Gynecologic Pathology I Pathology of the Cervix, Vagina, and Vulva

Transcription

1 Carey Z. August, M.D. Gynecologic Pathology I UIC College of Medicine Attending Pathologist, Advocate Illinois Masonic Medical M2 Pathology Course Center Lecture #53 Clinical Assistant Professor of Pathology, UIC Monday, January 26, 2004 Phone: :30-9:20 carey.august-md@advocatehealth.com Reading: Robbins Pathologic Basis of Disease, 6 th edition, 1999, pp Summary: This lecture will present infectious, inflammatory, preneoplastic, and neoplastic diseases of the lower female genital tract. Important concepts will include the significance of HPV in dysplasia and carcinogenesis and the role of the Pap smear in detection and prevention of dysplasia and cancer. Keywords: Cervix, vulva, vagina, HPV, Pap smear, dysplasia, squamous cell carcinoma, clear cell carcinoma. Goals and objectives: The student should know the information contained in the reading and the hand-out. In particular: 1. Explain the anatomy of the transformation zone, how it changes during a female s lifetime, and its significance in cervical disease. 2.Relate the evidence linking HPV to dysplasia and carcinogenesis. 3.Describe the morphology and clinical significance of varying degrees of dysplasia. 4.Know the natural history and staging of cervical cancer. 5.Explain the epidemiology of vaginal clear cell carcinoma

2 CERVIX I.A brief but necessary review of anatomy and histology A.Two parts of the cervix: portio vaginalis (stratified squamous epithelium) and endocervix (mucus-secreting glandular epithelium) which meet at the squamocolumnar junction (SCJ) B.Changes in the position of the SCJ: 1.At birth, SCJ is at cervical os 2.In child-bearing years, endocervix is everted. a.exposed columnar epithelium=ectropion; implications for STD s. b.squamous metaplasia of this ectropion leads to TRANSFORMATION ZONE, which is the site of development of most precancerous and cancerous conditions of the cervix. c.transformation zone location changes during reproductive years and migrates cephalad at menopause. II.Cervicitis, Nabothian cysts, polyps A.Normal cervicovaginal flora=doderlein bacilli B.Nonspecific cervicitis is common; associated with a variety of bacteria. C.Specific pathogens: Herpes Simplex (ulceration, multinucleated giant cells), Chlamydia trachomatis (follicular cervicitis), Trichomonas vaginalis (may induce cellular changes suggesting dysplasia-see below), gonococci, mycoplamsa. D.Nabothian cysts-mucous cysts which may be visible to the naked eye; reflect chronic inflammation; squamous metaplasia obliterates crypt opening of endocervical mucosa. E.Endocervical polyps-reflection of chronic cervicitis; may cause spotting or bleeding; NOT neoplastic. III.Cervical Intraepithelial Neoplasia CIN (Dysplasia) A.Precursors of squamous cell carcinoma of the cervix of varying degrees, manifested morphologically by varying degrees of cytologic atypia, yet ALWAYS INTRAEPITHELIAL (confined by basement membrane-do not infiltrate stroma). 1.Classified by degree of morphologic abnormality: a. CIN I-Mild dysplasia-undifferentiated, vertically-oriented cells occupy up to onethird of thickness of epithelium and mildly atypical cells are present on the surface. Changes may regress and are unlikely to progress to cancer. b. CIN II-Moderate dysplasia-undifferentiated, vertically-oriented cells occupy up to two-thirds of thickness of epithelium and moderately atypical cells are present on the surface. Less likely to regress and more likely to progress to cancer than mild dysplasia. c. CIN III-Severe dysplasia/carcinoma in situ-undifferentiated, vertically-oriented cells in full thickness of epithelium and severely atypical cells are present on the surface

