Chapter 22: The Female Genital Tract PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R The Female Genital Tract Lora Hedrick Ellenson Edyta C. Pirog...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R The Female Genital Tract Lora Hedrick Ellenson Edyta C. Pirog 22 CHAPTER CONTENTS Infections 986 BODY OF UTERUS AND Mucinous Tumors 1020 Infections of the Lower Genital ENDOMETRIUM 1001 Endometrioid Ovarian Tumors 1021 Tract 987 Endometrial Histology in the Clear Cell Carcinoma 1021 Herpes Simplex Virus 987 Menstrual Cycle 1001 Cystadenofibroma 1022 Other Lower Female Genital Tract Functional Endometrial Disorders Transitional Cell Tumors 1022 Infections 987 (Dysfunctional Uterine Clinical Course, Detection, and Prevention of Infections Involving the Lower and Upper Bleeding) 1002 Ovarian Epithelial Tumors 1022 Genital Tract 988 Anovulatory Cycle 1003 Germ Cell Tumors 1023 Pelvic Inflammatory Disease (PID) 988 Inflammatory Disorders 1004 Teratoma 1023 Acute Endometritis 1004 Dysgerminoma 1024 VULVA 989 Chronic Endometritis 1004 Yolk Sac Tumors 1025 Bartholin Cyst 990 Endometriosis and Choriocarcinoma 1025 Non-Neoplastic Epithelial Adenomyosis 1004 Other Germ Cell Tumors 1025 Disorders 990 Endometrial Polyps 1006 Sex Cord–Stromal Tumors 1026 Lichen Sclerosus 990 Endometrial Hyperplasia 1006 Granulosa Cell Tumors 1026 Squamous Cell Hyperplasia 990 Malignant Tumors of the Fibromas, Thecomas, and Fibrothecomas 1027 Benign Exophytic Lesions 990 Endometrium 1008 Sertoli-Leydig Cell Tumors 1027 Condyloma Acuminatum 991 Carcinoma of the Endometrium 1008 Other Sex Cord–Stromal Tumors 1028 Squamous Neoplastic Lesions 991 Endometrioid Endometrial Metastatic Tumors 1028 Vulvar Intraepithelial Neoplasia and Vulvar Carcinoma 1008 Carcinoma 991 GESTATIONAL AND PLACENTAL Serous Endometrial Carcinoma 1011 Glandular Neoplastic Lesions 993 DISORDERS 1028 Carcinosarcoma (Malignant Mixed Papillary Hidradenoma 993 Disorders of Early Pregnancy 1029 Müllerian Tumors) 1012 Extramammary Paget Disease 993 Spontaneous Abortion 1029 Tumors of Endometrial Ectopic Pregnancy 1029 VAGINA 994 Stroma 1013 Disorders of Late Pregnancy 1030 Developmental Anomalies 994 Adenosarcoma 1013 Twin Placentas 1030 Premalignant and Malignant Stromal Tumors 1013 Abnormalities of Placental Neoplasms of the Vagina 994 Tumors of the Myometrium 1014 Implantation 1031 Vaginal Intraepithelial Neoplasia and Leiomyoma 1014 Placental Infections 1031 Squamous Cell Carcinoma 994 Leiomyosarcoma 1014 Preeclampsia and Eclampsia 1031 Embryonal Rhabdomyosarcoma 995 Fallopian Tubes 1015 Gestational Trophoblastic Inflammations 1015 CERVIX 995 Disease 1033 Tumors and Cysts 1016 Inflammations 995 Hydatidiform Mole 1033 Acute and Chronic Cervicitis 995 OVARIES 1016 Complete Mole 1033 Endocervical Polyps 996 Non-Neoplastic and Functional Partial Mole 1033 Premalignant and Malignant Cysts 1016 Invasive Mole 1034 Neoplasms of the Cervix 996 Follicle and Luteal Cysts 1016 Choriocarcinoma 1034 Cervical Intraepithelial Neoplasia Polycystic Ovaries and Stromal Placental Site Trophoblastic Tumors 1035 (Squamous Intraepithelial Lesions) 997 Hyperthecosis 1016 Cervical Carcinoma 998 Ovarian Tumors 1016 Cervical Cancer Screening and Epithelial Tumors 1017 Prevention 1000 Serous Tumors 1018 985 986 C H A P T E R 22 The Female Genital Tract A brief review of the development and anatomy of the female various sites within the female genital tract and the adjacent genital tract is fundamental to understanding the diseases peritoneal surfaces. that affect this complex organ system. Normal development Diseases of the female genital tract are extremely common of the female genital tract proceeds through a series of tightly and include complications of pregnancy, infections, tumors, choreographed events involving the primordial germ cells, and hormonally induced abnormalities. The following dis- the m llerian (paramesonephric) ducts, the wolffian (meso- cussion presents the pathology of the major diseases that nephric) ducts, and the urogenital sinus (Fig. 22.1). result in clinical problems. Additional details can be found Germ cells arise in the wall of the yolk sac by the fourth in current textbooks of gynecologic pathology and clinical week of gestation. y the fifth or sixth week, they migrate obstetrics and gynecology. We will discuss the pathologic into the urogenital ridge and induce proliferation of the conditions peculiar to each segment of the female genital mesodermal epithelium, which gives rise to the epithelium tract separately, but before doing so we will briefly review and stroma of the ovary. infections and pelvic inflammatory disease because they can The lateral müllerian ducts form at about the sixth week affect many of the various anatomic structures concomitantly. of development through invagination and fusion of the coelomic lining epithelium. The ducts progressively grow caudally into the pelvis, where they swing medially to INFECTIONS fuse with the urogenital sinus at the müllerian tubercle (see Fig. 22.1A). Further caudal growth brings these fused A large variety of organisms can infect the female genital ducts into contact with the urogenital sinus. The unfused tract. Some infections with microorganisms such as Candida, upper portions of the müllerian ducts mature into the Trichomonas, and Gardnerella are very common and may cause fallopian tubes, while the fused lower portion develops significant discomfort, but