Download Gynecologic Pathology - Department of Obstetrics, Gynecology and

Gynecologic Pathology:
Making Sense of It…
(Or… What [the he*%] Do I
Do With This ??)
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Lichen Sclerosis
• thin, white or red epithelium
– fissures, scar, fusion
•
•
•
•
•
possible autoimmune phenomenon
“continuum”: can see with hyperplasia
classic histology
associated with SCC, but not “premalignant”
Rx: clobetasol (0.05%): best results
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
VIN
• subtypes
– warty: looks like HPV
– basaloid: looks like CIN
– well-differentiated: formerly squamous
hyperplasia
• different mechanisms, epidemiology, Rx, risk
– VIN (basaloid): invasive cancer: 7% (15 yr f/u)
• Rx:
– “squamous hyperplasia”: topical steroids
– VIN: excise (laser ??), follow-up
 possibly imiquimod
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Paget’s Disease
• atypical intraepithelial gland-type cells
• raised red/pink plaque (eczema-like)
• associated adenocarcinoma:
– non-contiguous: 10%-26%
– contiguous: 4%
• Rx: excise
– difficult to achieve negative margins
– 2-3 cm gross margin
• recurrence: 43% with WLE
– 31% with vulvectomy
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Microinvasive SCC of Cervix
• Stage Ia1
– < 3 mm invasion; < 7 mm lateral spread
• lymph-vascular involvement does not change
stage
– < 3mm: not predictive of node involvement or
recurrence
– possibly increased recurrence if 3-5 mm depth
• node involvement:
– < 3 mm: ~ 1%
– 3-5 mm: 2-6%
• Dx: LEEP or CKC
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Margin Status
• CIN
• Ia1
• What to do ???
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Margins
• positive LEEP (CIN):
– increased risk of recurrence (~14% - 69%)
– negative margin: 5% – 25%
– main risk: persistent/recurrent dysplasia
• positive CKC (HGSIL):
– persistence/recurrence: 22%; dysplasia *
 others: 5% - 16%
– cancer: 1.3% (earliest: 3 years)
 others: 0.9% - 1.6% with prolonged follow-up
 if hysterectomy: 0.5% coincidental microinvasion #
• Sum: positive margin – low risk of cancer
(takes years)
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
* Reich D, et al. Obstet Gynecol 2002; 99: 193-196
# Burghardt E, et al. Obstet Gynecol 1980; 55: 539-545
Margins - Microinvasion
• positive margin: 22% risk of residual invasion (50/51
with CIN at margin)
– negative margin: 3%
• If residual invasion after + margin:
– Ia1: 73%
– Ia2: 9%
– Ib: 18%
• other reports of residual invasion: 3% - 21%
– definitions vary
• sum: if invasion and + margin: risk of residual cancer is
substantial
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Roman LD, et al. Obstet Gynecol 1997; 90: 759-764
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Adenocarcinoma
• Treated “one step higher”
– Difficult to discern “early” invasion from AIS
– Difficult to “measure” depth of invasion
 Compared to squamous
– “skip” lesions
• Villoglandular type
– Younger patients; excellent prognosis
– Usually superficially invasive
– Cone biopsy may be sufficient for treatment
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Microinvasive Adenocarcinoma
• Difficult to measure extent of invasion
• More “accepted” outside US
• Criteria:
– ≤ 5 mm invasion
 Tumor thickness, not really depth
– Obliteration of endocervical crypts
– Extension beyond normal glandular area
– Stromal response
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Microinvasive Adenocarcinoma
Review
•
•
•
•
436 patients; 2% node metastases
15 recurrences in 436 patients
21 with cone biopsy; no recurrences
Summary: CKC acceptable if ≤ 5 mm
invasion, - LVS, - margins
• LEEP: not acceptable
Östör AG. Int J Gynecol Pathol 2000; 19: 29-38
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Microinvasive Adenocarcinoma
Conservative Treatment
• Additional series
– Bisseling, et al. (2007): CKC in 18 women
 2 patients with Stage 1A2
 No recurrences with mean F/U of 72 months
– Lee, et al. (2009): CKC in 22 patients
 Secondary procedures in 52% (repeat CKC)
 Microinvasive carcinoma in 2
• Summary: CKC with careful F/U “effective”
– Overall small N …..
