Reproductive System Pathology_FM Breast and FM Reproductive Systems

Marc Imhotep Cray, MD Photo: Color-enhanced scanning electron micrograph of a human spermatocyte fertilizing an oocyte; From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010

Learning Outcomes cont.

By the end of this sequence the learner will/should be able to: Breast:

1. List the inflammatory breast lesions and discuss their etiology.

2. Describe the morphology of the inflammatory breast lesions with special reference to breast abscess, duct ectasia and fat necrosis.

3. List the proliferative breast lesions and discuss their etiology.

4. Describe the morphology of the proliferative breast lesions with special reference to fibrocystic changes.

5. Explain the relationship between fibrocystic changes of the breast and breast cancer.

6. Classify breast tumors Marc Imhotep Cray, MD

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Female Breast Learning Outcomes cont.

7. Describe the morphology of the benign breast tumors with special reference to fibroadenoma and intraductal papilloma 8. List the risk factors of breast cancer 9. List the histological classification of breast cancer.

10.Explain the prognostic factors of the breast cancer with special reference to: stage at the time of diagnosis, histological features & Estrogen-receptor status 11.Describe the gross and microscopic features of different breast carcinoma with special reference to: in situ ductal carcinoma, in situ lobular carcinoma, invasive duct carcinoma, invasive lobular carcinoma & Paget’s disease of the breast.

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Learning Outcomes cont.

Female genital system: 1. Describe acute and chronic cervicitis.

2. Describe the pathogenesis, risk factors, clinical features and morphology of squamous cell carcinoma of cervix.

3. Describe the terms used in dysfunctional uterine bleeding and list its causes.

4. Describe endometritis with special references to various forms of endometritis.

5. Define endometriosis; explain the theories of endometriosis and its morphology and complications.

6. Describe endometrial polyps.

FM Reproductive Anatomy_ The Noted Anatomist Marc Imhotep Cray, MD

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FM Genital System Learning Outcomes cont.

7. Describe the three types of endometrial hyperplasia.

8. Describe risk factors, etiology, clinical features, morphology and pathogenesis of endometrial carcinoma as well its morphology.

9. Describe the morphology and clinical features of leiomyomas of the uterus.

10.List the differences between leiomyoma and leiomyosarcoma of the uterus.

11.Classify tumors and tumor like lesions of the ovary 12.Describe the pathogenesis and morphology of surface epithelium tumors, teratomas and granulose theca cell tumors Marc Imhotep Cray, MD

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Female Breast Pathology

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Female Breast Functional Anatomy  Functional unit of breast is lobule supported by a specialized intralobular stroma  Inner luminal epithelial cells produce milk during lactation  Basally located myoepithelial cells have contractile function to aid in milk ejection  Ducts are conduits for milk to reach the nipple Size of breast is determined primarily by interlobular stroma increases during puberty and involutes with age Each normal constituent is a source of both benign and malignant lesions

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Normal breast, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Breast, mammogram  A mammogram uses a small amount of x-radiation to visualize the breast parenchyma  This mammogram shows normal pattern of lactiferous sinuses and ducts. There is one suspicious density ( ), however, which could be a carcinoma or just an area of pronounced sclerosis with fibrocystic changes  A mammogram is a useful screening tool to find such lesions and to determine need for further workup  A mammogram may detect lesions that are not palpable  Women in their 30s begin to have some involution of lobules and adjacent stroma, and breast tissue becomes more radiolucent from an increased composition of adipose tissue replacing fibrous stroma and lobules Marc Imhotep Cray, MD

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal breast, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Origins of breast disorders  Benign epithelial lesions include intraductal papillomas that grow in sinuses below nipple & epithelial hyperplasia that arises in lobules  Malignant epithelial lesions are mainly breast carcinomas, which may remain in situ or invade into breast and spread by metastasis  Specialized intralobular stroma (green) cells may give rise to fibroadenomas and phyllodes tumors, whereas interlobular stroma (red) may give rise to a variety of rare benign and malignant tumors Marc Imhotep Cray, MD

Kumar, V; Abbas AK (Eds.), Robbins Basic Pathology, 10th Ed. Philadelphia: Elsevier, 2018; Fig.19.22, 736.

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Clinical Presentations of Breast Disease Predominant symptoms and signs of diseases of breast are pain, inflammatory changes, nipple discharge, “lumpiness,� or a palpable mass

Kumar, V; Abbas AK (Eds.), Robbins Basic Pathology, 10th Ed. Philadelphia: Elsevier, 2018; Fig.19.23, 737.

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Risk Factors for Breast Cancer Development Not Modifiable Age BRCA germline mutations Family history

Modifiable Body mass index Diet Alcohol

Chest radiation

Exogenous estrogen

Race/ethnicity Height

Exercise Smoking

Age at menarche Age at menopause Breast density

Reproductive history Age at first full-term delivery Lactation

Atypia on prior breast biopsy Redrawn after Rubin R and Strayer DS Eds. Rubin’s Essential of Pathology:, 6th Ed., 2014, Pg. 536.

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Clinical Presentations of Breast Disease: Key Points  Symptoms affecting breasts are evaluated primarily to determine if malignancy is present  Regardless of symptom, underlying cause is benign in majority of cases  Breast cancer is most commonly detected by palpation of a mass in younger women and in unscreened populations and by mammographic screening in older women

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Vignette #1 A 30-year-old woman presents to your clinic complaining of bilateral, diffuse breast pain. Her last menstrual period was 2 weeks ago and she says that she has felt several painful masses in both breasts during her self-examination in the shower. She is very concerned because she has a sister-in-law, who was recently diagnosed with breast cancer. On physical examination, you notice multiple, palpable masses on both breasts but no changes to the overlying skin. After taking a detailed history, you learn that the patient does not drink or smoke, has no immediate family members with a history of breast cancer, and there has been no nipple discharge. You order a fine needle aspiration cytology, which reveals an aspirate suggestive of a cyst. You reassure the patient that the lesion is benign and recommend that she avoid trauma to the affected regions and wear a brassiere that gives good support and protection.

What is the Diagnosis?

Marc Imhotep Cray, MD

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Fibrocystic Changes of the Breast Etiology and Epidemiology: Caused by hormonal imbalance (increased estrogens and/or decreased progesterones); Peak incidence is between 25 and 50 years old Pathology: Four histologic types: 1. Cystic: multiple fluid-filled cysts appear blue (blue-dome cyst)ďƒ cysts lined by polygonal cells with eosinophilic granular cytoplasm that are similar to apocrine epithelium (apocrine metaplasia), may see papillary projections of cystic epithelium; 2. Epithelial hyperplasia of breast duct: increase in number of epithelial layers in terminal duct lobules resulting in irregular lumens; 3. Stromal fibrosis: hyperplasia and fibrosis of breast stroma; 4. Sclerosing adenosis: increased number of acini, stromal fibrosis Marc Imhotep Cray, MD

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Fibrocystic Changes of the Breast cont.

