Clinical Management / Natural History of Cervical Dysplasia (CIN) and Related Findings

Edward J. Wilkinson, MD, FACOG, FCAP

University of Florida College of Medicine Department of Pathology

November 28, 2001

CERVICAL CANCER SCREENING IN THE USA

*Approximately 50 million Pap tests done annually.+

*Approximately 3.5 million ( 7%) interpreted as abnormal.+

*Approximately 800,000 LSIL (1.6%); ~ 1600 women with LSIL have invasive cervical carcinoma (0.2 %) *Approximately 250,000 interpreted as HSIL; ~ 2500 women with HSIL have invasive cervical carcinoma (1.0-2.0%)
+Jones HW, Cancer 1995:76:1914-18 +Jones BA and Davey, Arch Pathol Lab Med 2000;124:672-81

THE CERVICAL TRANSFORMATION ZONE

The cervical transformation zone extends from the endocervical margin of the original squamous epithelium of the ectocervix to the identified squamo-columnar junction. Over 95% of all cervical intraepithelial neoplasias (CIN) arise within the transformation zone of the cervix.

NORMAL AND NEOPLASTIC CELLULAR CHANGES WITHIN THE TRANSFORMATION ZONE

Normal Neoplastic Transforming Factors Reserve Cell l Cervical intraepithelial Neoplasia (CIN) Reserve cell hyperplasia l l l immature atypical CIN 1_________ squamous immature : l metaplasia metaplasia : regression l l CIN 2 l l l mature . l ..?. CIN 3 squamous l metaplasia Microinvasive l Squamous carcinoma stratified l mature squamous Squamous carcinoma epithelium
Wilkinson, 2001

CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN): Mild Dysplasia / CIN 1: Dysplasia confined to the lowest third of
the epithelium.

Moderate Dysplasia / CIN 2: Dysplasia involving the lower two thirds of the epithelium. Severe Dysplasia / CIN 3: Dysplasia extending into the upper third of the epithelium, but not involving the full thickness.
Carcinoma In Situ / CIN 3: A squamous intraepithelial lesion in which nuclear abnormalities involve the full thickness of the epithelium.
Scully et al, WHO; Histological Typing of Female Genital Tract Tumors, 2nd ed,1994

The Bethesda 2001 System

Major New Changes from Bethesda 1991: * Negative for intraepithelial lesion or malignancy replaces within normal limits. *Benign Cellular Changes Eliminated.

*ASCUS changed to ASC : either ASC-US or ASC-H

*AGUS changed to AGS

Bethesda 2001 Cervical Cytology Classification

Negative for squamous intraepithelial lesion or malignancy Epithelial cell abnormalities: Squamous Cell
Atypical Squamous cells of undetermined significance (ASC-US)

Atypical Squamous Cells, cannot exclude HSIL (ASC-H)

Low-Grade Squamous Intraepithelial Lesion (LSIL) encompassing: HPV / mild dysplasia / CIN 1 High-Grade Squamous Intraepithelial Lesion (HSIL) encompassing: moderate and severe dysplasia, CIS / CIN 2 & CIN 3 -with features suspicious for invasion (if invasion is suspected) Squamous cell carcinoma

Bethesda 2001 Cervical Cytology Classification

Epithelial cell abnormalities: Glandular Cell
Atypical Glandular Cells (AGC)
-endocervical cells (NOS) -endometrial cells (NOS) -glandular cells (NOS or specify in comments) Atypical Glandular Cells (AGC) -endocervical cells, favor neoplastic -glandular cells, favor neoplastic

Endocervical adenocarcinoma in situ Adenocarcinoma

-endocervical -extrauterine -endometrial -not otherwise specified (NOS)

COMPARISON OF THE WHO AND BETHESDA SYSTEM TERMINOLOGY

WHO histopathologic terms
CIN 1/ Mild Dysplasia

Bethesda Cytology Terms

LSIL

CIN 2 / Moderate Dysplasia

CIN 3 / Severe Dysplasia

HSIL
HSIL

CIN 3 / Carcinoma in Situ HSIL *LSIL: low-grade squamous intraepithelial lesion

*HSIL: high-grade squamous intraepithelial lesion

CAUSES OF NON-CORRELATION BETWEEN CYTOLOGY AND COLPOSCOPY

* Cervical lesion is in the endocervical canal, or not in the cervix. * Colposcopic findings are not apparent to the examiner, although the lesion is present. (eg. Severe atrophy obscures the colposcopic findings). *The biopsies performed did not include the visualized lesion. *The laboratory did not identify the lesion within the submitted biopsies. (Orientation of the biopsy, initial sections of the paraffin embedded tissue did not include the lesion.) *The cervical cytologic sample was classified as HSIL, but only contained immature metaplastic, or atrophic squamous cells (interpretative cytology issue). *Other issues.