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Bisseling KC, et al. Gynecol Oncol 2007; 107: 424-430
Lee SW, et al. Acta Obstet Gynecol Scand 2009; 88: 209-215
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Chronic Endometritis
• key to Dx: plasma cells
• 3 - 10% of AUB
• historical associations:
– abortion: 41%
– salpingitis: 25%
– IUD: 14%
– fibroids: 12%
– hyperplasia/cancer: 1-2%
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Chronic Endometritis
Overall (%)
Salpingitis
2
Postmenopausal
(%)
0
IUD
4
5
Polyps
40
55
Fibroids
28
8
Hyperplasia
9
18
Carcinoma
3
8
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Karney MY, Zahn CM. ACOG-AFD; 1997 (GAVE UP TRYING TO
GET THE DAMN THING PUBLISHED !!)
Endometrial Stromal Breakdown
“ESB”
• “estrogen withdrawal/breakthrough”
• “progesterone withdrawal/breakthrough”
• endometrial stromal breakdown
– estrogen-stimulated, no progestin
stabilization
– common oligo-ovulatory pattern
– focal shedding, AUB
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
ESB
• pathology:
– fragmented proliferative glands
– fragmented proliferative stroma
 key distinction form menstrual pattern
– “stromal balls”
• Rx:
– OCPs
– progestin
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Iatrogenic
• continuous HRT, OCP, injectables
– progestin-dominant
– simple glands
– decidualized stroma, later atrophy
• Rx: usually need estrogen
– biopsy can help
– don’t reflexly change
 “chasing your tail”
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Metaplasia
• tubal
– “ciliated cell change”
– very common; normal and neoplastic
• squamous
– more common in hyperplasia
• eosinophilic
– “syncytial metaplasia”, “papillary surface
metaplasia”
– surface cells with pink cytoplasm
– common in ESB
– no prognostic significance
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Disordered Proliferative
Endometrium
• should be:
– focally dilated, crowded glands
– “focal” simple hyperplasia
• should not be:
– fragmented, breaking down
• often inappropriately used for ESB
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Hyperplasia
• historically: numerous terms
– “cystic”, “Swiss cheese”, “adenomatous”
– later: AIS, EIN
• difficult to compare studies
– lack of uniformity
• International Society of Gynecologic Pathology
and WHO (1994)
– atypical vs non-atypical
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Hyperplasia - Behavior
• classic study
• 170 patients
• followed at least 1 year before
hysterectomy
• mean follow-up: 13.4 years
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Kurman RJ, et al. Cancer 1985; 56: 403-412
Hyperplasia
Architecture
• simple
– increased
gland/stroma
– larger glands
• complex
– back-to-back glands
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Nuclei (Atypia)
• loss of polarity
• increased N/C ratio
• coarse chromatin
– clumping
• prominent nucleoli
Behavior - Progression
N
regressed (%) progressed to
cancer (%)
80
1
simple w/o
93
complex w/o
29
80
3
simple w/
13
69
8
complex w/
35
57
29
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Kurman RJ, et al. Cancer 1985; 56: 403-412
Behavior - Progression
non-atypical
N
progressed to
cancer (%)
122
2
p = .001
atypical
48
23
•duration:
•non-atypical: 10 years
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
•atypical: 4 years
Hyperplasia vs Cancer
Coincidental
• hysterectomy soon after Dx
– not followed as in “progression” studies
• criteria developed to determine
“invasion”
• incidence of cancer at time of
hysterectomy for hyperplasia: 17% –
25%
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Hyperplasia vs Cancer
Criteria
• cribiforming
• desmoplasia (stromal response)
• extensive papillary proliferation
– squamous also considered
• greater than ½ LPF (2.1 mm)
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Kurman RJ, Norris HJ. Cancer 1982; 49: 2547-2559
Hyperplasia vs Cancer
carcinoma
Grade 1
Grade 2
Grade 3
myometrial invasion
inner 1/3
mid/outer 1/3
hyperplasia (%)
N=89
17
100
0
0
47 *
100
0
cancer (%)
N=151
50
66
24
10
72
67
33
* : all < 4 mm
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Kurman RJ, Norris HJ. Cancer 1982; 49: 2547-2559
Hyperplasia vs Cancer
Coincidental
Study
Year
N
Cancer (%)
Gusberg, Kaplan
1963
90
21
Tavassoli, Kraus
1978
98
25
Kurman, Norris
1982
89
17
King, et al
1984
119
15
Janicek,
Rosenshein
1994
44
43
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Hyperplasia vs Cancer
Reproducibility
kappa
proliferative
.86
hyperplasia
.60
AH
.47
WDC
.83
overall
.69
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
• N = 100
• intraobserver
agreement: .67-.85
• main atypical feature:
nucleoli