Clinical Manifestations: Presents with diffuse breast pain (midcycle tenderness) and multiple, palpable lesions, often bilateral; no changes in overlying skin or nipple; rapid fluctuation in size of masses is common

Treatment: Symptom management with pain control NB: Fibrocystic changes are most common breast disorder  Cystic and stromal fibrosis represent no increased risk for carcinoma, but  Epithelial hyperplasia and sclerosing adenosis do carry a mildly increased risk

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Fibrocystic changes, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

Marc Imhotep Cray, MD

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Fibrocystic changes, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Sclerosing adenosis, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Epithelial hyperplasia, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal breast, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal breast, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal breast, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal lactating breast, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Acute mastitis, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Breast abscess, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Vignette #2 A 21-year-old African American woman presents to the clinic complaining of a large mass in her left breast. She has no immediate family members with breast cancer. On physical examination, you notice that the mass is round, rubbery, mobile, and nontender.

It is approximately 4 cm in diameter. You order a needle biopsy that shows a combination of connective tissue and cystic spaces taking on a leaflike appearance. You inform the patient that this lesion is most often benign, but nevertheless you suggest that she be treated with a local excision to remove the growth.

What is the Diagnosis?

Marc Imhotep Cray, MD

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Benign Tumors of the Breast Epidemiology: Fibroadenoma (FA): Occurs in women < 40; tends to occur more frequently and at a younger age in African American women; Phyllodes tumor (PT): Occurs most commonly after the age of 50; Intraductal papilloma (IP): Occurs in middle-aged women Pathology:  FA: Gross: small, mobile, rubbery, firm mass with sharp, well-circumscribed edges; Microscopic: fibroblastic stroma surrounding cystic and glandular spaces; may regress after menopause and demonstrate calcifications.  PT: Gross: large, bulky mass of connective tissue and cysts; Microscopic: cystic spaces on cut section of stroma contains leaflike projections from cyst walls; leaflike appearance on breast surface; 5%–10% undergoes malignant change with atypia (cystosarcoma phyllodes).  IP: Gross: arising from major lactiferous ducts; Microscopic: proliferation of ductal epithelial tissue in papillary growth manner; apocrine metaplasia Marc Imhotep Cray, MD

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Benign Tumors of the Breast cont.

Clinical Manifestations: FA and PT: Increased size and tenderness of mass with pregnancy or menstrual cycle; no overlying skin changes; no lymphadenopathy; no nipple retraction IP: Presents with nipple discharge Treatment: FA: No treatment or simple excision PT: Local excision with wide margin; can recur after resection IP: Simple excision Of note: Phyllodes tumor and intraductal papilloma carry a mildly increased risk of breast carcinoma Marc Imhotep Cray, MD

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Fibroadenoma, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Fibroadenoma, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Phyllodes tumor, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Phyllodes tumor, mammogram  This mammogram shows a bright, solid 10-cm rounded mass lesion consistent with a phyllodes tumor  It still has discrete margins, similar to a fibroadenoma, but is much larger  The biologic behavior of a phyllodes tumor is difficult to predict, and it may recur locally, but rarely are there highgrade lesions that can metastasize  Tend to occur at an older age than do fibroadenomas, most commonly in sixth decade Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Intraductal papilloma, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Vignette #3 A 50-year-old woman presents to your clinic after finding a mass on the upper outer quadrant of her left breast. After taking a thorough history, you learn that her mother died from breast cancer and her maternal aunt was also diagnosed with breast cancer at an early age. The patient started her period at age 11, did not bear any children, and has not been through menopause. On physical examination, she is markedly obese and you notice retraction of the skin and the nipple on her left breast. You locate the mass in question during your breast examination and find that it is fixed, hard, and nontender. The mass was not present on her last mammogram dating back 2 years. You also feel palpable axillary lymph nodes. You schedule the patient for an immediate mammography and needle biopsy to confirm your suspicions.

What is the Diagnosis?

Marc Imhotep Cray, MD

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Breast Carcinoma Etiology and Epidemiology: Risk factors include:  Family history of first-degree relative with breast cancer at young age (highest risk),  Autosomal dominant inheritance of mutations in BRCA1 or BRCA2 gene,  female gender,  Increased age,

Marc Imhotep Cray, MD

     

Early first menarche, Delayed first pregnancy, Nulliparity, Late menopause, Radiation exposure, and exogenous estrogen use

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Breast Carcinoma Epidemiology cont.  Breast carcinoma is the most common malignancy of women globally (excluding nonmelanoma skin cancer) and causes majority of cancer deaths in women

Incidence in United States decreased slightly in 2002 and then stabilized  changes attributed to a decrease in use of postmenopausal hormone therapy and a plateau in number of women undergoing mammographic screening  Worldwide incidence and mortality is increasing at an alarming rate  major factors underlying this trend in developing countries are thought to be social changes that increase breast cancer risk—specifically, delayed childbearing, fewer pregnancies, and reduced breastfeeding—combined with a lack of access to optimal health care Marc Imhotep Cray, MD

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Breast Carcinoma Pathology  Almost all breast malignancies are adenocarcinomas (>95%)

 In the most clinically useful classification system, breast cancers are divided based on expression of hormone receptors:  estrogen receptor (ER) and progesterone receptor (PR)—and  expression of human epidermal growth factor receptor 2 (HER2, also known as ERBB2 & HER2/neu), into three major groups: • ER positive (HER2 negative; 50%–65% of cancers) • HER2 positive (ER positive or negative; 10%–20% of cancers) • Triple negative (ER, PR, and HER2 negative; 10%–20% of cancers) Marc Imhotep Cray, MD

NB: These three groups show striking differences in patient characteristics, pathologic features, treatment response, metastatic patterns, time to relapse, and outcome

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Age and incidence of breast cancer subtypes  The three hormone receptors expression groups of the previous slide show striking differences in  patient characteristics,  pathologic features,  treatment response,  metastatic patterns,  time to relapse, and  outcome Kumar, V; Abbas AK (Eds.), Robbins Basic Pathology, 10

th

Ed. Philadelphia:

Elsevier, 2018; Fig.19.26, 740.

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FM Breast Anatomy

Marc Imhotep Cray, MD

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Breast Carcinoma Pathology cont.

1. Infiltrating ductal carcinoma: Tumor cells arranged in cords, islands, or glands embedded in dense fibrous stroma; may arise from ductal carcinoma in situ (DCIS) 2. Intraductal comedocarcinoma: Sheet of tumor cells confined within duct; central necrosis; periductal fibrosis with inflammation 3. Inflammatory: Lymphatic involvement of overlying skin 4. Paget disease: Paget cells (large cells w clear halo of pale cytoplasm) extend from ducts and invade epidermis of nipple; underlying ductal adenocarcinoma within subareolar excretory ducts always present Marc Imhotep Cray, MD

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Breast Carcinoma Pathology cont.

