CORRECTION: Cervical Carcinoma 5 year survival rates

1. CORRECTION: Cervical Carcinoma 5 year survival rates • Use Robbins’ as your standard reference for this! • Stage IA—95% Stage IB—80-90% • Stage II—75% • Stage III and IV--<50%

2. Extra HPV slides 2005

3. HPV is required but not sufficient for cervical carcinogenesis.

4. HPV carcinogenesis in a nutshell • HPV infects and transcribes early genes in immature squamous cells. • E7 and E6 decrease levels of pRB and p53, respectively, by BINDING them. • HPV 6 and 11 (low risk virus types) do NOT bind the cellular proteins well. • HPV 16 and 18 (high risk virus types) DO bind these proteins well. • The resulting dysregulation of the cell-cycle leads to cellular transformation and potential carcinogenesis. • In some cancers, the viral genome is found to be integrated into the cell genome, often disrupting E2. (This event is not necessary for carcinogenesis).

5. Cervical squamous cell precursor lesions • CIN 1: mild dysplasia. • Viral effect (koilocytosis) and atypia in the upper 1/3 of the epithelium. • The important part would be that CIN 1 has only 1/3 epithelial thickness involvement. You may hear this described as atypia of lower third—referring to the intense proliferation of the basal layer—historically how mild dysplasia was described. The Harvard pathologists, however, interpret this as atypia in the upper third with proliferation, not real atypia, at the base. The Robbins’ chapter was written by a Harvard pathologist who also trained the pathologist who gave you your lecture on the subject and wrote the test questions. So the answer is…upper third epithelial atypia. • Condylomas are included in this category. • LSIL: A Pap smear of a CIN 1 lesion should result in the diagnosis of Low-grade Squamous Intraepithelial Lesion on the pap smear report.

6. CIN 2: moderate dysplasia • Squamous cell atypia extending through at least 2/3 of the epithelial thickness. Often there will be some maturation of the surface. • HSIL: A pap smear of a CIN 2 lesion should result in a High-grade Squamous Intraepithelial Lesion diagnosis.This is because atypia is present in the more immature cells. • This “mature” atypia may be similar to CIN 1, thus the final diagnosis should be based on biopsy (see next slide).

7. CIN 1-MILD DYSPLASIA --OBSERVE FOR PERSISTENCE Scrape Surface cells only PAP: LOW GRADE SIL If the atypical immature cells are sampled In the pap smear, the pap would be diagnosed As High-Grade SIL. CIN 2—MODERATE DYSPLASIA --ABLATE

8. CIN 3: severe dysplasia (squamous cell carcinoma in situ) • Full-thickness epithelial atypia. Usually no maturation seen, which indicates a severe dysregulation of the cells, since the cells can no longer even differentiate. • HSIL: A pap smear of this lesion should result in a High-grade Squamous Intraepithelial Lesion diagnosis.

9. Pap smear terminology • Low grade Squamous Intraepithelial Lesion (LSIL/LGSIL) and CIN 1. • Includes viral effect, koilocytosis, and mild dysplasia. • Why are warts (condyloma) included with mild dysplasia” • The two are difficult to consistently separate morphologically. • The two are managed the same way.

10. Female Genital TractReview Questions 2005

11. Lower FGT--Infections • What are the two most important viral pathogens of lower FGT? • HPV and HSV • What may HPV look like clinically? • Warts (non-painful) • What may HSV look like clinically? • Vesicles (painful)

12. Lower FGT—infections • Why care about HPV? • HPV is viral carcinogen. • After HPV or mild dysplasia is diagnosed, what does the clinician do? • Follow closely to see if it persists or progresses.

13. Lower FGT—Infections • Which organism causes a profuse, watery discharge? • Trichomonas • Which organism causes thick, white plaques or thick, white discharge? • Candida

14. What are the two types of vulvar dystrophy? • Lichen sclerosus and lichen simplex chronicus (squamous cell hypertrophy) • What’s a simple way to characterize their appearance? • Lichen sclerosus is thin (atrophic); Lichen simplex is thick. • How do you treat vulvar dystrophy? • Steroid cream (inhibit the inflammation). • What do you need for the diagnosis? • Tissue biopsy. You certainly wouldn’t want to treat vulvar neoplasia with an anti-inflammatory agent, thus removing the anti-tumor response.