are without serious sequelae. into the uterus, cervix, and upper vagina. Others, such as Neisseria gonorrhoeae and Chlamydia infections, The urogenital sinus develops when the cloaca is subdi- are major causes of infertility, while organisms such as Group vided by the urorectal septum; it eventually forms the B Streptococcus infections are implicated in preterm deliver- lower part of the vagina and the vestibule of the external ies, stillbirths, and neonatal infections. Viruses, especially genitalia (see Fig. 22.1B). herpes simplex viruses (HSVs) and human papillomaviruses The mesonephric ducts normally regress in the female, but (HPVs), also account for considerable morbidity; HSVs cause remnants may persist into adult life as epithelial inclusions painful genital ulcerations, whereas HPVs are involved in adjacent to the ovaries, tubes, and uterus. In the cervix the pathogenesis of cervical, vaginal, and vulvar cancers and vagina, these rests may be cystic and are termed (described later). Gartner duct cysts. Many of these infections are sexually transmitted, includ- ing trichomoniasis, gonorrhea, Mycoplasma, Chlamydia, HSV, The epithelial lining of the female genital tract as well and HPV as well as less common infections such as syphilis, as the ovarian surface share a common origin from coelomic chancroid, granuloma inguinale, and lymphogranuloma epithelium (mesothelium), which may explain why mor- venereum. Most of these conditions are considered in Chapter phologically similar benign and malignant lesions arise in 8; HPV is also discussed in Chapter 7 due to its important Fimbriae Suspensory ligament of ovary Ovary Ovarian ligament proper Mesovarium (broad ligament) Ovary Mesonephros Mesonephric remnants Corpus Müllerian duct (body) Mesonephric duct Mesonephric remnants Uterine canal Müllerian tubercle Fornix Cervix A Urogenital sinus B Vagina Figure 22.1 Embryology and anatomy of the female genital tract. (A) Early in development, the mesonephric (blue) and müllerian (red) ducts merge at the urogenital sinus to form the müllerian tubercle. (B) By birth, the müllerian ducts have fused to form the fallopian tubes, uterus, and endocervix (red), merging with the vaginal squamous mucosa. The mesonephric ducts regress, but may be found as a remnant in the ovary, adnexa, and cervix (Gartner duct cysts). (Modified from Langman J: Medical Embryology, Baltimore, 1981, Williams and Wilkins.)  Infections 987 role as a transforming virus. Here we touch only on aspects relevant to the female genital tract, including pathogens confined to the lower genital tract (vulva, vagina, and cervix) and those that involve the entire genital tract and are implicated in pelvic inflammatory disease. Infections of the Lower Genital Tract Herpes Simplex Virus Genital herpes simplex virus (HSV) infection is common and may involve the vulva, vagina, or cervix. HSVs are DNA viruses that include two serotypes, HSV-1 and HSV-2. HSV-1 typically results in perioral infection, whereas HSV-2 usually involves genital mucosa and skin; however, depend- ing on sexual practices, HSV-1 may be detected in the genital region and HSV-2 may cause oral infections as well (Chapter 8). By 40 years of age, approximately 30% of women are seropositive for antibodies against HSV-2. About one-third of newly infected individuals are symptomatic. Lesions typically develop 3 to 7 days after Figure 22.2 Herpes simplex virus (HSV) infection (cervical smear). The cell in the center shows HSV cytopathic effect. Infected cells become transmission and are often associated with systemic symp- multinucleated and contain intranuclear viral inclusions with a toms such as fever, malaise, and tender inguinal lymph characteristic “ground-glass” appearance. nodes. The earliest lesions usually consist of red papules that progress to vesicles and then to painful coalescent ulcers. The lesions are easily visible on vulvar skin and mucosa, mother. Cesarean delivery is warranted in such cases to while cervical and vaginal lesions present with purulent prevent transmission to the neonate. Another important discharge and pelvic pain. Lesions around the urethra may consequence of active genital HS infection is that it increases cause painful urination and urine retention. The vesicles the risk of HI -1 acquisition and transmission. and ulcers contain numerous viral particles, accounting The diagnosis is based on typical clinical findings and for the high transmission rate during active infection. The HSV detection. The purulent exudate is aspirated from the mucosal and cutaneous lesions heal spontaneously in 1 to lesions and inoculated into a tissue culture. The viral 3 weeks, but during the acute infection the virus migrates cytopathic effect can be seen after 48 to 72 hours, and the to the regional lumbosacral nerve ganglia and establishes virus can then be serotyped. In addition, some laboratories a latent infection. Because of viral latency, HSV infections offer more sensitive polymerase chain reaction tests, enzyme- persist indefinitely, and any decrease in immune function linked immunosorbent assays, and direct immunofluorescent due to stress, trauma, concurrent viral infection, or hormonal antibody tests for detection of HSV in the lesional secretions. changes can trigger reactivation of the virus and recurrence Individuals with primary, acute HSV infection do not have of the skin and mucosal lesions. As expected, recurrences