Specimen Adequacy
Satisfactory for Evaluation (describe presence or
absence of endocervical/ transformation zone component and any other quality indicators, e.g., partially obscuring blood, inflammation, etc)

Unsatisfactory for Evaluation

Specimen rejected (not processed) because Specimen processed and examined, but unsatisfactory for evaluation because of

Other Non-Neoplastic Findings

Optional to report; list not inclusive Reactive cellular changes associated with
inflammation (includes typical repair) radiation intrauterine contraceptive device (IUD)

Glandular cells status post hysterectomy Atrophy

Other
Endometrial cells (in a woman >40 years of age)
exfoliated (not abraded) endometrial cells not stromal cells or macrophages Optional Comment: Endometrial cells after age 40, particularly out of phase or after menopause, may be associated with benign endometrium, hormonal alterations, and, less commonly, endometrial abnormality. Clinical correlation recommended.

Atypical Squamous Cells (ASC)

Atypical squamous cells
of undetermined significance (ASC-US) cannot exclude HSIL (ASC-H)

ASC frequency and association with CIN Average frequency of ASC: Associated CIN 2 or CIN 3: ASC assoc. with cervical ca: 4.4 % 5 - 17 % 0.1 - 0.2 %

Jones and Davey Arch Pathol lab Med 2000,124:672 Jones and Novis. Arch Pathol Lab Med 2000;124:665

Sensitivity of a single repeat Pap test for detection of CIN 2 or CIN 3

Sensitivity of repeat cervical cytology to detect CIN 2 or CIN 3: 0.67 - 0.76
Manos, Kinney, Hurley et al. JAMA 1999;281:1605 Wright et al, Am J Obstet Gynecol 1998;178:962 Stoler and Shiffman JAMA 2001;285:1500 Shlay et al, Obstet Gynecol 2000;96:410

ALTS: ASCUS Cytology Review

ASCUS 3379 cases. On Review: Concurred ASCUS 55% Upgraded to LSIL Upgraded to HSIL Downgraded to Negative 11% 3% 31% = 14% SIL

Soloman D, et al, 2001 JNCI 93(4):293-99

Ancillary Testing
Provide a brief description of the test methods and report the result so that it is easily understood by the clinician Encourage use of simultaneous/integrated reporting of cytology and HPV testing Report test method (type specific vs cocktail) Report result as positive or negative

HPV High Risk Types (N=13)

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
Solomon D, et al, 2001, JNCI 93(4):293-99

HPV Testing vs. Cervical Cytology / ASCUS and above

Sensitive
HPV testing 1.0pg / mL Cervical cytol ASCUS 88.4%

Specificity* Referral for colposcopy 89% 12.3%

77.7%

94.2%

6.9%

*specificity - defining HSIL or cancer

Schiffmann M, et al, JAMA 87-93, 2000

HPV Testing or Reflex to Colposcopy

ASCUS 3488 HPV positive 1766 HPV results missing 164 Total referred to colposcopy ASCUS - CIN 3 Sensitivity to detect CN1 or CIN 3: HPV test Repeat cytology - HSILCyto. ASCUS or higher to detect CIN 2 % 50.6% 4.7% 5.3% 5.1% 96.3% 44.1% 85.3%

Solomon D, et al, 2001, JNCI 93(4):293-99

Histology and Other Test Results for Women With an ASCUS Pap Test Result* N=973
Consensus No. of Histology Patients
Normal LSIL HSIL Cancer Total 783 (80.4) 125 (12.8) 54 ( 6.7) 1 (0.1) 973 (100)

