid component
  • 45. Endometrioid Carcinoma • Survival of patients with grade 1 and 2 tumors is better that the one for patients with grade 3 tumors Kline RC et al, 1990
  • 46. Endometrioid Carcinoma • Somatic mutations of the beta-catenin(CTNNB1) and PTEN genes are the most common genetic abnormalities in these tumors • Compared with uterine endometrioid carcinomas, they show similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations
  • 47. Endometrioid Carcinoma • Beta-catenin mutations (seen in 38% to 50% of the cases) are associated with: – squamous differentiation – low tumor grade – favorable outcome
  • 48. Endometrioid Carcinoma • Type of ovarian cancer with the most favorable prognosis – Lower grade – Lower stage – Responsiveness to chemotherapy
  • 50. Discrepancy between the degree of atypia and the mitotic index
  • 51. Clear Cell Carcinoma • 10% of ovarian cancers • Up to 50 % of cases associated with endometriosis • Higher frequency of thromboembolic complications and hypercalcemia (compared to HGSCa) • Low-stage outcome better than stage matched HGSCa • High-stage outcome worse than stage matched HGSCa
  • 52. Clear Cell Carcinoma • Approximately 50% of the cases carry AR1D1A mutations and lack BAF250 protein • High rate of PIK3CA mutations • Low rate of p53 mutations • Low rate of KRAS, BRAF, PTEN mutations • Immunohistochemical Studies – HNF1-beta is positive in more than 90% of the cases – Usually negative for WT-1, estrogen and progesterone receptors – P53 wild pattern
  • 53. Glypican 3 HNF-1β Clear Cell Carcinoma Immunohistochemical Profile Napsin-A
  • 56. MLH1 Lynch Screening in the Ovary • Clear cell carcinoma • Endometrioid carcinoma PMS2 MSH2MSH6
  • 57. Microinvasive Mucinous Carcinoma • Focus of invasion into the stroma < 5mm in greatest linear extent • Marked cytologic atypia within the invasive focus WHO 2014
  • 59. Microinvasive Mucinous Carcinoma • Experience is limited • Rare cases have been reported with recurrences cause of death Nomura K, Aizawa S, Cancer 2000 Khunamornpong S. et al, Int J Gynecol Path 2011 WHO 2014
  • 60. Mucinous Carcinoma • Uncommon tumor • Accounts for less than 5% of the mucinous neoplasms of the ovary • Frequently, metastatic mucinous carcinomas to the ovary are diagnosed as an ovarian primary
  • 61. Mucinous Carcinoma • Most cases are stage I • Advanced stage cases have been shown to have – a lower response rate to platinum-based chemotherapy – a poorer prognosis when compared with serous carcinoma
  • 62. Mucinous Carcinoma – Cases that grossly appear to be confined to the ovary tend to have negative lymph nodes • This finding suggests that routine lymphadenectomy may be omitted in these patients Schmeler K, et al. 2010
  • 63. Mucinous Carcinoma • Non-invasive (intraepithelial) • Invasive
  • 64.
  • 65. Non-invasive (Intraepithelial) Mucinous Carcinoma • Behavior –Risk of recurrence for stage I cases: 5.8%
  • 66. Invasive Mucinous Carcinoma • Expansive or Confluent Type • Confluent glandular growth measuring more than 5 mm (Hopkins) or more than 10 mm2 (WHO)
  • 67. Invasive Mucinous Carcinoma – Infiltrative Type • Small glands, cells clusters or individual cells in the stroma measuring more than 5 mm (Hopkins) or more than 10 mm2 (WHO)
  • 68. Ker20 Ker7 SATB2 Mucinous carcinoma of the ovary: keratin 7 +++, keratin 20 ++, PAX-8 +/-, CDX2 +, HR - Metastatic colorectal adenocarcinoma to the ovary
  • 69. Mucinous Carcinoma –Invasive Carcinoma • 5 year survival = 91% for stage I cases – Advanced stage disease cases, all die of disease (Riopel MA, et al. 1999) • Infiltrative invasion appears to be more aggressive than the expansile type (Lee KR, and Scully RE. 2000; Rodriguez IM, and Prat J. 2002)
  • 70. Molecular Alterations in Ovarian Mucinous Carcinoma Molecular Alteration Ovarian Mucinous Carcinoma MSI-H 22% KRAS mutation 43% BRAF mutation 0% HER2 amplification 18% APC or CTNNB1 mutations 9% TP53 mutations 26% Kelemen LE, Köbel M. 2011
  • 71. Histotyping Pitfalls • Endometrioid carcinoma with mucinous metaplasia is the tumor usually seen in the context of a seromucinous borderline tumor • Seromucinous carcinoma arising in an endocervical type (seromucinous) borderline ovarian tumor is an extremely rare tumor
  • 72. Endometrioid Carcinoma with Mucinous Metaplasia
  • 73. Seromucinous Carcinoma Arising in a Mucinous LMP, Endocervical Type is an Extremely rare tumor
  • 74. Transitional Cell Pattern • It can be seen in serous or endometrioid carcinomas • It was originally described as a pattern related to a better response to chemotherapy • More recently associated with tumors detected in patient with BRCA mutations
  • 75.
  • 76. FIGURE. Transitional cell carcinoma of the ovary is composed of multilayered papillae (A). High-grade cytologic features can be seen on higher power (B) as well as foci of necrosis. ER (C) and WT1 (D) immunostains are both positive.
  • 77. FIGURE 1. Ribbon-like growth patterns simulating TCC, arising from cyst wall (A); showing fusion (B), interanastomoses (C), glandular architecture (D).
  • 78.

Editor's Notes

  1. s16-51345 CCa p16_1730.jpg
  2. S15-94804 mucinous tumor in ovary origin K20_1013.jpg