serum anti-HSV antibodies. Detection of anti-HSV antibodies are much more common in immunosuppressed individuals. in the serum is indicative of recurrent/latent infection. There is no effective treatment for latent HSV; however, antiviral agents like acyclovir or famciclovir shorten the MORPHOLOGY length of the initial and recurrent symptomatic phases. The By the time an HSV lesion is biopsied, it typically has ulcerated. ultimate solution is an effective vaccine, a tantalizing goal The epithelium is desquamated, and marked acute inflammation yet to be realized. is present in the ulcer bed. Smears of the inflammatory exudate from active lesions show characteristic cytopathic changes consist- Other Lower Female Genital Tract Infections ing of multinucleated squamous cells containing eosinophilic to As mentioned earlier, a variety of other viruses, fungi, and basophilic viral inclusions with a “ground-glass” appearance bacteria can also cause symptomatic infections of the lower (Fig. 22.2). genital tract. Those that are most common include the following: Molluscum contagiosum is a cutaneous or mucosal lesion Transmission of HSV takes place mainly during the active caused by poxvirus (Fig. 22.3A). There are four types of phase but occasionally may occur during the latent phase molluscum contagiosum viruses (MCVs), MCV-1 to due to subclinical virus shedding. Condoms and antiviral MCV-4, with MCV-1 being the most prevalent and MCV-2 therapies reduce the risk of transmission, but do not prevent being most often sexually transmitted. The infections are it completely. As with other sexually transmitted diseases, common in young children between 2 and 12 years of the virus is more readily transmitted to women than to age, in whom they are transmitted through direct contact men. Previous infection with HSV-1 seems to reduce sus- or shared articles (e.g., towels). Molluscum may affect ceptibility to HS -2 infection. The gravest consequence of any area of the skin but is most common on the trunk, HSV infection is transmission to the neonate during birth. arms, and legs. In adults, molluscum infections are typi- This risk is highest if the infection is active during delivery cally sexually transmitted and affect the genitals, lower and particularly if it is a primary (initial) infection in the abdomen, buttocks, and inner thighs. The average 988 C H A P T E R 22 The Female Genital Tract A B Figure 22.3 Molluscum contagiosum infection. (A) Low-power appearance of a dome-shaped papule with dimpled center. (B) High-power magnification reveals intracytoplasmic viral inclusions. incubation period is 6 weeks. Diagnosis is based on the streptococci. In pregnant patients, bacterial vaginosis has characteristic clinical appearance of pearly, dome-shaped been implicated in premature labor. papules with a dimpled center. The papules measure 1 Ureaplasma urealyticum and Mycoplasma hominis species to 5 mm in diameter, and their central waxy core contains account for some cases of vaginitis and cervicitis and cells with cytoplasmic viral inclusions (see Fig. 22.3B). have been implicated in chorioamnionitis and premature Fungal infections, especially those caused by yeast (Candida), delivery in pregnant patients. are extremely common; in fact, yeast are part of many Chlamydia trachomatis infections mainly take the form of women s normal vaginal microflora, and the develop- cervicitis. However, in some patients the infection may ment of symptomatic candidiasis is typically a result of a ascend to the uterus and fallopian tubes, resulting in disturbance in the patient’s vaginal microbial ecosystem. endometritis and salpingitis; thus Chlamydia is one of Diabetes mellitus, antibiotics, pregnancy, and conditions the causes of pelvic inflammatory disease, as discussed that compromise neutrophil or Th17 T-cell function next. increase the risk of symptomatic candidal infection, which manifests itself by marked vulvovaginal pruritus, Infections Involving the Lower and erythema, swelling, and curdlike vaginal discharge. Severe Upper Genital Tract infection may result in mucosal ulcerations. The diagnosis is made by finding the pseudospores or filamentous Pelvic Inflammatory Disease (PID) fungal hyphae in wet KOH mounts of the discharge PID is an infection that begins in the vulva or vagina and or on Papanicolaou (Pap) smear. Even though sexual spreads upward to involve most of the structures in the transmission of yeast infection has been documented, female genital system, resulting in pelvic pain, adnexal candidiasis is not considered a sexually transmitted tenderness, fever, and vaginal discharge. Neisseria gonor- disease. rhoeae continues to be a common cause of PID, the most Trichomonas vaginalis is a large, flagellated ovoid protozoan serious complication of gonorrhea in women. Chlamydia that is usually transmitted by sexual contact. Infected infection is another well-recognized cause of PID. Infec- patients may be asymptomatic or may complain of yellow, tions after spontaneous or induced abortions and normal frothy vaginal discharge, vulvovaginal discomfort, dysuria or abnormal deliveries (called puerperal infections) are also (painful urination), and dyspareunia (painful intercourse). important causes of PID. In these situations, the infections are The vaginal and cervical mucosa typically has a fiery-red typically polymicrobial and may be caused by staphylococci, appearance, with