Serous Carcinogenesis, the Salpinx and the Surgical Pathologist

Serous Carcinogenesis, the Salpinx and the
Surgical Pathologist
Christopher P. Crum, MD
Division of Women’s and Perinatal Pathology
Brigham and Women’s Hospital
and Harvard Medical School
www.obgynpath.org
Pathogenesis
HPV-related neoplasms: Monoclonal
selection and pre-cursor definition is
concurrent with HPV infection
The pathologist can diagnose the
precursor and dictate management
designed to reduce cancer risk
Pathogenesis
Endometrial and upper genital tract
neoplasia : Clonal selection may
predate or occur in the absence of
morphologic changes that can be
characterized as neoplasia
The pathologist may or may not be able
to identify the “precursor”
Premise
• Malignancies are preceded by
precursors
• Prevention of precursors interrupts the
pathway to malignancy
• Precursor prevention/intervention is
more efficient than managing late-stage
malignancy
Terminology and its Significance
• Dysplasia or intraepithelial neoplasia is
recognizable and not capable of
metastasizing.
• Latent precursors may not be
recognizable and are not capable of
metastasizing
• Intraepithelial carcinomas are noninvasive but capable of spread
Model Systems in the Upper FGT
• Endometrium
– Latent precursors (PTEN null glands)
– EIN – non invasive, not malignant
– SEIC – non invasive malignant
– EGD – non invasive, presumably not
malignant
• Fallopian tube
– P53 signature – latent precursor
– STIC – non invasive, malignant
– Lesions in transition - unclear
Outline
• Rationale for serous carcinogenesis in the
fallopian tube
• Tubal intraepithelial carcinoma
• Latent precursors (p53 signature)
• Intermediate lesions
• Management decisions
The Pathogenesis of Ovarian Cancer
• Epithelial source
– Mesothelial to mullerian transformation
theory
– Transport theory (fallopian tube or
endometrium)
• Molecular pathways
– Slow transitions involving multiple genes,
including KRAS/BRAF, pTEN, beta-catenin,
APC (Type 1)
– Rapid transitions involving p53,c-myc
mutations (Type 2)
Shih and Kurman 2005
Proposed Origin of Mullerian
Transformation
• Assumes the ovarian surface
undergoes mullerian metaplasia with
development of inclusions.
• The inclusions evolve to acquire the
tubal or endometrioid phenotype
• Tumors arising from these inclusions
reflect this or similar phenotypes
Cortical Inclusion Cysts
High Grade Serous Carcinoma
•
•
•
•
Appears to develops rapidly.
Involves the ovarian surface.
Intra-peritoneal metastases.
Origin often unclear
High Grade Serous Carcinoma
Origin of High Grade Serous
Carcinomas and the Ovary
• Most are not associated with an
endometriotic cyst or pre-existing cystoma
• Early serous carcinoma initiating in the
ovarian cortex is rarely demonstrated.
– Bell and Scully – 14 cases of microscopic cortical
carcinoma (precursor in 3)
– Barakat et al – Did not detect any early
(intraepithelial) carcinomas in the ovaries of
BRCA+ women.
• Encouraged the concept of an origin from the
ovarian surface epithelium or peritoneum
(primary peritoneal carcinoma)
BRCA as a Model for Early Ovarian
Cancer
Opportunity to evaluate the tubes and ovaries
in women who undergo prophylactic
salpingo-oophorectomy
and detect tumors early in their course
Colgan 2001, Leeper 2002, Powell 2005, Finch 2005, Cass 2005, Medeiros 2006
Distribution of Early Serous Carcinoma
in BRCA+ Women
Author
Leeper ’02
Powell ’05
No. Tumor(%)
30
67
5(17)
7(10)
Tubal (% tumors)
3(60)
4 (57)
SEE-FIM Protocol
• Sectioning and extensively examining
the fimbriated end
• Based on the hypothesis that the
fimbriated end is unique and
susceptible to tubal neoplasia
Medeiros et al 2006
Callahan et al 2007
• Seven consecutive early cancers
detected in BRCA+ patients over a
three year period.
