California Society of Pathology San Francisco, CA 66th Annual Meeting Seminars in Pathology Surgical Pathology of the Female Genital Tract During Pregnancy: Selected Problems Teri A Longacre, M.D. Stanford University, Stanford CA longacre@stanford,edu Disclosure Statement

Dr. Longacre reports no relevant financial relationship(s) with commercial interests to disclose.

Introduction

Things that go bump in pregnancy… Uterus Clinical History

• 33 year old with vaginal bleeding and endometrial biopsy

Arias-Stella Reaction

• Endometrial (or endocervical/tubal) glands during pregnancy (as early as 17 days following conception) • Gestational trophoblastic disease • Premenopausal and postmenopausal women treated with progestins • Occasionally no apparent source of progestin stimulation

EndomCa with Pill 05-19676 EndomCa with Pill 05-19676

Clear Cell Carcinoma Arias-Stella Reaction

• Mass • No mass • Hyalinized stroma • Decidualized stroma • Infiltrative pattern • Noninfiltrative • Tubulocystic or solid • Glandular only • Papillary with cores • No true papillae • No history of progestin • History of progestin or or pregnancy pregnancy • Rare in uterus • Common in uterus

Clinical History

• 27 year old with uncontrolled post- partum hemorrhage, requiring hysterectomy

Uterine Atony

• Most common cause of postpartum hemorrhage • Increasing in incidence • Dilated vasculature due to failure of physiologic vessel contracture Pathology

• Flabby uterus with fresh, clotted blood • Dilated vessels may simulate vascular malformation • Exclude perforation, other cause of atony (retained products, leiomyoma, etc)

Uterine Atony: Risk Factors • Age <20 or ≥40 years • Cesarean delivery • Hypertensive diseases of pregnancy • Polyhydramnios • Chorioamnionitis • Multiple gestation • Retained placenta • Antepartum hemorrhage Postpartum Hemorrhage • Uterine atony • Retained products of conception • Placenta creta • Chronic endometritis • Acute suppurative endometritis (puerperal sepsis) • Subinvolution of placental site • Uterine rupture

Subinvolution of Placental Site

• Delayed postpartum bleeding • Typically 2nd week postpartum, but may be 1 week to several months • Implantation site reaction does not promptly regress after delivery Subinvolution of Placental Site

1) Superficial dilated and clustered myometrial arteries that are partially occluded by thrombi of various ages 2) Extravillous interstitial or endovascular trophoblasts

Postpartum Endometritis

• Fever, leukocytosis • Can occur up to 6 weeks postpartum • Typically polymicrobial • Aerobic and anaerobic • Early: Gp B strep and E coli

Clinical History

• 33 year old with uterine mass

Progestin Effect

• Pseudodeciduation reaction • Edema • Nuclear hypochromasia • Decreased mitotic figures • May see degenerative changes Ovary Clinical History

• 32 year old woman with ovarian mass discovered during C-section

Pregnancy Luteoma

• Second half of pregnancy • Incidental finding at C-section • Often multiple (50%) • May be bilateral (30%) • May be androgenic: – mom (25%) – Baby (70%) Pregnancy Luteoma • Well circumscribed • Eosinophilic cytoplasm • Necrosis & degenerative changes • Lipid-poor • Mitotic figures may be present, but not nuclear atypia • Benign – will regress following pregnancy

Differential Diagnosis

• Steroid cell tumor, not otherwise specified (55-60%) • Stromal luteoma (20-25%) • Leydig cell tumor (20%) • Hilar cell tumor (rare – location)

Steroid Cell Tumor

• Solid, yellow-orange, red-brown or black • May have cystic degeneration, necrosis, hemorrhage • By definition > 3.0 cm • Diffuse polygonal rounded cells w/ distinct cell borders, central nuclei, prominent nuceloli

Steroid Cell Tumor • May form clusters or cords of cells • Cytoplasm granular and eosinophilic or vacuolated • Mitotic figures usually few (<2 MFs/10HPFs) • Up to 40% malignant • Extraovarian spread in 20% at diagnosis

Steroid Cell Tumor

• Mean age 43 years, but 25% less than 30 • Androgenic (50%), estrogenic, progestagenic, Cushing’s symptoms common • If stage IA, unilateral adnexectomy in premenopasual patient Steroid Cell Tumor

• Inhibin + • Calretinin + • Cytokeratin +

Leydig cell tumor

Luteinized thecoma Clinical History

• 32 year old woman with 25 cm cystic ovarian tumor discovered during C- section

Large Solitary Luteinized Cyst of Pregnancy and Peurperium

• Occurs only during pregnancy • Large, unilocular cyst • Luteinized granulosa and theca cells with ample cytoplasm lining cyst wall • Theca cells inconspicuous • Nuclear hyperchromasia & focal marked nuclear pleomorphism • No mitotic figures Large Solitary Luteinized Cyst of Pregnancy and Peurperium: Differential Diagnosis

• Unilocular cystic granulosa cell tumor • Surface epithelial cyst (benign, borderline or malignant) • Pregnancy luteoma Unilocular Cystic (Adult) Granulosa Cell Tumor*

• Large cyst with discrete intramural proliferation of granulosa cells • May need to sample extensively • Has same prognosis as usual histology – so can recur!