marked dilation of cervical mucosal streptococci, coliforms, and Clostridium perfringens. vessels resulting in characteristic colposcopic appearance With gonococcus, inflammatory changes start to appear of “strawberry cervix.” approximately 2 to 7 days after inoculation. The initial infec- Gardnerella vaginalis is a gram-negative coccobacillus that tion most commonly involves the endocervical mucosa, but is implicated as the main cause of bacterial vaginosis it may also begin in the Bartholin gland and other vestibular, (vaginitis). Patients typically present with thin, green-gray, or periurethral, glands. From these sites, the organisms may malodorous (fishy) vaginal discharge. Pap smears reveal spread upward to involve the fallopian tubes and tubo- superficial and intermediate squamous cells covered with ovarian region. The non-gonococcal bacterial infections a shaggy coat of coccobacilli. Bacterial cultures in such that follow induced abortion, dilation and curettage of the cases reveal G. vaginalis and other bacteria, including uterus, and other surgical procedures are thought to spread anaerobic peptostreptococci and aerobic α-hemolytic upward from the uterus through the lymphatics or venous  Vulva 989 A B Figure 22.4 Salpingitis. (A) Acute salpingitis; note the dilated tube lumen and edematous tubal plicae expanded by inflammatory cell infiltrates. Pus fills the center of the fallopian tube. (B) Chronic salpingitis showing scarring and fusion of the plicae with formation of glandlike spaces. Such scarring may cause infertility or ectopic tubal pregnancy. channels rather than on the mucosal surfaces. Therefore, also develop as a consequence of the fusion of the fimbriae and these infections tend to produce more inflammation within the subsequent accumulation of the tubal secretions and tubal the deeper layers of the organs than gonococcal infections. distention. As compared to gonococcal infections, PID caused by staphy- MORPHOLOGY lococci, streptococci, and the other puerperal invaders tends to show less involvement of the mucosa and the tube lumen, and Gonococcal infection is characterized by marked acute more inflammation within the deeper tissue layers.These infections inflammation of involved mucosal surfaces. Smears of the often spread throughout the wall to involve the serosa and the inflammatory exudate disclose phagocytosed gram-negative broad ligaments, pelvic structures, and peritoneum. Bacteremia diplococci within neutrophils; however, definitive diagnosis requires is a more frequent complication of streptococcal or staphylococcal culture or detection of gonococcal RNA or DNA. If infection PID than of gonococcal infections. spreads, the endometrium is usually spared (for unclear reasons), but within the fallopian tubes, an acute suppurative salpingitis The acute complications of PID include peritonitis and ensues (Fig. 22.4A). The tubal mucosa becomes congested and bacteremia, which in turn may result in endocarditis, diffusely infiltrated by neutrophils, plasma cells, and lymphocytes, meningitis, and suppurative arthritis. The chronic sequelae resulting in epithelial injury and sloughing of the plicae. The tubal of PID include infertility and tubal obstruction, ectopic lumen fills with purulent exudate that may leak out of the fimbri- pregnancy, pelvic pain, and intestinal obstruction due to ated end. The infection may then spread to the ovary to create adhesions between the bowel and pelvic organs. In the early a salpingo-oophoritis. Collections of pus may accumulate within stages, gonococcal infections are usually readily controlled the ovary and tube (tubo-ovarian abscess) or tubal lumen with antibiotics, although penicillin-resistant strains have (pyosalpinx) (see Fig. 22.4A). With time, the infecting organisms emerged. Infections that become walled off in tubo-ovarian may disappear, but the tubal plicae, denuded of epithelium, adhere abscesses are difficult to eradicate with antibiotics, and it to one another and slowly fuse in a reparative, scarring process sometimes becomes necessary to remove the organs surgi- that forms glandlike spaces and blind pouches, referred to as cally. Postabortion and postpartum PIDs may also be chronic salpingitis (see Fig. 22.4B). The scarring of the tubal amenable to treatment with antibiotics, but are far more lumen and fimbriae may prevent the uptake and passage of oocytes, difficult to control because of the broad spectrum of patho- leading to infertility or ectopic pregnancy. Hydrosalpinx may gens that may be involved. Vulva Diseases of the vulva in the aggregate constitute only a than skin elsewhere on the body. Nonspecific vulvitis is small fraction of gynecologic practice. Many inflammatory particularly likely to occur in the setting of immunosup- diseases that affect skin elsewhere on the body also occur pression. Most skin cysts (epidermal inclusion cysts) and on the vulva, such as psoriasis, eczema, and allergic der- skin tumors such as squamous cell carcinoma, basal cell matitis. Because it is constantly exposed to secretions and carcinoma, and melanoma can also occur in the vulva. Here moisture, the vulva is more prone to superficial infections we discuss vulvar disorders that are relatively specific and 990 C H A P T E R 22 The Female Genital Tract A B Figure 22.5 Non-neoplastic epithelial vulvar disorders. (A) Lichen sclerosus. There is marked thinning of the epidermis, sclerosis of the