5. Infiltrating lobular: Often multiple and bilateral; cells line up (Indian file) with tumor cells surrounding lobule in target fashion; signet ring cells; may arise from lobular carcinoma in situ (LCIS) after many years 6. Medullary: Solid sheets of cells with large nucleoli in scant stroma; lymphocytic infiltrate 7. Mucinous (colloid): Pools of extracellular mucin surrounding tumor cell clusters; gelatinous consistency

Note: Breast carcinoma is second most common cause of cancer death among women Marc Imhotep Cray, MD

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Breast Cancer Morphology  Most common location of tumors within breast is in upper outer quadrant (50%), followed by central portion (20%)  About 4% of women with breast cancer have bilateral primary tumors or sequential lesions in the same breast  Breast cancers are classified morphologically according to whether they have penetrated the basement membrane • Those that remain within this boundary are termed in situ carcinomas, and • those that have spread beyond it are designated invasive carcinomas Marc Imhotep Cray, MD

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Breast Cancer Morphology cont.

In classification, above main forms of breast carcinoma are as follows: A. Noninvasive 1. Ductal carcinoma in situ (DCIS) 2. Lobular carcinoma in situ (LCIS) B. Invasive 1. Invasive ductal carcinoma (includes all carcinomas that are not of a special type)-70% to 80% 2. Invasive lobular carcinoma- 10% to 15% 3. Carcinoma with medullary features-5% 4. Mucinous carcinoma (colloid carcinoma) -5% 5. Tubular carcinoma-5% 6. Other types Adapted from: Kumar, V; Abbas AK (Eds.), Robbins Basic Pathology, 10th Ed. Philadelphia, Pa : Elsevier, 2018;742.

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Noninvasive (in Situ) Carcinoma  Two morphologic types of noninvasive breast carcinoma: ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) “ terms ductal and lobular are misleading, as both types of CIS are thought to arise from cells in terminal duct that give rise to lobules*”

 By definition, both "respect" the basement membrane and do not invade into stroma or lymphovascular channels •

DCIS has a wide variety of histologic appearances, including solid, comedo, cribriform, papillary, micropapillary, and "clinging" types

*From: Kumar, V; Abbas AK (Eds.), Robbins Basic Pathology, 10th Marc Imhotep Cray, MD

Ed. Philadelphia: Elsevier, 2018;743.

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Carcinoma in situ.

(A) Lobular carcinoma in situ (LCIS).

(B) Ductal carcinoma in situ (DCIS). DCIS partially involves the lobule in the lower half of this photo and has completely effaced the upper lobules, producing a ductlike appearance.

(C) Mammographic detection of calcifications associated with DCIS.

Kumar, V; Abbas AK (Eds.), Robbins Basic Pathology, 10th Ed. Philadelphia: Elsevier, 2018; Fig.19.28,743.

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Vignette #4 A 49-year-old woman presents to your office concerned about a rash on her left nipple that has developed over the past month. The rash is itchy, but painless. On physical examination, you find a large eczematous-like patch over the left nipple as well as a fixed mass in the left breast. You perform both a skin biopsy as well as a needle biopsy of the mass. When the skin biopsy reveals large cells with a clear halo of pale cytoplasm invading the epidermis, you become certain that the biopsy of the mass will reveal carcinoma of the breast.

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Breast Carcinoma cont.

Clinical Manifestations: Painless, usually fixed, hard, nontender mass often found in upper outer quadrant of breast; retraction of overlying skin and nipple; palpable axillary lymph nodes  Infiltrating ductal carcinoma: Firm, fixed, fibrous mass  Inflammatory: Red, swollen, hot, painful to touch, orange-peel appearance of skin  Paget disease: Itchy, scaly, painless, eczematous patches on nipple  Medullary: Soft, fleshy-consistency mass Lab findings: Paraneoplastic syndrome with secretion of PTH-related peptide may lead to hypercalcemia Imaging: Mammogram with microcalcifications, spiculated or enlarging mass Marc Imhotep Cray, MD

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Breast Carcinoma cont.

Treatment:  Surgery and radiation therapy;  Chemotherapy;  Hormonal therapy (tamoxifen or aromatase inhibitors) for patients with cancer cells expressing estrogen receptor in their nuclei (ER/PR+);  Biologic therapy Trastuzumab (herceptin) for patients with HER2/neu expression NB: Metastasis occurs to lymph nodes, lung, liver, and bone.

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Ductal carcinoma in situ, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Lobular carcinoma in situ, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Paget disease of breast, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Invasive ductal carcinoma, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Invasive ductal carcinoma, gross and mammogram

Marc Imhotep Cray, MD

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Infiltrating ductal carcinoma, gross and mammogram

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Breast Carcinoma Key Points Summary  The lifetime risk of developing breast cancer for an American woman is 1 in 8.

 A majority (75%) of breast cancers are diagnosed after the age of 50.  The major risk factors for developing breast cancer are related to hormonal factors and inherited susceptibility.  About 12% of all breast cancers are caused by identified germline mutations; BRCAI and BRCA2 genes account for one-half of the cases associated with single-gene mutations.  DCIS is a precursor to invasive ductal carcinoma and is most often found on mammographic screening as calcifications.  When carcinoma develops in a woman with a previous diagnosis of untreated it isMDusually is an invasive ductal carcinoma in the same breast.

Marc DCIS, Imhotep Cray,

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Breast Carcinoma Key Points Summary (2)  LCIS is both a marker of increased risk and a precursor lesion.  When carcinoma develops in a woman with a previous diagnosis of LCIS, twothirds are in the same breast and one-third is in the contralateral breast.  Invasive carcinomas are classified according to histologic type and biologic type: ER-positive/HER2-negative, HER2-positive, and ER/PR/HER2-negative (triple-negative). The biologic types of cancer have important differences in patient characteristics, grade, mutation profile, metastatic pattern, response to therapy, time to recurrence, and prognosis.  Prognosis is dependent on the biologic type of tumor, stage, and the availability of treatment modalities.