HPV ThinPrep Pap Repeat Pap Positive Result Abnormal Result Abnormal
239 (30.5) 87 (69.6) 57 (89.1) 1 (100) 384 (39.5) 335 (42.8) 82 (65.6) 54 (84.4) 1 (100) 472 (48.6) 245 / 770 (31.8) 79 / 124 (63.1) 47 / 62 (75.8) 1 / 1 (100) 372 / 957 (38.9)

Manos MM, et al, JAMA 281:1605-10, 1999

Management of women with ASCUS (ASC) with HPV testing

Author Bergeron Manos Solomon* Wright* No. Pts. 111 995 2324 144 HPV DNA Testing Sensitivity % Referred 0.83 0.89 0.96 0.78 43% 40% 56% 54% Repeat Cytology Sensitivity % Referred 0.67 0.76 0.85 0.67 32% 39% 58% 63%

*HPV DNA testing was performed from liquid-based cytology specimens Wright et al, 2001 Consensus Conference, submitted

Triage test performance of HC 2 and cytology at different thresholds for detection of histologically confirmed CIN3 and CIN2 in the combined human papillomavirus (HPV) triage and immediate colposcopy arms

% sensitivity
CIN3+ HC2 HSIL+ cytology LSIL+ cytology ASCUS + cytology CIN2+ HC2 HSIL+ cytology LSIL+ cytology ASCUS+ cytology

Colposcopy % referral 96.3 44.1 64.0 85.3 56.1 6.9 26.2 58.6

Positive predictive value 10.0 37.5 14.3 8.5

Negative predictive value 99.5 96.5 97.1 97.9

95.9 34.8 59.2 85.0

56.1 6.9 26.2 58.6

19.6 58.1 25.9 16.7

98.9 92.0 93.6 95.8

Solomon D, et al, 2001 JNCI 93(4):293-99

ASC-H (cannot exclude HSIL): association with CIN 2 or CIN 3

ASC overall: Associated CIN 2 or CIN 3: ASC-H: 5 - 17 %

Associated with CIN 2 or 3:

24 - 94 %

Jones and Davey Arch Pathol lab Med 2000,124:672 Jones and Novis. Arch Pathol Lab Med 2000;124:665 Malik, Wilkinson et al, Acta Cytol 1999;43:376

MANAGEMENT OF ASC-H
* Refer directly to colposcopy * Do not perform HPV testing

Wright et al, 2001 Consensus Conference, submitted

HPV Triage for ASC-US Pap test ________ | ____________

| | HPV positive HPV negative | | colposcopy or repeat pap 12 mos. repeat pap at 6 & 12 mos.
Manos MM, et al, JAMA 281:1605-10, 1999 Solomon D, et al, 2001, JNCI 93(4):293-99 Wright et al, 2001 Consensus Conference, submitted

MANAGEMENT OF ASC-US
Acceptable Options: * Follow-up with repeat cervical cytology in 6 and 12 months; if ASC-US or more severe, refer to colposcopy. * Perform HPV DNA testing for high-risk HPV types; - if HPV negative: return to screening in 12 months - if HPV positive: repeat cervical cytology in 6 & 12 months, if ASC-US or more severe, refer to colposcopy. Use of HPV DNA testing in late follow-up.
Wright et al, 2001 Consensus Conference, submitted

LSIL frequency and association with CIN Mean frequency of LSIL: Associated CIN 2 or CIN 3: 1.6 % 15 - 30 %

LSIL assoc. with cervical ca: under 0.1 %

Jones and Davey Arch Pathol lab Med 2000,124:672 Jones and Novis. Arch Pathol Lab Med 2000;124:665

FOLLOW-UP: OBSERVATION VS. THERAPY

70% (of 972) of the patients with LSIL Pap tests who had colposcopic follow-up and biopsy had CIN diagnosed on colposcopic directed cervical biopsies. 41.7% (of 405) had CIN 1 28.4% (of 276) having CIN 2 or CIN 3.
Takezawa et al, J Lower Gen. Tract Dis 1998;2:136-40

MANAGEMENT OF LSIL
Recommend option: * Refer directly to colposcopy. * If colposcopy and biopsies fail to identify CIN, follow-up with repeat cytology at 6 and 12 months, refer to colposcopy if repeat is ASC-US or more severe.