superficial dermis, and chronic inflammatory cells in deeper dermis. (B) Squamous cell hyperplasia, displaying thickened epidermis and hyperkeratosis. common, including Bartholin cyst, non-neoplastic epithelial that resembles porcelain or parchment. When the entire disorders, benign exophytic lesions, and tumors of the vulva. vulva is affected, the labia become atrophic and agglutinated, and the vaginal orifice constricts. Histologically, the lesion is characterized by marked thinning of the epidermis (Fig. BARTHOLIN CYST 22.5A), degeneration of the basal epithelial cells, excessive keratinization (hyperkeratosis), sclerotic changes of the Infection of the artholin gland produces an acute inflamma- superficial dermis, and a bandlike lymphocytic infiltrate in tion (adenitis) and may result in an abscess. Bartholin duct the underlying dermis. The disease occurs in all age groups cysts are relatively common, occur at all ages, and result from but is most common in postmenopausal women. It may obstruction of the duct by an inflammatory process. These also be encountered elsewhere on the skin. Its pathogenesis cysts are usually lined by transitional or squamous epithelium. is uncertain, but the presence of activated T cells in the They may become large, up to 3 to 5 cm in diameter, and subepithelial inflammatory infiltrate and the increased produce pain and local discomfort. Bartholin duct cysts are frequency of autoimmune disorders in affected women either excised or opened permanently (marsupialization). suggest that an autoimmune reaction is involved. Although lichen sclerosus is not itself a premalignant lesion, women with symptomatic lichen sclerosus have a slightly increased NON-NEOPLASTIC chance of developing squamous cell carcinoma of the vulva. EPITHELIAL DISORDERS Squamous Cell Hyperplasia Leukoplakia is a descriptive clinical term for opaque, white, plaquelike epithelial thickening that may produce pruritus Previously called hyperplastic dystrophy or lichen simplex and scaling. Leukoplakia (literally, white plaques) may be chronicus, squamous cell hyperplasia is a nonspecific condi- caused by a variety of benign, premalignant, or malignant tion resulting from rubbing or scratching of the skin to disorders, including the following: relieve pruritus. Clinically it presents as leukoplakia, and Inflammatory dermatoses (e.g., psoriasis, chronic histologic examination reveals thickening of the epidermis dermatitis) (acanthosis) and hyperkeratosis (see Fig. 22.5B). Lymphocytic Lichen sclerosus and squamous cell hyperplasia infiltration of the dermis is sometimes present. The hyper- Neoplasias, such as vulvar intraepithelial neoplasia ( IN), plastic epithelium may show mitotic activity but lacks cellular Paget disease, and invasive carcinoma atypia. While squamous cell hyperplasia is not considered premalignant, it is sometimes present at the margins of Inflammatory dermatoses associated with leukoplakia vulvar cancers. are described in Chapter 25, while neoplastic disorders are discussed later in this chapter. Here the major non-neoplastic causes of leukoplakia—lichen sclerosis and squamous cell BENIGN EXOPHYTIC LESIONS hyperplasia—are briefly discussed. Benign raised (exophytic) or wartlike lesions of the vulva Lichen Sclerosus may be caused by infection or may be reactive conditions of unknown etiology. Condyloma acuminatum, a papillomavirus- Lichen sclerosis presents as smooth, white plaques or macules induced lesion, also called a genital wart, and syphilitic that in time may enlarge and coalesce, producing a surface condyloma latum (described in Chapter 21) are consequences  Vulva 991 A B Figure 22.6 Condyloma acuminatum. (A) Low-power view showing exophytic, papillary architecture. (B) High-power view reveals human papillomavirus cytopathic effect (koilocytic atypia) characterized by atypical, enlarged, hyperchromatic nuclei with perinuclear halos (arrow). of sexually transmitted infections. Vulvar fibroepithelial polyps, years of age. Squamous cell carcinoma is the most common or skin tags, are similar to skin tags occurring elsewhere histologic type of vulvar cancer. In terms of etiology, on the skin. Vulvar squamous papillomas are benign exo- pathogenesis, and histologic features, vulvar squamous cell phytic proliferations covered by nonkeratinized squamous carcinomas are divided into two groups: epithelium that develop on vulvar surfaces; they may be Basaloid and warty carcinomas are related to infection with single or numerous (vulvar papillomatosis). The etiology of high-risk HPVs, most commonly HPV-16. These are less fibroepithelial polyps and squamous papillomas is unknown. common (30% of cases) and occur in younger women (average 60 years of age). Condyloma Acuminatum Keratinizing squamous cell carcinomas are unrelated to HPV infection. These are more common (70% of cases) and Condylomata acuminata are benign genital warts caused occur in older women (average 75 years of age). by low-risk HPV, mainly types 6 and 11. They may be solitary, but are more frequently multifocal, and they may Basaloid and warty carcinomas develop from an in situ involve vulvar, perineal, and perianal regions as well as precursor lesion called classic vulvar intraepithelial neoplasia the vagina and, less commonly, the cervix. The lesions are (VIN). This form of VIN occurs mainly in reproductive age identical to those found on the penis and around the anus women and