• All were in the fallopian tube
• Six of seven were in the fimbria
• Five of seven were serous
• Two ovaries were involved (surface
implant)
Topography and Immunophenotype of Early tubal Carcinoma
FIM
MIB1
p53
AMP
MIB1
FIM
MIB1
p53
FIM
MIB1
p53
Medeiros et al
Finch et al
Cass et al
Distribution of Early Serous Carcinoma
in BRCA+ Women
Author
No. Tumor(%)
Leeper ’02
30
Powell ’05
67
Finch ’06
159
Medeiros ’05 120
and Callahan ‘07
5(17)
7(10)
7(4)
7(5.5)
Tubal (% tumors)
3(60)
4 (57)
6 (86)
7 (100)
“Primary Peritoneal” Serous Carcinoma
Omentum
Tube
Kindelberger et al 2007
Ovarian serous carcinoma associated
with tubal intraepithelial carcinoma (TIC)
“Ovarian” Carcinoma
Coexisting ovarian serous
carcinoma and tubal
intraepithelial carcinoma
that shared identical p53
mutations
Fimbria
TIC Invasion
Endosalpingiosis
Mullerian metaplasia
Endometrial transport
Mullerian
inclusions
Precursor
condition
Carcinoma
Exfoliated tumor cells from
TIC or invasive carcinoma
Surface or invasive
carcinoma
Ovary or
Peritoneum
Pelvic Carcinoma in BRCA+ Women
Symptomatic vs Asymptomatic
100
90
80
70
60
50
40
30
20
10
0
Ovary
FT
Perit
SBRCA ABRCA
Piek ’03
Medeiros ’06
OVCA
K’berger ’07
PPCA
Carlson (unpub)
Routine p53 Immunostaining
• Was initially limited to BRCA+
specimens.
• Employed to identify subtle forms of
tubal intraepithelial carcinoma.
• Revealed focally strong positivity in
normal appearing tubal mucosa.
Tubal Intraepithelial Carcinoma
“p53 Signature”
Intense p53 nuclear accumulation in non-neoplastic tubal mucosa
Proposed as a precursor to pelvic serous carcinoma
Lee, Miron, Drapkin et al, J of Pathol 2007
Parameters
• Location (Fimbria vs proximal tube)
• Cell type (secretory vs. ciliated), using
HMFG2, p73, and LHS28 antibodies.
• DNA damage (γ-H2AX)
• p53 mutations via LCM and direct
sequencing
Lee and Miron et al, J Pathol 2007
Distribution of p53 Signatures
100
90
80
70
60
50
40
30
20
10
0
FTBR
FTNL
OSEBR
CICBR
Cell types in the Fallopian Tube
H&E
HMFG2
LHS28
Lee and Miron et al, J Pathol 2007
p73
P53 Signatures
Identical location
Identical cell type
Localization of γ-H2AX
Evidence that TICs
arise from p53
signatures
p53Sig
BRCA+ Patient
Both entities share the same
p53 mutation
TIC
1004delG (codon 335)
Frameshift mutation
Lee et al 2007
Jarboe et al Poster 921
Serous Carcinogenic Sequence in the Fimbria
Clonal
P53 mutation
Clonal
P53 mutation
+ expansion
Clonal
P53 mutation
+ expansion
+ proliferation
Step I
Step II
Latent precursor
(p53 signature)
H&E
p53
MiB1
Lesion in transition
H&E
p53
Clonal
P53 mutation
+ expansion
+ proliferation
+ loss of polarity
+ exfoliation
Step III
Intraepithelial CA
MiB1
Jarboe et al, 2007 (Int J Gynecol Pathol in press)
H&E
MiB1
Practical Issues in Management
• Detection of latent precursors (p53
signatures), while of interest, is of no
practical value.
• Assigning origin (endometrium vs upper
FGT) may be important in terms of
chemotherapy.
• Detecting and precisely classifying early
serous neoplasia in BRCA+ women will
influence management.
TIC and Serous EIC of the Endometrium
• A small percentage of endometrial
serous carcinomas are associated with
TIC, specifically those with minimal
endometrial disease
• Possible role of the distal tube in the
pathogenesis of superficial serous
carcinomas of the endometrium
Results: p53 – matched EIC and TIC
Jarboe et al 2008
Results: Shared p53 mutations between TICs and
endometrial carcinomas
Epithelium
p53 mutation
Mutation effect
p53 immunostaining
TIC
Normal
None
TIC
818G>A
Arg to His
Endometrial
tumor
818G>A
Arg to His
Normal
None
TIC
430C>T
Gln to Stop
Endometrial
tumor
430C>T
Gln to Stop
Jarboe et al 2008
Endometrium
Results:
Tubal Intraepithelial Carcinoma (TIC) vs. depth
of myometrial invasion
100
Total=17
Depth of myometrial
invasion (%)
90
80
70
60
50
40
30
20
10
Total=5
0
TIC present
TIC absent
BRCA+ Women
• Approximately 5% of mutation-positive
women will harbor an early malignancy in
their prophylactic specimen.