* acceptable option to follow with Pap in 6 and 12 months with referral as above, in special circumstances.
Wright et al, 2001 Consensus Conference, submitted

HSIL frequency and association with CIN

Mean frequency of HSIL: Associated CIN 2 or CIN 3: HSIL assoc. with cervical ca: 0.45 % 70 - 75 % 1-2%

Jones and Davey Arch Pathol lab Med 2000,124:672 Jones and Novis. Arch Pathol Lab Med 2000;124:665 Massad et al, Gynecol Oncol 2001;82:516 Kinney et al, Obstet Gyncol 1998:91:973

MANAGEMENT OF HSIL
Recommend option: * Refer directly to colposcopy. * If colposcopy and biopsies fail to identify CIN, review of the original cytology, biopsy and colposcopy findings are recommended. * If the above review confirms HSIL, a diagnostic excisional procedure, such as electro-loop excision, of the transformation zone is recommended in non-pregnant patients.
Wright et al, 2001 Consensus Conference, submitted

HPV results by HC 2
Clinical Center cytology Negative (row %) Positive (row %) TOTAL (N)

Missing (164) Negative ASCUS LSIL HSIL-CIN2 HSIL-CIN3 TOTAL

50 64 47.7 10.6 3.4 0 44.7

33.3 31.0 48.9 83.3 92.3 92.3 50.6

18 1460 1134 630 207 39 3488

Solomon D, et al, 2001 JNCI 93(4):293-99

HIGH RISK HPV DETECTION

Group Women with CIN 2-3 disease HPV detected 83.9%

Women with no disease

15.5%

Wright TC, et al, JAMA 283:81-86, 2000

Risk of high-grade CIN in relation to time since first exposure to HPV 16

Time since first exposure (months)
Unexposed <6 6-12 12-18 >18

Relative hazards ratio (95% CI)*

100 598 (133-2685) 1802 (550-5903) 1422 (376-5386) 260 (075-899)
Woodman CBJ, et al Lancet 2001;357:1831-36

HPV=human papillomavirus; CIN=cervical intraepithelial neoplasia; *Controlling for any other HPV exposure

Pap test Results Preceding the Identification of women with CIN 2 or CIN 3
Pap test Finding
HSIL LSIL

Percent with CIN 2,3

31 % 15 - 30 %

AGC (AGUS)
ASC (ASCUS)
Jones and Davey Arch Pathol lab Med 2000,124:672 Jones and Novis. Arch Pathol Lab Med 2000;124:665

30 - 40 %
10 %
Kinney et al, Obstet Gynecol 1998;91:973 Takezawa et al J Lower Gen. Tract Dis 1998;2:136

AGC frequency and association with CIN, Adenocarcinoma in situ (AIS) or Cervical or Endometrial Adenocarcinoma Mean frequency of AGC: 0.3 %
Associated CIN 1, 2, or 3: AGC assoc. with AIS: 9 - 54 % 0 - 8%
Jones and Davey Arch Pathol lab Med 2000,124:672 Jones and Novis. Arch Pathol Lab Med 2000;124:665 Ronnett et al, Hum Pathol 1999;30:816 Veljovich et al, Am J Obstet Gynceol 1998;179:382 Soofer and Sidaway Cancer 2000;90:207

AGC assoc. with carcinoma:

1 - 9%

Glandular Cell Abnormalities

Atypical
endocervical cells (NOS or specify in comments) endometrial cells (NOS or specify in comments) glandular cells (NOS or specify in comments)

Atypical
endocervical cells, favor neoplastic glandular cells, favor neoplastic

Endocervical adenocarcinoma in situ

Glandular Cell Abnormalities

Adenocarcinoma
endocervical endometrial extrauterine not otherwise specified

AGC associated with CIN 2 or CIN 3 AGC, Not Otherwise specified:

CIN 2 or CIN 3 detected: 9 - 41 % 27 - 96 %
Ronnett et al, Hum Pathol 1999;30:816 Soofer and Sidaway Cancer 2000;90:207

AGC, favor neoplasia:

CIN 2 or CIN 3 detected:
Jones and Novis. Arch Pathol Lab Med 2000;124:665 Veljovich et al, Am J Obstet Gynceol 1998;179:382 Wright et al, 2001 Consensus Conference, in press

Cervical Adenocarcinoma Associated with HPV Types 16 and 18

Of 38 cases, 60.5% had HPV DNA detected

HPV 16 detected in 23.7% (9 of 38)

HPV 18 detected in 26.3% (10 of 38) In patients 59 years of age or younger, 84.6% had HPV
Skyldberg et al Mod Pathol 1999;12(7):675-82

MANAGEMENT OF AGC
Recommend option: * Refer directly to colposcopy. * Colposcopy should include endocervical sampling. *In symptomatic women, and women over 35 years of age, endometrial sampling should also be performed. * A diagnostic cervical cone biopsy may be needed, and referral to a clinician experienced in management of complex cervical cytologic situations is recommended.
Wright et al, 2001 Consensus Conference, submitted

Natural history of mild dysplasia (CIN 1)

n Total 4,504 Regress 57%
Progress Persist (to CIS)

32%

11%

17 studies, N 12-1,269 Followup <1-18 yrs.

str AG, Int J Gyne Path 1993;12:186-192

Natural history of moderate dysplasia (CIN 2)

n Total 2,247 Regress 43% Progress Persist (to CIS) 35% 22%

12 studies, N 12-894 Followup 0.3-18 yrs

str AG, Int J Gyne Path 1993;12:186-192

Natural history of CIS (CIN 3)

n Regress
Progress Persist (to invasion)

Total

767

32%

56%

12%

21 studies: N5-109 Follow up 0.5-20 yrs.

str AG, Int J Gyne Path 1993;12:186-192

Natural history of CIN: summary

Regress Persist

Progress Progress to CIS to invasion

CIN 1 CIN 2 CIN 3

57% 43% 32%

32% 35% < 56%

11% 22% --

1% 5% >12%

64 studies, 274 carcinomas, 15,473 CIN cases Followup <1-12 years

str AG, Int J Gyne Path 1993;12:186-192

Regression
80 70 60 50 40 30 20 10 0 Low range Mean High range

ASCUS

Low Grade SIL

ASCUS + Low Grade SIL

High Grade SIL

Melnikow J et al. Obstet Gyne 1998;92:727-35

Progression
35 30 25 20 15 10 5 0 Low 6 mos. Mean 6 mos. High 6 mos. Low 24 mos. Mean 24 mos. High 24 mos.

ASCUS

Low Grade SIL

ASCUS + Low Grade SIL

High Grade SIL

Melnikow J et al. Obstet Gyne 1998;92:727-35

Invasive Cancer
4 3.5 3 2.5 2 1.5 1 0.5 0

Low 6 mos Mean 6 mos High 6 mos Low 24 mos. Mean 24 mos. High 24 mos.

ASCUS

Low Grade SIL

ASCUS + Low Grade SIL

High Grade SIL

Melnikow J et al. Obstet Gyne 1998;92:727-35

MANAGEMENT OF CIN 1
Risk of follow up of CIN 1 1. Invasive cancer already exists and was missed by Pap, colpo and biopsy. 2. Invasive cancer develops between follow up visits. 3. Patient lost to follow up and develops invasive cancer.

FOLLOW UP FOR CIN 1

Atypia / LSIL Pap

Follow up 24 mo 135 pts.

Histology Negative CIN 1/HPV CIN 2-3 Invasion

Immediate LLETZ 171 pts.

20% 55% 24% l pt.

<1% 76% 23% -Shafi, BJOJ, 1997

FOLLOW-UP: OBSERVATION VS. THERAPY

Patients with Pap smears interpreted as LSIL may have colposcopy directly if reliable and have the ability to be followed, may be followed by repeat smears at 4 to 6 months.
A meta-analysis of women with LSIL Pap tests had a pooled rate of regression reported as 47.39%, with a very low risk of invasive carcinoma, varying from 0.00% to 0.74% of the patients.
Melnikow J et al. Obstet Gyne 1998;92:727-35

FOLLOW-UP: OBSERVATION VS. THERAPY

Should the Pap return as ASCUS, LSIL or HSIL, the patient should have colposcopy done, with directed biopsies if needed. If colposcopy is performed, and a lesion is identified, colposcopic directed biopsies are indicated to establish the diagnosis.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996 ; ASCCP Practice Guidelines.