includes lesions formerly designated as carcinoma in males (Chapter 21). On histologic examination, they in situ or Bowen disease. The risk factors for VIN are the consist of papillary, exophytic, treelike cores of stroma same as those associated with cervical squamous intraepi- covered by thickened squamous epithelium (Fig. 22.6A). thelial lesions (e.g., young age at first intercourse, multiple The surface epithelium shows characteristic viral cytopathic sexual partners, male partner with multiple sexual partners), changes referred to as koilocytic atypia (see Fig. 22.6B), which as both are related to HP infection. IN is frequently manifest as nuclear enlargement, hyperchromasia, and a multicentric, and 10% to 30% of patients with VIN also have cytoplasmic perinuclear halo (see the Cervix section later vaginal or cervical HPV-related lesions. Spontaneous regres- in this chapter). Condylomata acuminata are not precan- sion of classic VIN has been reported, usually in younger cerous lesions. HPV vaccines (described later) provide women. The risk of progression to invasive carcinoma is excellent protection against infection by low-risk HPV and higher in women who are older than 45 years of age or who genital warts. are immunosuppressed. Keratinizing squamous cell carcinoma occurs most often in individuals with long-standing lichen sclerosus or squamous SQUAMOUS NEOPLASTIC LESIONS cell hyperplasia and is not related to HPV. It arises from a precursor lesion referred to as differentiated vulvar intraepi- Vulvar Intraepithelial Neoplasia and thelial neoplasia (differentiated VIN). It is postulated that Vulvar Carcinoma chronic epithelial irritation in lichen sclerosus or squamous cell hyperplasia may contribute to a gradual evolution to the Carcinoma of the vulva is an uncommon malignant neoplasm malignant phenotype, presumably through acquisition of (approximately one-eighth as frequent as cervical cancer) driver mutations in oncogenes and tumor suppressor genes. representing about 3% of all genital cancers in the female; In line with this idea, some investigators have reported a approximately two-thirds occur in women older than 60 high frequency of TP53 mutations in differentiated VIN. 992 C H A P T E R 22 The Female Genital Tract A B Figure 22.7 Human papillomavirus (HPV)-related vulvar pre-neoplastic and malignant lesions. (A) Classic vulvar intraepithelial neoplasia (HPV positive), showing small, immature basaloid cells encompassing full thickness of the epithelium. No invasion is present. (B) Basaloid vulvar carcinoma (HPV positive), composed of invasive small, immature (basaloid) cells. There is a focus of necrosis (red area). MORPHOLOGY tightly packed cells that lack maturation and resemble the basal layer of the normal epithelium. The tumor may have foci of central The lesions of classic VIN may be discrete and white (hyper- necrosis. By contrast, warty carcinoma is characterized by exo- keratotic) or slightly raised and pigmented. Microscopically, it is phytic, papillary architecture and prominent koilocytic atypia. characterized by epidermal thickening, nuclear atypia, increased Differentiated VIN is characterized by marked atypia of the mitoses, and lack of cellular maturation (Fig. 22.7A), features basal layer of the squamous epithelium and normal-appearing analogous to those seen in cervical squamous intraepithelial lesions differentiation of the more superficial layers (Fig. 22.8A). Invasive (SIL, see the Cervix section later in this chapter). Invasive carci- keratinizing squamous cell carcinomas that arise in differentiated nomas that arise from classic VIN may be exophytic or indurated VIN contain nests and tongues of malignant squamous epithelium with central ulceration. On histologic examination, basaloid with prominent central keratin pearls (see Fig. 22.8B). carcinoma (see Fig. 22.7B) consists of nests and cords of small, A B Figure 22.8 Non–human papillomavirus (HPV) vulvar pre-neoplastic and malignant lesions. (A) Differentiated vulvar intraepithelial neoplasia (HPV negative), showing maturation of the superficial layers, hyperkeratosis, and atypia of basal epithelial cells. No invasion is present. (B) Well-differentiated, keratinizing squamous cell carcinoma of the vulva (HPV negative) composed of invasive tumor nests with central keratin pearls.  Vulva 993 The risk of cancer development in VIN depends on dura- tion and extent of disease, and the immune status of the patient. Invasive carcinomas associated with lichen sclerosus, squamous cell hyperplasia, and differentiated IN may develop in an insidious fashion and may be misinterpreted as dermatitis or leukoplakia for long periods. Once invasive cancer develops, the risk of metastatic spread is determined by the size of tumor, the depth of invasion, and whether there is lymphatic invasion. The initial spread is to ingui- nal, pelvic, iliac, and periaortic lymph nodes. Ultimately, hematogenous dissemination to the lungs, liver, and other internal organs may occur. Patients with lesions less than 2 cm in diameter have a 90% 5-year survival rate after treat- ment with vulvectomy and lymphadenectomy; however, larger lesions with lymph node involvement have a poor prognosis. GLANDULAR NEOPLASTIC LESIONS Like the breast, the vulva contains modified apocrine sweat glands. Presumably because of these “breastlike” features, the vulva may be involved by two tumors with counterparts in the breast, papillary