3 2.The Papanicolaou Smear-a success story in cancer screening a. Since most cervical cancers are preceded by CIN, regular Pap smears allow for detection of precancerous changes. Pap smear can also detect cancers of cervix and other genital organs. b. Morphologic evaluation of the cytologic changes in the most superficial cell layers of the endocervix, ectocervix, and vagina. c. Adequate sampling, good preparation, and careful evaluation are all key features. d. Bethesda System-most current classification of Pap smears. e. Pap smear is a screening technique with false positives and false negatives. Pap smear diagnoses are confirmed by colposcopy and biopsy. 3.HPV (Human Papilloma Virus)-the most important (although not only) factor in cervical carcinogenesis. a. Risk factors for cervical cancer implicate a sexually transmitted agent (such as HPV): early age at first intercourse; multiple sexual partners; male partner with multiple previous sexual partners. Co-carcinogens include immune status, cigarette smoking. b. Causative agent of condyloma accuminatum (seen on external genitalia). c. Detected by in situ hybridization in 85% of cervical cancers and 90% of CIN. d. Low-risk HPV: 6,11,42,44-associated with condyloma and low grade CIN; exists in their squamous cells in free (episomal) form. e. High-risk HPV: 16,18,31,33-associated with high grade CIN and cancer; exists in their squamous cells integrated (covalently linked) into host DNA. f. High-risk HPV can transform cells in culture because their E6 and E7 viral oncogenes have the ability to do this; the E6 and E7 of low-risk HPV have different sequences and cannot transform cells in culture. g. High -risk E6 binds to tumor-suppressor gene p53 and accelerates is degradation. h. High -risk E7 binds to RB gene and displaces transcription factors normally sequestered by RB. i. Some high-risk HPV (HPV 16) are associated with chromosomal abnormalities. IV.Carcinoma-The vast majority (>75%) of carcinomas of the cervix are squamous cell carcinoma, but other forms, including adenocarcinoma and small cell carcinoma (which may be associated with HPV 18) occur as well. A.Peak age incidence: years. Symptoms: abnormal Pap, bleeding (especially post-coital), leukorrhea, dyspareunia. B.Gross morphology: Fungating, ulcerating, infiltrative C.Microscopic morphology of squamous cell carcinoma: can be keratinizing or nonkeratinizing. D.Spreads locally, as reflected in staging system: I.Confined to cervix II.Beyond cervix but not onto the pelvic wall or to the lower third of the vagina

4 III.To the pelvic wall or to lower third of the vagina. IV.Beyond the true pelvis (distant metastasis, mucosa of bladder or rectum). VAGINA I.Vaginal intraepithelial neoplasia (VAIN) and Squamous cell carcinoma A.Much less common than cervical intraepithelial neoplasia and carcinoma. B.Generally associated with HPV C.Frequent association with cervical and/or vulvar HPV, intraepithelial neoplasia, and cancer. II.Clear cell adenocarcinoma-association of many (but not all) with DES in utero. A.Daughters of women given DES in pregnancy may have vaginal adenosis (considered a precursor lesion)-glandular epithelium in the vagina. B.A small percentage of these patients develop clear cell adenocarcinoma of the vagina. III.Embryonal rhabdomyosarcoma A.Pediatric malignancy (sarcoma arising from primitive skeletal muscle). B.Called sarcoma botryoides because of gross morphology: grape-like clusters projecting out of vagina. C.Characteristic cell is the rhabdomyoblast with striations. D.Conservative surgery and chemotherapy. VULVA I. Vulvar dystrophies A.Lichen sclerosus-(aka lichen sclerosus et atrophicus )generally (but not always) postmenopausal 1.Vulvar skin appears parchment-like ; epidermis may be atrophic; dermal collagen hyalinized; chronic inflammation. 2.May be associated with autoimmune disorders. 3.Patients RARELY develop squamous cell carcinoma NOT considered a premalignant lesion. B.Squamous hyperplasia (aka hyperplastic dystrophy ) II.Condyloma accuminatum-cauliflower-like growths, generally HPV 6 or 11 III.Vulvar intraepithelial neoplasia (VIN) and squamous cell carcinoma A.VIN I, II, III representing mild, moderate, and severe dysplasia/cis, respectively. Most cases of VIN are VIN III

5 B.Two types of VIN III- 1. Classic ( Bowenoid )- younger patients (<45), associated with HPV, may be multicentric, may regress, less likely to progress to invasive carcinoma than the simplex type. 2. Simplex -older patients, less likely associated with HPV, more likely to progress to or be associated with invasive cancer. C.Invasive squamous cell carcinoma 1.Generally exophytic lesions. 2.Risk of metastasis related to size, depth of invasion, lymphatic invasion. IV.Extramammary Paget s disease A.Intraepithelial adenocarcinoma cells (contain mucin) localized within the squamous epithelium. B.Origin of cells unknown; perhaps primitive epithelial progenitor cells. C.Different from Paget s disease of the nipple since, unlike the mammary Paget s, extramammary Paget s is very infrequently associated with an invasive carcinoma of the vulva. D.Forms a red, maplike area. Infiltrates microscopically beyond its gross borders, so difficult to excise completely; likely to recur. E.May be associated with a malignancy of breast, bladder, or GI tract. V.Miscellaneous A.Vulvovaginal melanoma-rare but bad prognosis because often detected late. B.Bartholin cyst-benign cyst from inflammation of Bartholin s gland