OBSERVATIONAL FOLLOW-UP, CIN 1

If the patient has a follow-up Pap smear that is within normal, or benign cellular changes, repeat follow-up at 4 to 6 month intervals should continue. If the smears remain within normal, or benign cellular changes, the patient may return to annual yearly screening if four consecutive smears remain unremarkable.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996

TREATMENT VS. OBSERVATION

The treatment decision on such patients is dependent upon the pathologic findings. Individuals that have CIN 2 and CIN 3, require appropriate treatment for cervical intraepithelial neoplasia. Patients with CIN 1 may have observational follow-up by cytology if acceptable to the patient and physician.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996

TREATMENT VS. OBSERVATION Grossly visible lesions of the cervix require cervical biopsy for pathologic evaluations. Grossly visible CIN 2 and CIN 3 lesions may be associated with invasive squamous cell carcinoma, usually microinvasion, and rarely adenocarcinoma, in situ, or invasive adenocarcinoma.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996

The see and treat approach using electroloop excision of any visible lesion is generally not recommended due to common treatment of non CIN lesions, and the potential unnecessary excision of part of the cervix.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG et al, 1996.

TREATMENT OUTCOMES FOR CIN

A systemic review of controlled and randomized trials in women with CIN 1 (low grade lesions), or CIN 2 or CIN 3 (high grade lesions) determined that the outcomes as far as recurrence of CIN, or non-recurrence of CIN between cone biopsy, cryotherapy, laser ablation, or electro-loop excision demonstrated no substantive difference in outcomes.
Nuovo et al. Int J Gynecol Obst 2000;68:25.

METHODS TO TREAT CIN

There are a variety of accepted methods of therapy to treat CIN, including: cryosurgery ablation, laser ablation or excision, electro-loop excision, cone biopsy
ACOG: 1997; Nuovo et al, 2000; Wright et al, 1995

RISK OF SIGNIFICANT HEMORRHAGE ASSOCIATED WITH TREATMENT FOR CIN

Treatment Cone biopsy Laser ablation Electro-loop Cryotherapy Total

No. 627 1419 635 1130 3811

Hemorrhage 4.6% 1.75% 1.35% 0.00%

Nuovo et al. Int J Gynol 2000;68:25

RESIDUAL CIN AFTER LEEP/CONE

-/ECC/MARGIN -/+ +/+/+

Felix (1994)
Husseinzadeh (1989)

1/38

2/4

1/3

9/12

3/19

9/29

2/5

24/30

Kobak (1995)

4/22

11/37

4/10

12/27

8/79 (10%) 22/70 (31%) 7/18 (39%) 45/69 (65%) risk of residual if (+) Margin = 48% if (+) ECC = 59% But, overall rate of residual = 45% and rate of (+) margin = 59%
Dunton, Obstet Gynecol Surv, 2000

MANAGEMENT OF CIN
Ablative therapy is not recommended if the SCJ and/or the limits of the lesion cannot be seen colposcopically. A negative ECC prior to ablative therapy has been suggested by experts. An ECC at the time of LEEP/cone may indicate an increased risk of residual disease but may not influence post-LEEP/cone management. See and treat approach for low-grade lesions leads to a significant number of patients with negative histology.

CERVICAL CARCINOMA STAGING

Tis: Carcinoma in situ T1a1: FIGO, IA1: Invasive carcinoma diagnosed by microscopy with stromal invasion 3.0 mm or less in depth and 7.0 mm or less in horizontal spread.

T1a2: FIGO, IA2: Invasive carcinoma diagnosed by microscopy with stromal invasion more than 3.0 mm and not more than 5.0 mm with horizontal spread 7.0 mm or less.
T1b1 : FIGO, IB1: clinically visible lesion confined to the cervix or microscopic lesion greater than T1a2
AJCC Cancer Staging Manual, 5th ed. 1997;190-1

Clinical Management / Natural History of Cervical Dysplasia (CIN) and Related Findings
Edward J. Wilkinson, MD, FACOG, FCAP
University of Florida College of Medicine Department of Pathology