*Exclude granulosa cell proliferations of pregnancy

Adult Granulosa Cell Tumor, Inhibin What Are Granulosa Cell Proliferations of Pregnancy?

• Microscopic, typically < 5 mm • Occur in atretic follicles • Uniform, non-luteinized granulosa cells • Arranged in cords, nests, or microfollicles • Often theca component present

Clinical History

• 32 year old woman develops bilateral ovarian “masses” during ovulation induction

Hyperreactio Luteinalis

• Bilateral ovarian enlargement secondary to development of multiple luteinized cysts • Rare in normal pregnancy, but may occur in 10-40% of women with gestational trophoblastic disease and in women undergoing ovulation induction (esp if preexisting polycystic ovaries) • Virilization (15%) Hyperreactio Luteinalis

• Multiple follicle cysts lined by luteinized theca interna and granulosa cells. • Marked stromal edema • Occasional atypia of granulosa cells Hyperreactio Luteinalis Differential Diagnosis • Surface epithelial neoplasm (benign, borderline or malignant) • Pregnancy luteoma • Large solitary luteinized follicle cyst of pregnancy and peurperium Clinical History

• 31 year old female develops bilateral ovarian “masses” during pregnancy. Laparoscopic exam discloses ovarian masses and multiple peritoneal nodules

Serous Borderline Tumor with Stromal Microinvasion

• Numerous, often complex papillae • Cellular tufting (≥ 3 stratified cells) • Mild to moderate nuclear atypia • Mitotic figures present but uncommon • May be associated with extra-ovarian implants, lymph node involvement, positive washings • No stromal invasion Serous Borderline Tumor

• Fourth and fifth decade (mean, 46 years) – but can present during reproductive years • Bilateral (30-40%) • Advanced stage (30-40%) • Cystic mass with profuse papillary projections

Stromal Microinvasion in S-LMP

• Approximately 10- 15% of S-LMP • Increased incidence in pregnancy (up to nine-fold) • Detached cells & simple papillae in stroma

D2-40

Am J Surg Pathol 2008;32:261-8 What is Microinvasion* in S-LMP? • Likely bona fide invasion – represents histologic link between S-LMP & low grade serous carcinoma • Commonly encountered in association with areas of unequivocal destructive stromal invasion in low grade serous carcinomas • Commonly associated with lymphatic vessel invasion *Should be <5 mm or <10 sq mm Serous Borderline Tumor

• Cystectomy or adnexectomy with preservation of uterus and remaining ovarian tissue, even if high stage • Recurrence in ipsilateral or contralateral ovary common, so follow-up is required Peritoneum Clinical History

• 33 year old with multiple nodules distributed over the ovaries & throughout the peritoneum at C-section

Disseminated Peritoneal Leiomyomatosis (DPL) • Reproductive age (mean, 37 years) • Pregnancy, oral contraceptive use, endogenous estrogen production (e.g., thecoma, granulosa cell tumor, etc.) • Uterine leiomyomas often present • May be heightened response to hormones - estrogen/progesterone • Nonrandom X chromosome inactivation

Disseminated Peritoneal Leiomyomatosis (DPL)

• Often asymptomatic and incidental finding during pregnancy or procedure for other indication • Regression or if completely excised, no recurrence in most cases • Rarely more aggressive course reported, but these cases are atypical Disseminated Peritoneal Leiomyomatosis • Multiple subperitoneal nodules ranging from mm to cm in size – typically <2 cm, but 10 cm reported • Firm, tan white nodules with whorled pattern on cut section • No necrosis, hemorrhage or soft, fleshy foci • Spindle-shaped cells with blunt-ended nuclei arranged in intertwining bundles

Disseminated Peritoneal Leiomyomatosis

• May feature endometriosis - “miniature uteri” (disseminated adenomyosis) • Deciduation or hyalinization may be present • No atypia, no hypercellularity, no necrosis • Low mitotic index (< 3MF/10 HPF)

Differential Diagnosis

• Benign metastasizing leiomyoma • Leiomyosarcoma • Gastrointestinal stromal tumor Clinical History

• 33 year old with multiple nodules distributed over the ovaries & throughout the peritoneum at C-section

Decidual Reaction During Pregnancy

• Peritoneum • Lymph nodes – can mimic metastatic squamous cell carcinoma • Cervix • Fallopian tube • Vagina

Fallopian Tube Clinical History

• 28 year old with post-partum tubal ligation. Has germline BRCA1 mutation. Metaplastic Papillary Tumor

• Postpartum finding • Very rare • Noninvasive, mitotically inactive, and cytologically bland • Resembles exuberant serous borderline tumor with abundant eosinophilic cytoplasm

Differential Diagnosis

• Serous borderline tumor • Tubal hyperplasia • Serous tubal intraepithelial carcinoma Tubal Intraepithelial Carcinoma

• Serous histology • Nuclear pleomorphism • Increased nuclear/cytoplasmic ratio • Increased proliferation • Disorganized growth • Nucleoli often present • Typically fimbria or distal tube