• Most will be located in the distal tube.
• Most will be non-invasive (TIC)
• Examination of ovarian surfaces essential
• Must be distinguished from normal
mucosa.
Spectrum of TIC
• Common variables
– Loss of epithelial cell polarity, fractures,
exfoliation
– Nuclear enlargement, nucleoli
– Homogeneous cell type, absence of cilia
– P53+ (80-90%)
– High MIB1 index
• Variants
– Non-stratified
– Degenerative
Fallopian Tube (TIC)
Papillary
Serous
Carcinoma
TIC
TIC
TIC
TIC
TIC
Normal
TIC
TIC from Patient Previously Treated for Breast CA
Observer Reproducibility for TIC
• For 12 reviewers = 0.333
• For pathology residents= 0.253
• For experienced gynecologic
pathologists = 0.453
• It is highly advisable to corroborate this
diagnosis with another observer
Carlson et al 2008
Normal Salpingeal Mucosa with Secretory and Ciliated Cells
Benign Salpingeal Epithelium
Heterogeneous, normal nuclear morphology
Tubal Intraepithelial Carcinoma
Homogeneous, abnormal nuclear morphology
Combinations of p53/MIB1 Immunostaining
Non-neoplastic
p53
MIB1
Non-neoplastic
p53
MIB1
TIC
p53
MIB1
Problematic Lesions
• Tubal intraepithelial lesions in transition
(TILT).
– Maintenance of pseudo-stratified epithelium
– Mixture of ciliated and secretory cells
– Moderate MIB1 immunoreactivity
– Should be reviewed by more than one
observer if necessary to exclude TIC
– The report should state clearly that the lesion
is or is not diagnostic of TIC
Evidence of Transition
Tubal Intraepithelial Lesion in Transition (TILT)
P53
MiB1
P53 signature (upper)
merging with TIC (lower)
TILT, showing cohesion,
preserved polarity, moderate
MIB1 index
TILT, admixed with ciliated
cells.
Expectations when searching for TIC
• 5% of prophylactic specimens from
BRCA+ women
• Very uncommon in other “high risk”
women without BRCA mutations
• Present in 50% of women with PPSCA or
OVSCA
• Occasionally seen in Uterine SCA
• Exceedingly rare in benign specimens
removed for reasons other than the above
Outcome (Stage I)
• Obermair (2001): 8/20 recurred
• Gaducci (2001): 5/21 recurred
• Hellstrom (200): 7/7 recurred
Outcome (Stage 0 (TIC))
Au
Agoff
Colgan
Carcangiu
Paley
Cyto
Neg
Neg
Neg
Neg
Neg
Pos
Pos
Chemo
Yes
UK
No
No
No
FU
NED 36
NED<12
NED87
NED38
NED7
NED48
NED46
Final Comments
•
•
•
•
•
Prophylactic surgery reduces the risk of serous carcinoma by
approximately 80%
The cumulative risk of recurrence in BRCA+ women following
prophylactic surgery is approximately 4% at 20 years.
The short to intermediate term risk of recurrence following a
diagnosis of TIC appears to be low, provided there is no
invasion and the peritoneal cytology is negative.
The value of treating TIC with negative peritoneal cytology is
unclear.
There is no justification for treating atypias that fall short of a
diagnosis of TIC.
Finch et al 2006, Carcangiu et al 2006
Bibliography
Carcangiu ML et al. Incidental carcinomas in prophylactic specimens in
BRCA1 and BRCA2 germ-line mutation carriers, with emphasis on fallopian
tube lesions. Am J Surg Pathol 2006;30:1222-1230
Colgan TJ. Challenges in the early diagnosis and staging of Fallopian-tube
carcinomas associated with BRCA mutations. Int J Gynecol Pathol.
2003;22:109-20.
Piek JM et al. Dysplastic changes in prophylactically removed Fallopian
tubes of women predisposed to developing ovarian cancer. J Pathol. 2001
Nov;195(4):451-6.
Cass I et al BRCA mutation-associated fallopian tube carcinoma: a distinct
clinical phenotype? Obstet Gynecol. 2005;106:1327-34
Jarboe E et al. Serous carcinogenesis in the fallopian tube: a descriptive
classification.Int J Gynecol Pathol. 2008;27:1-9
Lee Y et al. A candidate precursor to serous carcinoma that originates in the
distal fallopian tube. J Pathol. 2007;211:26-35.