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Ovaries and Uterus Pathology

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Normal internal genitalia, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal internal genitalia, radiograph

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal fallopian tube, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal adult ovary, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Normal ovary, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Corpus luteum, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Menstrual cycle capsular summary:  Menstrual cycle is divided into follicular phase and luteal phase Ovulation defines transition between these two phases  During follicular phase, gonadotroph cells of anterior pituitary gland secrete LH and FSH in response to pulsatile GnRH stimulation  Circulating LH and FSH promote growth and maturation of ovarian follicles  Developing follicles secrete increasing amounts of estrogen  At first, estrogen has an inhibitory effect on gonadotropin release Just before midpoint in menstrual cycle, however, estrogen exerts a brief positive feedback effect on LH (LH Surge) and FSH release This is followed by follicular rupture and release of an egg into fallopian tube  During second half of cycle, corpus luteum secretes both estrogen and progesterone  Progesterone induces a change in endometrium from a proliferative to a secretory type  If fertilization and implantation of a blastocyst do not occur within 14 days after ovulation corpus luteum involutes secretion of estrogen and progesterone declines, menses occurs, and a new cycle begins Marc Imhotep Cray, MD

Cairo CW, Simon JB, Golan DE. (Eds.). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. LLW, 2012.

Hormonal Control of the Menstrual Cycle, Animation.

Marc Imhotep Cray, MD

Online Version

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Menstruation terminology  Dysmenorrhea= Pain with menses often associated with endometriosis  Oligomenorrhea > 35-day cycle  Polymenorrhea < 21-day cycle  Metrorrhagia= Frequent or irregular menstruation

 Menorrhagia= Heavy menstrual bleeding > 80 mL blood loss or > 7 days of menses  Menometrorrhagia= Heavy, irregular menstruation

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Vignette #5 A 45-year-old woman presents to the clinic complaining of vague abdominal pain for the past 4 days. She describes her pain as more of a pelvic pressure that is generalized bilaterally. Her last menstrual period was 2 weeks ago and she states that she has regular menstrual cycles. She denies the possibility of pregnancy and is currently not taking oral contraceptives. She has not had any changes in digestive functions and denies any nausea, vomiting, constipation, or diarrhea.

She has no family history of ovarian cancer. When an ultrasound confirms your suspicions, you place the patient on oral contraceptive pills, believing that her symptoms will disappear in 2 months, and you schedule her for a follow-up ultrasound.

What is the Diagnosis?

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Ovarian Cysts Etiology and Epidemiology:  Follicular (F) cyst: Associated with hyperestrinism and endometrial hyperplasia; most common cause of ovarian enlargement; mostly found during menstrual years  Corpus luteum (CL) cyst: Found during menstrual years  Theca-lutein (TL) cyst: Associated with choriocarcinoma, hydatidiform moles, and clomiphene (synthetic gonadotropin) therapy Pathology  F: Often bilateral; distention of unruptured Graafian follicle; lined by granulosa cells  CL: Often unilateral; contains clear fluid; lined by yellowish luteal cells with cytoplasmic lipid droplets; may hemorrhage into persistent mature corpus luteum  TL: Often bilateral and multiple; lined by luteinized theca cells Marc Imhotep Cray, MD

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Ovarian Cysts cont.

Clinical Manifestations: All may be asymptomatic or present with pelvic pressure/pain or vague GI discomfort  F: Pain not associated with menstruation  CL: Delayed menstruation  TL: Amenorrhea Lab findings: hCG elevated as a result of trophoblastic proliferation

Treatment:  F: Often disappears with 2-month regimen of oral contraceptives; follow with serial ultrasounds; laparoscopic removal if persistent  CL and TL: Cyst removal or unilateral oophorectomy Marc Imhotep Cray, MD

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Vignette #6 A 30-year-old white woman presents to the fertility clinic with her husband, complaining of the inability to conceive. The couple has already checked the husbandâ&#x20AC;&#x2122;s sperm motility and count, which are within the normal range. The patient informs you that she has not menstruated for the last 4 months and that she has had a very irregular and sporadic menstrual cycle all of her life. You perform a physical examination, finding that the patient is obese with an inordinate amount of facial hair. She denies any abnormal uterine bleeding. You order serum studies that show elevated plasma LH and testosterone and decreased FSH levels. Based on these findings, you inform the patient that weight reduction will be the most effective treatment for restoring ovulation and that adjunct therapy with clomiphene can aid in ovulation.

What is the Diagnosis?

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Polycystic Ovarian Syndrome (Stein-Leventhal Syndrome) Etiology and Epidemiology: Etiology unclear, but it is believed that a dysregulation of enzymes involved in androgen biosynthesis may be caused by increased LH secretionď&#x192; thereby resulting in excessive production of androgens; associated with obesity, Cushing syndrome, congenital adrenal hyperplasia, genetic predisposition, and androgen-secreting adrenal tumors Common endocrine disorder affecting 2%â&#x20AC;&#x201C;5% of women during reproductive age Pathology and Pathophysiology: Pathophysiology: Increased androgen production causes anovulation, multiple follicular cysts, and theca cell hyperplasia Gross: Ovaries enlarged; pearly white thickened ovarian capsule; multiple cysts Microscopic: Cysts have granulosa cell layer and luteinized theca cells; cortical stromal fibrosis Marc Imhotep Cray, MD

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PCOS cont.

Clinical Manifestations: Amenorrhea; infertility; obesity; hirsutism (in 70%); insulin resistance with increased risk of diabetes; virilism; increased risk of breast and endometrial carcinoma Lab findings: Increased LH, decreased FSH, increased testosterone, evidence of insulin resistance Treatment: Weight loss; oral contraceptives; metformin for insulin resistance; gonadotropin analogs; ovulation induction with clomiphene

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Polycystic ovary, MRI

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Polycystic ovarian syndrome, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015.

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Vignette #7 A 40-year-old woman presents to the emergency room with generalized abdominal pain and pelvic pressure. After taking a more complete history, you learn that she has not passed stool for the last 3 days and vomited this morning. She tells you that the pain has been steady over the last week. You order an abdominal/pelvic CT scan, which is inconclusive, but does demonstrate bilateral enlargement of the ovaries. The patient is taken to the operating room for an exploratory laparotomy that shows extensive mucinous ascites, cystic epithelial implants on the peritoneal surfaces, and several adhesions. You believe that the patientâ&#x20AC;&#x2122;s mucinous peritoneal involvement is caused by her ovarian condition.

What is the Diagnosis?

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Ovarian Tumors of Surface Epithelium Origin Epidemiology: Usually occurs in women > 20 years of age Pathology:  Serous cystadenoma: Bilateral, benign cyst with fallopian tube-like epithelium  Papillary serous cystadenocarcinoma: Bilateral, malignant cysts lined by stratified atypical epithelium; papillary growth; psammoma bodies  Mucinous cystadenoma: Multilocular, benign cysts with columnar cells filled with mucin  Mucinous cystadenocarcinoma: Malignant tumor with mucus-secreting atypical columnar epithelium; loss of gland architecture; necrosis  Brenner tumor: Benign tumor with nests of cells resembling bladder transitional epithelium interspersed in fibrous stroma  Endometrioid tumor: Malignant tumor resembling endometrium Clear cell tumor: Rare, malignant tumor composed of sheets of clear cells Marc Imhotep Cray, MD

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Ovarian Tumors of Surface Epithelium Origin cont.