15. What’s the acronym for cervical dysplasia? • CIN • For vulvar dysplasia? • VIN • And for vaginal dysplasia? • VAIN

16. What are the two clinical types of vulvar squamous cell carcinoma? • Those associated with dysplasia (VIN) and HPV, younger women • Those not associated with precursor lesions, older women

17. What are the two most important organisms in ascending Pelvic Inflammatory Disease? • Gonococcus • Chlamydiae • What are sequelae of PID? • Hydrosalpinx • Infertility • Pelvic adhesions • What causes atrophic vaginitis? • Estrogen deficit

18. What is the definition of dysfunctional uterine bleeding? • Abnormal vaginal bleeding without demonstrable anatomic cause. • What do leiomyomata look like? • Round tumors of the myometrium. • Why care about leiomyomata? • May be malignant (leiomyosarcoma); may cause infertility; may cause abnormal bleeding.

19. What is the precursor to endocervical adenocarcinoma? • Adenocarcinoma in situ • What may be a precursor to endometrial adenocarcinoma? • Endometrial hyperplasia (especially complex hyperplasia with atypia). • Endometrial intraepithelial neoplasia (EIN)—a new diagnostic entity with similar histologic criteria to complex hyperplasia with atypia.

20. What are the two clinical subtypes of endometrial adenocarcinoma? • Those associated with excess estrogen, endometrial hyperplasia, and relatively young age. • Those not responsive to hormones and occurring primarily in the elderly. • What virus is endocervical adenocarcinoma sometimes associated with? • HPV 18

21. Mucinous tumors derive from what cell in the ovary? • Surface epithelium • What other tumors derive from the surface epithelium? • Serous, endometrioid, Brenner types of adenomas, borderline tumors, and carcinomas. • Teratomas are derived from which cell type? • Germ cells

22. What other tumors are derived from germ cells? • Dysgerminoma, yolk sac tumor, embryonal carcinoma, choriocarcinoma • Name some sex cord-stromal tumors. • Granulosa cell, thecoma, fibroma, Sertoli-Leydig cell tumors • What’s a Krukenberg tumor? • A metastatic tumor to the ovary, comprised mainly of signet ring cells.

23. What other tumor does a primary peritoneal tumor look and act like???? • Serous carcinomas of the ovary. • What are the clinical characteristics of PCOD? • Chronic anovulation (irregular menses, if any) • Hirsutism • Obesity • Insulin resistance • What do PCOD ovaries look like? • Large, cystic ovaries. Read the morphologic description of PCOD on page 1092. I’m serious, do it!

24. An 18-year old woman presents with a pelvic mass. What is the first diagnosis on your differential? • Germ cell tumor, most commonly, teratoma. • A 65-year old woman presents with a pelvic (ovarian) mass. What is first in your diagnostic differential? • Epithelial tumor—especially need to rule out carcinoma.

25. How would you describe simple hyperplasia of the endometrium? • Increased gland to stroma ratio with tubular or cystic-appearing glands. • How would you describe complex hyperplasia of the endometrium? • Increased gland to stroma ratio with branched and budding glands.

26. What is the most likely cause of endometrial hyperplasia (of any type)? • Estrogen excess • Where would one get estrogen excess? • Anovulation (no corpus luteum to provide progesterone to counteract the estrogen). • Hormone (estrogen) replacement therapy (no progestin or not enough) • Birth controls pills typically have higher amounts of progestins in relationship to the estrogens and don’t have the proliferative effect on the endometrium. • Obesity • Estrogen-secreting tumors (sex-cord/stromal classification)—unusual.

27. Leiomyomas are generally a problem of reproductive-age women? Why? • Growth of the smooth-muscle is stimulated by estrogen and progesterone. • Will fibroids grow during pregnancy? • Well, of course! See above question.