Kendall BS, et al. Am J Surg Pathol 1998; 22: 1012-1019
Hyperplasia vs Cancer
Reproducibility
% agreement
cyclic
67
hyperplasia
46
AH
25
WDC
49
overall
64
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
• N = 56
• kappa statistic:
– range: .39 - .64
– mean: .52
• individual kappa
statistic not reported
Bergeron C, et al. Am J Surg Pathol 1999; 23: 1102-1108
Hyperplasia vs Cancer
• 1975 vs 1994 WHO classification
– N = 128
• overall κ (all classifications): 0.20 – 0.30
• classification reduced to 2 categories:
– atypcial vs all others
– κ : 0.42 – 0.59
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Skov BG, et al. Int J Gynecol Pathol 1997; 16: 33-37
Hyperplasia vs Cancer
• GOG # 167:
– study of diagnosis (Phase I)
– study of progestin Rx (Phase II)
• problems with interpretation
– wide range of diagnoses
– lack of reproducibility
 approximately 33% agreement with community pathologic
interpretation
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Hyperplasia vs Cancer
Reproducibility
kappa
normal
0.48
hyperplasia
0.38
AH
0.28
carcinoma
0.51
overall
0.40
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
• GOG 167 study
• N = 302
• Reproducibility for
study panel
pathologists
– experts
Zaino RJ, et al. Cancer 2006; 106: 804-811
Hyperplasia vs Cancer
• Study panel review of 289 “AH” specimens
• Only 39.8% remained with “AH” diagnosis
– 25.6% down-graded
– 29.1% up-graded to carcinoma
• Rate of concurrent carcinoma: 42.6%
– Myometrial invasion: 30.9%
– Outer half invasion: 10.6%
• No consensus in 5.5%
– Endometrial cancer in 62.5% of these patients
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Trimble CL, et al. Cancer 2006; 106: 812-819
Endometrial Hyperplasia
• Study of relevance of “qualifying comments”
– “cannot exclude a more severe lesion”
• Risk of cancer in hysterectomy:
– Non-qualified: 37.5%
– Qualified: 60%
 OR: 4,7, p = 0.03
• Summary: findings may vary depending on additional
comments
• Separate studies: intraoperative frozen section may be
useful
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Miller C, et al. Am J Obstet Gynecol 2008; 199(1):69.e1-4
Atypical Hyperplasia: Staging?
• Due to high risk of cancer: stage all?
• 67 patients with AH underwent node dissection
(additional 21 unstaged)
– Cancer at hysterectomy: 28% (25 patients)
– Surgical outcome same in staged vs unstaged
 No additional morbidity
• Node dissection influenced management in 7 of the 25
patients (28%)
• Summary: node dissection should be considered
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Whyte JS, et al. Am J Obstet Gynecol 2010; 202(2):176.e1-4
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Hyperplasia: EIN
• Endometrial Collaborative Group
– self-convened group of gynecologic pathologists
– discussion of diagnosis and management of
premalignant disease
• reason: improve diagnostic accuracy
– standardization
• background: data supports clonal basis of
premalignant disease
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
EIN
• computerized morphometric analysis
• architectural features:
– epithelial crowding displaces stroma
– Key: VPS < 55%
 single best predictive value
• nuclear features also included
• attempt to develop standardized features for
diagnosis
• validated with clonal and clinical studies
• database of referenced tissues available on Web
– www.endometrium.org
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
EIN: Classification
• EH: endometrial hyperplasia
– disordered proliferative through complex
hyperplasia
– not premalignant
• EIN: endometrial intraepithelial neoplasia
– true neoplasm; premalignant
– single category
 subdivision: not reproducible, prognostic
– still potentially difficult to distinguish from
carcinoma
 but can distinguish from non-premalignant
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Morphometry
Baak, et al. (2005)
• Multicenter trial; 477 patients
• Compared WHO 1994 criteria to EIN
• WHO:
– 13% of AH progressed
– 2.3% of non-AH progressed
• EIN:
– 19% of EIN progressed
– 0.6% of non-EIN progressed
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Baak JP, et al. Cancer 2005; 103: 2304-2312
Morphometry
Baak, et al. (2005)
• Sensitivity for detecting premalignant
lesions:
– EIN: 92%
– WHO: 67% (all atypical hyperplasias)
– Complex atypical hyperplasia alone: 46%
• Regression analysis:
– EIN was strongest prognostic index of future
carcinoma
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Baak JP, et al. Cancer 2005; 103: 2304-2312
Morphometry
• Baak, et al (2002):
– OR for carcinoma based on D-score: 115
• BUT: studies of computer-based system
– requires equipment, training
– can be applied subjectively (??)