Clinical Manifestations: Mild, nonspecific abdominal discomfort; malignant forms may present with weakness, weight loss, and anorexia; pseudomyxoma peritonei (intraperitoneal accumulation of mucinous material) is associated with mucinous cystadenocarcinoma Lab finding: Elevated CA-125 in ovarian carcinomas Treatment: Tumor removal; oophorectomy or hysterectomy; chemotherapy Of note: Ovarian epithelial tumors make up 75% of ovarian tumors.

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Serous cystadenoma, gross

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Serous cystadenoma, MRI and CT image

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Multiloculated ovarian tumor, gross

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Cystadenoma, serous, mucinous, microscopic

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Borderline serous tumor, microscopic

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Borderline tumor, gross

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Cystadenocarcinoma & peritoneal metastases, CT images

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Cystadenocarcinoma, gross

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Cystadenocarcinoma, microscopic

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Endometrioid tumor, microscopic

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Brenner tumor, microscopic

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Vignette #8 An 18-year-old white woman is admitted to your gynecologic service with a 1month history of increasing abdominal pain and a rapidly enlarging pelvic mass. While admitting the patient, you perform a bimanual pelvic examination that reveals a left ovarian mass. This finding is consistent with the admitting note and was confirmed by abdominal/pelvic CT, which showed that the left ovary was twice as large as the right ovary. Serum studies demonstrate an elevated AFP level. There is no inguinal lymph node involvement and no signs of metastasis on imaging studies. Based on your findings, you perform a unilateral oophorectomy and send the diseased ovary for pathologic analysis.

Histology shows glomerulus-like structures composed of a central blood vessel enveloped by germ cells within a space similarly lined by germ cells. These histologic bodies confirm your suspected diagnosis and you start the patient on combination chemotherapy What is the Diagnosis?

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Ovarian Tumors of Germ Cell Origin Etiology and Epidemiology: Risk factors include nulliparity, positive family history of ovarian cancer, mutations in BRCA1 and BRCA2 genes and high expression of HER2/neu oncogene; Occurs most commonly in children and young adults (except for teratomas, which can occur at all ages) Pathology:  Dysgerminoma: Malignant unilateral tumor comprised of large vesicular cells with clear cytoplasm and central nuclei; analogous to male testicular seminoma  Yolk sac tumor: Malignant tumor with Schiller-Duval bodies (glomerulus-like structure composed of central blood vessel enveloped by germ cells)  Choriocarcinoma: Aggressive and malignant tumor with areas of necrosis and hemorrhage composed of neoplastic syncytiotrophoblasts and cytotrophoblasts  Teratoma: 90% of germ cell tumors; mature teratomas (dermoid cysts) are benign; immature are malignant ; Histology: structures from all germ layers.  Struma ovarii: Unilateral ovarian teratoma composed of thyroid tissue Marc Imhotep Cray, MD

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Ovarian Tumors of Germ Cell Origin cont.

Clinical Manifestations: Mild, nonspecific abdominal discomfort; struma ovarii may lead to hyperthyroidism Lab findings: Increased AFP (yolk sac), increased hCG (choriocarcinoma) Tx: Tumor removal; oophorectomy or hysterectomy; chemotherapy Note: Germ cell tumors make up 25% of ovarian tumors

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Mature cystic teratoma, gross

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Mature cystic teratoma, CT image

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Mature cystic teratoma, microscopic

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Dysgerminoma, gross

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Dysgerminoma, microscopic

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Vignette #9 A 12-year-old girl is brought into the emergency room because of heavy vaginal bleeding. The child is also complaining of GI discomfort and pelvic pressure. She states that she had her last menstruation 2 weeks earlier and she is not sexually active. Her first menstruation was at the age of 10. On physical examination, the child appears to have undergone precocious puberty. A pelvic examination reveals a palpable right ovarian mass, which is confirmed by a CT scan. Serum studies show a significantly increased level of circulating estrogen.

When a biopsy reveals distinctive, gland-like structures filled with an acidophilic material, you worry that this patient may have an increased risk of developing endometrial carcinoma later in life if this mass is not removed.

What is the Diagnosis?

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Ovarian Tumors of Sex Cord–Stromal Origin Etiology and Epidemiology: Risk factors include nulliparity, positive family history of ovarian cancer, mutations in BRCA1 and BRCA2 genes, and high expression of HER2/neu oncogene; Affects all age groups Pathology and Pathophysiology:  Ovarian fibroma-thecoma (OFT): Secretes estrogen; tumor composed of round lipid-containing cells in addition to well-differentiated fibroblasts  Granulosa cell tumor (GCT): Secretes estrogen causing endometrial hyperplasia/carcinoma in adults; characterized by Call-Exner bodies (small follicles filled with eosinophilic secretions) and small cuboidal, deeply stained granulosa cells arranged in anastomotic cords  Sertoli-Leydig cell tumor (SLCT): Secretes androgens; tumor composed of Sertoli or Leydig cells interspersed with stroma Marc Imhotep Cray, MD

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Ovarian Tumors of Sex Cord–Stromal Origin cont.

Clinical Manifestations: Mild, nonspecific abdominal discomfort  OFT: Presents with Meig syndrome (triad of ovarian tumor, ascites, and hydrothorax)  GCT: Vaginal bleeding from endometrial hyperplasia; cystic disease of breast; endometrial carcinoma  SLCT: Virilism Lab findings: Increased estrogen levels (OFT and GCT)

Treatment: Tumor removal; oophorectomy or hysterectomy; chemotherapy Note: Ovarian sex cord–stromal tumors are rare Marc Imhotep Cray, MD

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Granulosaâ&#x20AC;&#x201C;theca cell tumor, gross

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Granulosa cell tumor, microscopic

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Thecoma-fibroma, gross

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Thecoma-fibroma, microscopic

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Vignette #10 A 31-year-old woman presents to the clinic complaining of abnormal vaginal bleeding. She states that her last menstrual period was 1 week ago and that she has not experienced abnormal bleeding before. Her past medical history is notable for two prior episodes of pelvic inflammatory disease in the last year. She has also been trying to conceive for the last year without success. On pelvic examination, redness and inflammation of the cervix is visible, but no discharge is apparent. You obtain an endometrial biopsy, which you suspect will show plasma cells along with macrophages and leukocytes in the glandular lumen. You begin empiric antibiotic therapy to prevent possible sequelae from the suspected diagnosis.

What is the Diagnosis?