hidradenoma and extramammary Paget disease. Papillary Hidradenoma Figure 22.9 Papillary hidradenoma of the vulva, a well-circumscribed tumor composed of benign papillary projections covered with columnar Papillary hidradenoma presents as a sharply circumscribed secretory epithelium and underlying myoepithelial cells. nodule, most commonly on the labia majora or interlabial folds, and may be confused clinically with carcinoma because of its tendency to ulcerate. Its histologic appearance is identical to that of intraductal papilloma of the breast and consists of papillary projections covered by two cell layers, an upper layer of columnar secretory cells and a deeper In contrast to Paget disease of the nipple, in which 100% layer of flattened myoepithelial cells. These myoepithelial of patients have an underlying ductal breast carcinoma, elements are characteristic of sweat glands and sweat gland vulvar Paget is typically not associated with underlying tumors (Fig. 22.9). cancer and is confined to the vulvar epidermis. Treatment consists of wide local excision, which is necessary because Extramammary Paget Disease Paget cells spread laterally within the epidermis and may be present beyond the confines of the grossly visible This curious and rare lesion of the vulva is similar in its lesion. Intra-epidermal Paget disease may persist for many manifestations to Paget disease of the breast (Chapter 23). years or even decades without invasion or metastases. In In the vulva, it presents as a pruritic, red, crusted, maplike the rare instances when invasion develops, the prognosis area, usually on the labia majora. is poor. MORPHOLOGY Paget disease is a distinctive intraepithelial proliferation of malignant cells. Paget cells are larger than surrounding keratinocytes and KEY CONCEPTS are seen singly or in small clusters within the epidermis (Fig. Approximately 30% of vulvar cancers are caused by infection 22.10A). The cells have pale cytoplasm containing mucopolysac- with high-risk HPVs, principally HPV-16. These cancers develop charide that stains with periodic acid–Schiff (PAS), Alcian blue, or from an in situ lesion termed classic vulvar intraepithelial mucicarmine stains. In addition, unlike squamous epithelium, the neoplasia (classic VIN). cells express cytokeratin 7 (see Fig. 22.10B). Ultrastructurally, Most vulvar cancers (70%) are not related to HPV and develop Paget cells display apocrine, eccrine, and keratinocyte differentiation in a background of lichen sclerosus or squamous cell hyperplasia and presumably arise from multipotent cells found within the from the premalignant lesion called differentiated vulvar mammary gland–like ducts of the vulvar skin. intraepithelial neoplasia (differentiated VIN). 994 C H A P T E R 22 The Female Genital Tract A B Figure 22.10 Paget disease of the vulva. (A) The epidermis is infiltrated by large cells with pale-pink cytoplasm that are spreading along the basal portion of the squamous epithelium. There is inflammation in the underlying dermis. (B) Immunostaining for cytokeratin 7 highlights the intraepidermal Paget cells. Vagina The vagina is a portion of the female genital tract that is fluid-filled submucosal cysts. Other cysts, including mucus remarkably resistant to diseases that affect nearby structures. cysts, which occur in the proximal vagina, are derived from For example, in the adult, inflammation that begins in the vulva müllerian epithelium. Another müllerian-derived lesion, and perivulvar structures often spreads to the cervix without endometriosis (described later), may occur in the vagina significant involvement of the vagina. Primary lesions of the and clinically simulate a neoplasm. vagina are rare, the most serious being vaginal squamous cell carcinoma; they are discussed only briefly here. PREMALIGNANT AND MALIGNANT NEOPLASMS OF THE VAGINA DEVELOPMENTAL ANOMALIES Most benign tumors of the vagina occur in reproductive-age Septate, or double, vagina is an uncommon anomaly that arises women and include stromal tumors (stromal polyps), leio- from a failure of müllerian duct fusion and is accompanied myomas, and hemangiomas. The most common malignant by a double uterus (uterus didelphys). These and other tumor to involve the vagina is carcinoma spreading from the anomalies of the external genitalia may be the manifestations cervix, followed by primary squamous cell carcinoma of the of genetic syndromes, in utero exposure to diethylstilbestrol vagina. Infants may develop a unique, rare malignancy— (DES, used to prevent threatened abortions in the 1940s to embryonal rhabdomyosarcoma (sarcoma botryoides). 