 Mutter: subjective vs computer-based morphometry
κ: 0.69
 not studied
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Morphometry: Summary
• needs further study
– initial data compelling
• WHO incorporating into guide
• potential management applications
– Netherlands:
 D-score > 1: progestin, follow EMS
 D-score >0, < 1: progestin; repeat sample, D-score
 D-score < 0: hysterectomy
 Cost savings: $8M per year average
 avoiding unnecessary hysterectomy
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Micropapillary Tumors
• pathology: delicate fine branching papillae
– arise directly from thick papillae
– must be > 5 mm, otherwise APT
• implants: more frequent
– 44 cases: 55% invasive (6% - 9% for APT)
• prognosis:
– 5 year survival: 84%
– 10 year survival: 58%
– recurrence of cancer: 35% with advanced stage
micropapillary
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Micropapillary Tumors
• bilateral: 64%
• Stage:
– Stage 1: 45%
– Stage 2: 18%
– Stage 3: 37%
55%
 Stage 2/3 for serous: 40%
• surface involvement: 54% (>> APT)
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Serous APT: Facts
• extraovarian “disease”: 40%
– endosalpingiosis: 40%
– APT implants: 40%
 noninvasive: 31%
 invasive: 9%
– unilateral: 15% > Stage 1; bilateral: 56% > Stage 1
• survival: Stage 1, > 2000 pts, 6.7 year follow-up:
99.5%
• microinvasion: 1.3% - 10%
– prognosis: 94 pts, 7 year follow-up: 100%
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Implants - Problems
• incidence, survival vary
• biopsies often superficial
• definitions vary
– strict: not as common
 only true invasion: infiltration into underlying tissue
– less stringent: more common
 less effect on survival
– if relax criteria, less significance in prognosis
• small number of patients
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Implants and Nodes
• types:
– noninvasive:
 epithelial
 desmoplastic
– invasive:
• survival (89 month follow-up)
– noninvasive: 95.3%
– invasive: 66%
• nodes: rare with APT (63 total cases)
– 43 pts with + nodes, 6.5 year follow-up: 98%
survival
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Placental Reports:
Exaggerated Placental Site
• “exhuberant” proliferation of normal
implantation site intermediate trophoblast
– Considered a normal variant
• Normal pregnancies or abortion
• Preserves normal placental site
architecture
• Main DDx: PSTT
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Placental Reports:
Placental Site Nodule
• Well-circumscribed aggregates of chorionic (not
implantation site) intermediate trophoblast
– Key: hyalinized stroma
– Immunohistochemistry correlates with chorionic
trophoblast
• Etiology: formerly involuted placenta
– Now considered benign counterpart to ETT
• DDx: PSTT, exaggerated placental site, SCC
(cervix)
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
Placental Reports:
Placental Site Nodule
• Many patients have had prior EAB or C-S
• Most often incidental findings
– Evaluation of abnormal Paps; AUB
– May be multiple
– May occur in cervix (up to 40%) or tube
• Antecedent pregnancy: 2 – 108 months
• Non-neoplastic: no further treatment needed
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology
UNIFORMED SERVICES UNIVERSITY
of the Health Sciences
Department of Obstetrics and Gynecology