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Endometritis Etiology:  Acute endometritis: Caused by trauma, Staphylococcus aureus and Streptococcus species; usually occurs after delivery or miscarriage;  Chronic endometritis: Caused by granulomatous disease, chronic PID, postpartal or postabortal states, and TB Pathology: Endometrium: Plasma cells seen with macrophages and lymphocytes Clinical Manifestations: Acute: Presents with inflammation after delivery or miscarriage Chronic: Presents with abnormal vaginal bleeding, pain, discharge, and infertility

Treatment: Antibiotic Tx (helps to prevent other sequelae, such as salpingitis) Of Note: Endometrial polyps are masses composed of endometrial tissue within endometrial cavity  occur in women older than 40 years of age and may result in uterine but are usually benign Marc Imhotepbleeding, Cray, MD

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Acute endometritis, microscopic

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Chronic endometritis, microscopic

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Granulomatous endometritis, microscopic

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Vignette #11 A 24-year-old woman presents to the clinic complaining of increased pain and bleeding during menstruation. Her last three menstruations have been accompanied by increasing intensity of cramping and larger amounts of blood. She tells you that her menstrual cycle has been irregular for the last 6 months. After taking a complete history, you learn that she has been having increased pelvic pain with intercourse. On pelvic examination, you palpate fixed, bilateral ovarian masses and an MRI reveals chocolate cysts on the ovary. You begin the patient on oral contraceptives and you suggest surgical removal of the masses if the pain persists.

What is the Diagnosis?

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Endometriosis Etiology and Epidemiology: Etiology unknown, but thought to be caused by a combination of genetic, hormonal, and immune factors; Afflicts 10% of women, usually between the ages of 20 and 30 Pathology: ď&#x201A;§ Gross: Non-neoplastic nodules, composed of endometrial tissue in abnormal locations outside the uterus, including ovary (most common), uterine ligaments, rectovaginal septum, and pelvic peritoneum; presence of chocolate cysts on ovaries that have resulted from cyclic bleeding (menstrual type) of ectopic endometrial tissue ď&#x201A;§ Microscopic: Endometrial glands; endometrial stroma; presence of hemosiderin pigment Marc Imhotep Cray, MD

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Endometriosis cont.

Clinical Manifestations: Presents with fixed, palpable, bilateral ovarian masses, pain during menses (dysmenorrhea), and pain during intercourse (dyspareunia); menstrual irregularities may lead to infertilityď&#x192; presenting complaint of 30%â&#x20AC;&#x201C;40% of pts.

Treatment: Oral contraceptives; progesterone; danazol; GnRH; surgical removal/coagulation (cauterization) of lesion Note: Adenomyosis is endometriosis within the myometrium and usually presents with uterine enlargement and irregular bleeding Marc Imhotep Cray, MD

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Adenomyosis, MRI

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Adenomyosis, gross

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Adenomyosis, microscopic

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Endometriosis, gross

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Endometriosis, gross

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Endometriosis, microscopic

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Endometrial polyp, gross

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Vignette #12 A 35-year-old African American woman presents to the clinic complaining of more frequent menstrual periods and profuse menstruation. She also complains of increased weakness and fatigue during her menstruations. On physical examination, you find a firm abdominal mass in the pelvic region. When questioned, she states that she was aware of the mass, but she notes that the mass often only appears during menstrual periods. When a biopsy of the mass reveals whorled bundles of smooth muscle cells, you reassure this patient that her condition is unlikely to proceed to malignancy.

What is the Diagnosis?

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Leiomyoma (fibroids) Etiology and Epidemiology: Etiology unknown, but chromosomal abnormalities have been found in tumor cells; Most common benign neoplasm of female genital tract; Most commonly seen in women of reproductive age with an increased incidence in African Americans Pathology: Gross: Multiple, enlarged, irregular, heterogenous tumors in the myometrium (intramural), beneath endometrium (submucosal), or beneath serosa (subserosal); tumor is estrogen-sensitive with its size increasing during pregnancy and decreasing with menopause Microscopic: Whorled pattern of smooth muscle bundles; rare mitoses in muscle cells, although cellular atypia and giant cells may be present

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Leiomyoma (fibroids) cont.

Clinical Manifestations: Profuse menstruation; frequent menstrual periods; acute or recurrent pelvic pain; urinary frequency (owing to compression of bladder); infertility Lab findings: Iron deficiency anemia (owing to blood loss)

Treatment: Myomectomy or hysterectomy; uterine artery embolization Note: Also called uterine fibroids, leiomyomas do not progress to leiomyosarcomas ď&#x201A;§ Leiomyosarcomas are fleshy, irregular tumors with areas of necrosis and hemorrhage that arise de novo and may protrude from cervix ď&#x201A;§ Leiomyosarcomas are more prevalent among African Americans, are malignant, and can be treated with combination chemotherapy Marc Imhotep Cray, MD

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Leiomyomata, gross

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Uterine fibroids as seen during laparoscopic surgery

https://commons.wikimedia.org/wiki/File:Uterine_fibroids.jpg Marc Imhotep Cray, MD

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Leiomyomata, MRI and CT image

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Leiomyoma, microscopic

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Leiomyosarcoma, gross

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Leiomyosarcoma, microscopic

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Vignette #13 A 60-year-old woman presents to the clinic with postmenopausal vaginal bleeding. After taking a complete history, you learn that she is nulliparous and suffers from type 2 diabetes, which is well-controlled with diet and insulin. On physical examination, the woman is obese and has a blood pressure reading of 150/96. You decide to perform a PAP smear as well as an endometrial biopsy. Based on the patientâ&#x20AC;&#x2122;s presenting signs and medical history, you are worried that you might find well-defined gland patterns lined by malignant stratified columnar epithelial cells on endometrial biopsy.

What is the Diagnosis?

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Endometrial Carcinoma Etiology and Epidemiology: Risk factors include unopposed estrogen use, obesity, diabetes, HTN, nulliparity, and late menopause Peak incidence is between 55 and 65 years of age Endometrial carcinoma is most common gynecologic malignancy Pathology: Typically preceded by endometrial hyperplasia Gross: Localized polypoid tumor or diffuse tumor involving entire endometrial surface Microscopic: Adenocarcinoma characterized by well-defined gland patterns lined by malignant stratified columnar epithelial cells; may see some squamous cells

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Endometrial Ca. cont.