28. What are the two types of placental infection? • Ascending • Hematogenous • Which type is generally caused by low virulence organism and has fewer serious sequelae? • Ascending • What is the common deleterious side effect of ascending infections? • Premature delivery

29. What are the usual pathologic findings in ascending infections? • Acute inflammation of the umbilical cord (funisitis) and/or membranes (chorioamnionitis) • What are the usual pathologic findings in hematogenous infections? • Villitis; intrauterine growth retardation.

30. Choriocarcinoma is more likely to result from partial or complete moles? • Complete • Why is it important to diagnose choriocarcinoma? • Aggressive but treatable. • What is the ploidy of complete moles? • Diploid • What is the ploidy of partial moles? • Triploid • Which molar pregnancy may contain fetal parts? • Partial moles

31. What are the signs of preeclampsia? • Hypertension • Proteinuria • Edema • How do you cure eclampsia? • Deliver the baby and placenta. • Where is the most common location for an ectopic pregnancy to occur? • Fallopian tube

32. Which of the following patients has the worst prognosis? • 52 y/o with endometrioid endometrial adenocarcinoma, grade 1/3 • 75 y/o with papillary serous carcinoma of the endometrium, grade 3/3 • Answer: the 75 year old

33. Which of the following has the worse prognosis? • Mucinous cystadenocarcinoma • Brenner tumor • Clear cell carcinoma • Papillary serous adenocarcinoma • Answer: Clear cell carcinoma

34. What are the main histologic patterns/types of female genital carcinomas? • Serous • Endometrioid • Mucinous • Answer: Serous is most commonly found in ovarian tumors. Endometrioid is most common in endometrial tumors. Mucinous type is also seen, predominantly in the endocervix, but is less common, overall.

35. Which of the following is the MOST helpful in differentiating pre-eclampsia from other conditions during pregnancy: • Proteinuria • Hypertension • Edema • Answer: Proteinuria is necessary to make this diagnosis. Hypertension can be found by itself in pregnancy without the implications of preeclampsia. Likewise, most women have edema during pregnancy.

36. What do you expect, histologically, with a diagnosis of vaginal rhabdomyosarcoma (sarcoma botryoides)? • Spindled-cell tumor with occasional/rare strap-shaped cells containing cross-striations (evidence of skeletal muscle differentiation).

37. HPV E7 causes deregulation of the cell cycle by manipulating which cellular protein? • There are a number of mechanisms by which E7 affects the cell cycle, but the most important effect is on pRB. • What happens to this cellular protein? • Levels of pRB actually decrease. This may be due to increased degradation of the protein. • What other cellular protein is affected by E7 and helps identify HPV lesions? • p16 (levels of p16 increase due to upregulation by E2F-1)

38. Which cellular protein is manipulated by HPV E6? • p53. • What happens to this cellular protein? • p53 is bound by E6 and then degraded.

39. The pap smear on your 22 year old patient returns with the diagnosis of “low-grade squamous intraepithelial lesion.” What is the next step in her care? • Colposcopy. Low-grade type cells sometimes overlie higher grade lesions. Her ultimate diagnosis should be based on a biopsy, not a pap smear.

40. The pap smear of your 22 year old patient returns with a diagnosis of “atypical squamous cells of undetermined significance.” What do you do now? • One of 3 things: • Repeat the pap smear in 3 months (if other problems with interpretation were listed on the report, such as drying artifact or blood, avoid those issues on the repeat) • Have HPV testing performed on the leftover cytology fluid (can’t do with a conventional smear). • Colposcopy. This would be appropriate in a high-risk patient or one where a lesion was visible on speculum exam.

41. You perform colposcopy for an abnormal pap smear. You see an abnormal-appearing area and biopsy it. The biopsy is diagnosed as “inflammation and reactive changes”. Now what do you do? • You repeat the pap smear and make sure that it is consistently normal. • Why might you get this result? • A lesion (the one found on Pap smear) may have been missed on colposcopy. • The pap smear may be a “false positive” (over-call). • The lesion may be regressing and all that is left is inflammation and reactive changes.