Serous Tubal Intraepithelial Carcinoma

• 90% fimbria, 10% ampulla/isthmus • Approx 10-20% bilateral • Approx 20% multifocal

Am J Surg Pathol 2010;34:1407-16. Serous Papillary Tubal Hyperplasia

• Small rounded clusters of tubal epithelium • Small papillae • Cytologically banal • Psammoma bodies may be present • Putative precursor of serous borderline tumor*

Am J Surg Path 2011; 35:1605-14

Serous Tubal Intraepithelial Carcinoma

• 90% fimbria, 10% ampulla/isthmus • Approx 10-20% bilateral • Approx 20% multifocal

Am J Surg Pathol 2010;34:1407-16. Transitional Cell Metaplasia

• Common (25%) • Multifocal (2/3) with involvement of the tip, edges, or base of the fimbrial plicae • Small: mean 1.3 mm (range, 0.1 to 10 mm) • Histologically identical to Walthard rests

Am J Surg Pathol 2009;33:111-9

Squamous Metaplasia

• Diffuse pattern associated with band-like subsurface fibrosis in peritoneal dialysis patients • Micronodular pattern associated with inflammatory conditions.

Int J Gynecol Pathol 2008;27:465-74

Conservative (Medical) Management

• Oral Progestin Therapy • Levonorgestrel-releasing Intrauterine System (LNG-IUS) Oral Progestin Therapy

• Side effects • Requires compliance • Type of progestin product variable • Optimal dose not well defined • Duration of treatment not well defined Levonorgestrel-releasing Intrauterine System (LNG-IUS)

• Locally acting • Increased effect on endometrium • Improved compliance • Less side effects • Still relatively new treatment

Response Rate • Depends on pathology (but data conflicting): – Nonatypical hyperplasia > atypical hyperplasia > endometrioid carcinoma • Depends on menopausal status: – Mean time to regression 7.5 months in premenopausal women (range, 4-16 mos) – Mean time to regression 6.8 months in postmenopausal women (range, 4-10 mos). – Postmenopausal women may have better overall response than premenopausal, but data conflicting

Am J Surg Pathol 2007;31:988-998; Am J Clin Pathol 2012;138:524-534; Gynecol Oncol 2012;125:477-82 TREATMENT EFFECTS

• Architectural-stromal changes • Metaplastic changes • Cytological changes

Am J Surg Pathol 2007;31:988-998; Am J Clin Pathol 2012;138:524-534 Architectural-Stromal Changes

• Predecidual change • Decreased gland confluence and complexity • Papillary or cystic architecture

Am J Surg Pathol 2007;31:988-998; Am J Clin Pathol 2012;138:524-534

Metaplastic Changes

• Eosinophilic metaplasia • Mucinous metaplasia • “Secretory” • Squamous metaplasia (uncommon) • Mixed metaplasia

Mucinous Metaplasia

• Common • Often focal & mixed in postmenopausal women • Must distinguish from mucinous carcinoma • Localization issues: cervix, colon, appendix. other

Evaluation of Treated Hyperplasia/Carcinoma

• Compare prior, pre-treatment biopsy & all interval biopsies whenever possible • Evaluate entire specimen – ensure it is representative • Consider level sections (persistence of hyperplasia/carcinoma may be focal)

Evaluation of Treated Hyperplasia/Carcinoma

• No response • Partial response • Complete response (regression) No Response*

• No progestin effect – i.e., no stromal predicudation or metaplasia over and above pre-treatment • Gland complexity similar to pre-treatment biopsy • Cytological atypia similar to pre-treatment biopsy (if present)

*Requires at least 6 mos treatment Complete Regression

• Atrophy of glands • Proliferative or secretory pattern • Edematous fibrotic stroma • Stromal pseudodecidualization • No evidence of hyperplasia/carcinoma – depends on initial diagnosis • No cytological atypia Partial Response

• Decreased gland complexity with increased metaplasia • Persistent atypia may be present, but decreased compared to prior • Often focal residual gland complexity – must exclude focal process pre-treatment

Classification of Progestin-treated Lesions of the Endometrium Diagnosis Description Progestin-treated nonatypical No cytologic atypia. Crowded, hyperplasia back-to-back glands and/or a confluent glandular pattern

Progestin-treated atypical Cytologic atypia. Crowded, back- hyperplasia to-back glands that lack a confluent glandular pattern Progestin-treated well- Cytologic atypia. Confluent differentiated carcinoma glandular pattern (cribriform and/or papillary pattern).

Modified from Am J Surg Pathol 2007;31:988-998 Poor Prognostic Signs*

• Persistence of cytological atypia • Complex papillary architecture • Cribriform architecture - if more than minor element

Provided sufficient progestin treatment (dose, at least 6 mos duration, etc)

Am J Surg Pathol 2007;31:988-998; Am J Clin Pathol 2012;138:524-534 Cribriform Architecture Cribriform (higher magnification) The Pathology Report

• Note whether sampling is adequate • Note whether progestin effect is present • Compare priors !!! • Report all findings – requires microscopic description • Comment required in almost all cases

Thank you for your attention…