Clinical Manifestations: Presents with postmenopausal vaginal bleeding, leading to early diagnosis; may cause obstruction of cervix with collection of pus (pyometra) or blood (hematometra) presenting with lower abdominal pain Treatment: Total hysterectomy and bilateral salpingo-oophorectomy; radiation therapy Important Note:  Endometrial hyperplasia is abnormal endometrial gland proliferation caused by excess estrogen (eg, polycystic ovarian syndrome, estrogen-secreting ovarian tumor, estrogen replacement therapy)  It manifests clinically with postmenopausal vaginal bleeding  may lead to endometrial cancer depending on degree of atypia Marc Imhotep Cray, MD

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Endometrial atypical hyperplasia, microscopic

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Endometrial carcinoma, gross

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Endometrial carcinoma, gross (2)

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Endometrial carcinoma, type I, microscopic

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Endometrial carcinoma, type II, microscopic

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Vignette #14 A 42-year-old woman presents to the clinic complaining of postcoital bleeding and vaginal discharge. She complains of a 3-month history of spotting in her underwear after intercourse and an odorous vaginal discharge that is not purulent. Her social history is significant for past practice of prostitution and her past medical history is significant for several STDs that were appropriately treated. She has not had a routine PAP smear in over 10 years. After a PAP smear reveals abnormal cells, you perform a cervical biopsy, worrying that you may find invasive malignant cells in the cervix and adjacent koilocytosis.

You fear that the patient will need to undergo a hysterectomy with possible adjunct radiation therapy if your suspected diagnosis is confirmed.

What the Marc Imhotepis Cray, MD Diagnosis?

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Dysplasia, Carcinoma in Situ, and Squamous Cell Carcinoma of the Cervix Etiology and Epidemiology: Associated with human papilloma virus (HPV) types 16, 18, 31, and 33, early age of first intercourse and multiple sexual partners Occurs most commonly between the ages of 30 and 45 Pathology: Cervical dysplasia: Involves squamocolumnar junction; characterized by cells with hyperchromatic nuclei, irregular nuclear contours, and scant cytoplasm; epithelial growth begins at basal layer extending outward; classified as Cervical Intraepithelial Neoplasia (CIN) Subtypes Grades I-III (or Squamous Intraepithelial Lesions Low-grade to High-grade )  CIN I (LSIL) is characterized by atypical undifferentiated cells only in lower third of epithelium, whereas  CIN II (HSIL) superficial layer of cells still shows differentiation and koilocytosis  CIN III (HSIL) has atypia through > 2/3 thickness of epithelium, koilocytotic change usually is absent Marc Imhotep Cray, MD

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Dysplasia, Carcinoma in Situ, and Squamous Cell Carcinoma of the Cervix (2) Pathology cont: Cervical carcinoma in situ (CIS): Dysplastic cells extending through entire epithelium, but without invasion of basement membrane Invasive cervical carcinoma (ICC): Gross: can be exophytic, ulcerating, or infiltrating mass Microscopic: usually squamous cell carcinoma with large cells and keratinization; can be adenocarcinoma or undifferentiated carcinoma; arises from preexisting CIN at squamocolumnar junction; non-neoplastic epithelial cells often demonstrate koilocytosis (assoc. w. HPV infection) Koilocytes, also known as halo cells, are a type of epithelial cell that develops following a human papillomavirus (HPV) infection; They are structurally different from other epithelial cells, in that, their nuclei are an irregular size, shape, or color Marc Imhotep Cray, MD

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Natural History of Squamous Intraepithelial Lesions (SILs) Lesion LSIL (CIN I)

Regress 60%

Persist 30%

Progress 10% (to HSIL)

HSIL (CINII,III)

30%

60%

10% (to carcinoma)*

*Progression within 10 years. LSIL, Low-grade SIL; HSIL, high-grade SIL Redrawn after Kumar V and Abbas AK. Robbins and Cotran Basis Pathology, 10th Ed. Philadelphia: Saunders, 2018, Fig. 19.1 , Pg. 718.

Remember: Cervical Intraepithelial Neoplasia (CIN) Subtypes Grades I-III (or Squamous Intraepithelial Lesions Low-grade to High-grade )  CIN I (LSIL) is characterized by atypical undifferentiated cells only in lower third of epithelium, whereas,  CIN II (HSIL) superficial layer of cells still shows differentiation and koilocytosis  CIN III (HSIL) has atypia through > 2/3 thickness of epithelium, koilocytotic change usually is absent Marc Imhotep Cray, MD

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Three Stages of squamous intraepithelial lesions (SIL)

Spectrum of squamous intraepithelial lesions (SIL) with normal squamous epithelium for comparison: LSIL with koilocytotic atypia; HSIL w progressive atypia in all layers of the epithelium; and HSIL w diffuse atypia and loss of maturation (carcinoma in situ, far right image) Kumar V and Abbas AK. Robbins and Cotran Basis Pathology, 10th Ed. Philadelphia: Saunders, 2018, Fig. 19.6 , Pg. 719.

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Cytologic features of squamous intraepithelial lesion (SIL) in a Papanicolaou Smear

Superficial squamous cells may stain either red or blue.

(A) Normal exfoliated superficial squamous epithelial cells. (B) Low-grade squamous intraepithelial lesion (LSIL).

(C and D) Both high-grade squamous intraepithelial lesions (HSILs). Note the reduction in cytoplasm and the increase in the nucleus-to-cytoplasm ratio as the grade of the lesion increases. This observation reflects progressive loss of cellular differentiation on surface of cervical lesions from which these cells are exfoliated Kumar V and Abbas AK. Robbins and Cotran Basis Pathology, 10th Ed. Philadelphia: Saunders, 2018, Fig. 19.7 , Pg. 719.

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Dysplasia, Carcinoma in Situ, and Squamous Cell Carcinoma of Cervix (3) Clinical Manifestations: ICC: Irregular vaginal bleeding; postcoital spotting; cervical ulceration; nonpurulent discharge; dysuria; invasive disease can obstruct uretersď&#x192; and lead to renal failure Treatment ICC: Hysterectomy; radiation therapy; prevention with HPV vaccine

NB: Screening for cervical cancer with PAP smears should begin 3 years after intercourse and no later than age 21 and continue every 1â&#x20AC;&#x201C;3 years until age 70 Marc Imhotep Cray, MD

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Normal cervix, gross

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Normal cervix, microscopic

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Normal cervical transformation zone, microscopic

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Chronic cervicitis, gross

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Chronic cervicitis, microscopic

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Cervical squamous metaplasia, microscopic

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Human papillomavirus effect, microscopic

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Cervical squamous dysplasia, Pap smear

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Cervical squamous carcinoma, Pap smear

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Squamous cell carcinoma, gross

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Squamous cell carcinoma, gross (2)

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Squamous cell carcinoma, gross (3)

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Vignette #15 A 27-year-old woman presents to the emergency room with lower abdominal pain, chills, fever, and a purulent vaginal discharge. After taking a history, you learn that she has had multiple sexual partners over the last year and has not practiced safe sex. She states that the pain started 3 days ago with subsequent fevers, chills, and night sweats. On physical examination, she is febrile with a temperature of 102.4°F. Pelvic examination is significant for cervical motion tenderness with foul-smelling, purulent, cervical discharge. Her pregnancy test is negative. You admit the patient to the hospital and you begin her on IV cefoxitin plus doxycycline while awaiting the results of her endocervical culture.

What is the Diagnosis?

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Pelvic Inflammatory Disease Etiology and Epidemiology: Common causes include Chlamydia trachomatis (subacute), Neisseria gonorrhoeae (acute), Gardnerella vaginalis, and Trichomonas vaginalis; Usually occurs in young, nulliparous, sexually active women with multiple partners Pathology: Fallopian tubes: Edematous tubal serosa with fibrin covering; purulent exudate in lumen; collections of pus may form a pyosalpinx or degrading pus may form a hydrosalpinx (water-filled fallopian tubes) Infection can also involve the ovaries and other pelvic structures

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PID cont.

Clinical Manifestations: High fever; lower abdominal pain; cervical motion tenderness (chandelier sign); purulent cervical discharge; RUQ pain indicates perihepatitis (Fitz-Hugh-Curtis syndrome); Salpingitis is a risk factor for ectopic pregnancy, infertility, chronic pelvic pain, and adhesions

Treatment: Antibiotics effective against causative organism Note: Ectopic pregnancy occurs most often in fallopian tubes, but may also occur in ovary, abdominal cavity, or cervix  Risk factors include salpingitis, endometriosis, and tubal ligation  Clinical manifestations include severe abdominal pain 6 weeks after LMP and elevated hCG which is lower than normal for pregnancy stage

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Pathogenesis of gonococcal infections

Click for large view

 Neisseria gonorrhoeae is a gram-negative diplococcus whose surface pili form a barrier against phagocytosis by neutrophils

 Pili contain an immunoglobulin A (IgA) protease that digests IgA on luminal surface of mucous membranes of urethra, endocervix and fallopian tube thereby facilitating attachment of gonococci  Gonococci cause endocervicitis, vaginitis and salpingitis  In men, gonococci attached to mucous membrane of urethra cause urethritis and, sometimes, urethral stricture  GC may also attach to sperm heads and be carried into the fallopian tube Penetration of mucous membrane by gonococci leads to stricture of fallopian tube, pelvic inflammatory disease (PID) or tuboovarian abscess Marc Imhotep Cray, MD

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012; Fig. 9.18, 394.

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Gonorrhea of the fallopian tube Cross-section of a “pus tube” shows thickening of wall and a lumen swollen with pus

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Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012; Fig. 9.19, 394.

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Acute salpingitis, microscopic

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Tubo-ovarian abscess, gross

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Ectopic pregnancy, gross

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Vignette #16 After vaginally delivering a newborn from a 32-year-old woman, you find the mother to be hemorrhaging an abnormally large amount of blood. You recall that she has had one previous C-section and extensive scarring. Given the amount of blood after delivery and the abnormal gross appearance of the placental remnants, you believe that the patientâ&#x20AC;&#x2122;s pregnancy was complicated by a defective decidual layer that allowed the placenta to attach directly to the myometrium.

You call the operating room to set up for an emergency hysterectomy, which you believe may be necessary to control the patientâ&#x20AC;&#x2122;s massive hemorrhage.

What is the Diagnosis?

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Placental Attachment Abnormalities (Abruptio Placentae, Placenta Previa, Placenta Accreta) Etiology: Abruptio placentae: May be associated with DIC; increased risk with smoking, cocaine, and hypertension Placenta accreta: Predisposed by prior C-section scars or endometrial inflammation Placenta previa: Predisposed by prior C-section scars Pathophysiology: Abruptio placentae: Premature separation of placenta Placenta accreta: Defective decidual layer allows placenta to attach directly to myometrium Placenta previa: Attachment of placenta to lower uterine segment or cervix; may occlude cervical os; may coexist with placenta accreta Marc Imhotep Cray, MD

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Placental Attachment Abnormalities cont.

Clinical Manifestations: Abruptio placentae: Painful uterine bleeding usually during third trimester; can result in fetal death Placenta accreta: Massive hemorrhage after delivery Placenta previa: Painless bleeding in any trimester; premature labor Treatment: Abruptio placentae: Immediate fetal delivery; control of maternal bleeding Placenta accreta: Hysterectomy may be necessary to stop bleeding Placenta previa: Bed rest; possible hospitalization

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Vignette #17 A 31-year-old pregnant woman is brought to the emergency room complaining of headaches and blurred vision of 1-week duration. She is currently 32 weeks into her first pregnancy. On physical examination, you find edema of the face and lower extremities. Her blood pressure is 160/100, but she has no prior history of hypertension. Laboratory studies show a mild thrombocytopenia, elevated AST and ALT, and significant proteinuria. Based on these findings, you admit the patient for immediate bed rest, close monitoring, and blood pressure control. You tell the patient that it is possible that you may need to deliver her baby early in order to treat the patientâ&#x20AC;&#x2122;s current condition.

What is the Diagnosis?

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Preeclampsia and Eclampsia Etiology and Epidemiology: Risk factors include preexisting hypertension, diabetes, chronic renal disease, autoimmune disorders, or twin gestation Affects 7% of pregnant women usually during the third trimester of a womanâ&#x20AC;&#x2122;s first pregnancy Pathology and Pathophysiology: Placenta: Evidence of infarct; presence of retroplacental hematomas; decreased vascularity; fibrinoid necrosis ď&#x201A;§ Pathophysiology: Intrinsic defect in invading cytotrophoblast leads to remodeling of uterine vasculature and resulting placental ischemia; decreased placental perfusion induces vasoconstrictive effects leading to toxemic hypertension in susceptible women

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Preeclampsia and Eclampsia cont.

Clinical Manifestations: Preeclampsia: Triad of hypertension, proteinuria, and edema; associated Sx include headache, blurry vision, and abdominal pain Eclampsia: Preeclampsia triad plus seizures, altered mentation, hyperreflexia, and possibly DIC Lab findings: Thrombocytopenia, elevated LFTs, hyperuricemia, hemolytic anemia Treatment: Preeclampsia: Delivery of fetus as soon as possible; bed rest; salt restriction; treatment of hypertension Eclampsia: Medical emergency; treat with IV magnesium sulfate and diazepam; delivery of fetus NB: HELLP syndrome refers to hemolysis, elevated LFTs, and low platelets and is a severe form of preeclampsia (Video on HELLP syndrome & â&#x20AC;&#x153;USMLEâ&#x20AC;?)

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THE END

See next slide for further study.

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Companion Tools and Resources (online) Discipline (Pathology) Track Folder  Reproductive Pathology Organ Systems Track Folders  M and FM Reproductive System & FM Breast  Pregnancy, Childbirth, & the Puerperium Textbooks: Kumar V and Abbas AK. Robbins and Cotran Basis Pathology, 10th Ed. Philadelphia: Saunders, 2018.

Rubin R and Strayer DS Eds. Rubin’s Essential of Pathology:, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2014.

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