1960s), or other unknown factors that perturb reciprocal epithelial-stromal signaling during fetal development. Vaginal Intraepithelial Neoplasia and Squamous During embryonal development, the vagina is initially Cell Carcinoma covered by columnar, endocervical-type epithelium. This is normally replaced by squamous epithelium advancing Virtually all primary carcinomas of the vagina are squamous upward from the urogenital sinus. Small patches of residual cell carcinomas associated with high-risk HPV infection. glandular epithelium may persist into adult life; such areas Vaginal carcinoma is extremely uncommon (about 0.6 per are recognized as vaginal adenosis, which on examination 100,000 women yearly) and accounts for about 1% of malig- presents as red, granular areas that stand out from the sur- nant neoplasms in the female genital tract. The greatest risk rounding normal pale-pink vaginal mucosa. Microscopically, factor is a previous carcinoma of the cervix or vulva; 1% to adenosis consists of columnar mucinous epithelium indis- 2% of women with an invasive cervical carcinoma eventually tinguishable from endocervix. Adenosis is found in only a develop a vaginal squamous cell carcinoma. Squamous cell small percentage of adult women, but has been reported in carcinoma of the vagina arises from a premalignant lesion, 35% to 90% of women exposed to DES in utero. Rare cases vaginal intraepithelial neoplasia, analogous to cervical squamous of clear cell carcinoma arising in DES-related adenosis were intraepithelial lesion (SIL; see the Cervix section later in this recorded in teenagers and young adult women in the 1970s chapter). Most often the invasive tumor affects the upper and 1980s, resulting in discontinuation of DES treatment. vagina, particularly the posterior wall at the junction with Gartner duct cysts are relatively common lesions found the ectocervix. The lesions in the lower two-thirds of the along the lateral walls of the vagina that are derived from vagina metastasize to the inguinal nodes, whereas lesions wolffian (mesonephric) duct rests. They consist of 1- to 2-cm in the upper vagina tend to spread to regional iliac nodes.  Cervix 995 Embryonal Rhabdomyosarcoma Also called sarcoma botryoides, this uncommon vaginal tumor composed of malignant embryonal rhabdomyoblasts is most frequently found in infants and children younger than 5 years of age. These tumors tend to grow as polypoid, rounded, bulky masses that have the appearance and consistency of grapelike clusters (hence the designation botryoides, or grapelike) (Fig. 22.11). The tumor cells are small and have oval nuclei, with small protrusions of cytoplasm from one end, resembling a tennis racket. Rarely, striations (indicative of muscle differentiation) can be seen within the cytoplasm. Beneath the vaginal epithelium, the tumor cells are crowded in a so-called cambium layer, but in the deep regions they lie within a loose edematous fibromyxomatous stroma that may contain many inflam- matory cells. Such lesions can be mistaken for benign inflammatory polyps. The tumors tend to invade locally and cause death by penetration into the peritoneal cavity or by obstruction of the urinary tract. Conservative surgery Figure 22.11 Sarcoma botryoides (embryonal rhabdomyosarcoma) of the coupled with chemotherapy offer the best hope, particularly vagina appearing as a polypoid mass protruding from the vagina. (Courtesy in cases diagnosed sufficiently early. Dr. Michael Donovan, Children’s Hospital, Boston, Mass.) Cervix Anatomically the cervix consists of the external vaginal junction is variable and changes with age and hormonal portio (ectocervix) and the endocervical canal. The ectocervix influence, but in general the junction moves upward into is visible on vaginal examination and is covered by a mature the endocervical canal with time. The replacement of the squamous epithelium that is continuous with the vaginal glandular epithelium by advancing squamous epithelium wall. The squamous epithelium converges centrally at a is a process called squamous metaplasia. The area of the small opening termed the external os that leads to the cervix where the columnar epithelium coexists with the endocervical canal. The endocervix is lined by columnar, squamous epithelium is termed the “transformation zone.” mucus-secreting epithelium. The point where the squamous The unique epithelial environment of the cervix renders it and the columnar epithelium meet is referred to as the highly susceptible to infection with HPV, the main cause squamocolumnar junction (Fig. 22.12). The position of the of cervical cancer. Immature squamous cells in the trans- formation zone are most susceptible to HPV infection, and as a result this is where the majority of cervical precursor Mature squamous cells lesions and cervical cancers develop. INFLAMMATIONS Immature Acute and Chronic Cervicitis squamous cells At the onset of menarche, the production of estrogens by the ovary stimulates maturation of the cervical and vaginal Squamocolumnar squamous mucosa and formation of intracellular glycogen junction vacuoles in the squamous cells. As these cells are shed, the glycogen provides a substrate for various endogenous vaginal aerobes and anaerobes, but particularly lactobacilli, Columnar which are the dominant microbial species in the normal glandular vagina. Lactobacilli produce lactic acid, which maintains cells the vaginal pH below 4.5, suppressing the growth of other saprophytic and pathogenic organisms. In addition, at low pH, lactobacilli produce bacteriotoxic hydrogen peroxide Figure 22.12 Cervical squamocolumnar junction showing a transition (H2O2). If the pH becomes alkaline due to bleeding, sexual from mature, glycogenized squamous epithelium to columnar endocervical glandular epithelium. The superficial, mature squamous epithelial cells are intercourse, or vaginal douching, H2O2 production by lactoba- not susceptible to human papillomavirus (HPV) infection. The HPV- cilli decreases. Antibiotic therapy that suppresses lactobacilli susceptible cells include immature basal squamous cells and endocervical can also cause the pH to rise. In each of these settings, glandular cells. the altered vaginal environment promotes the overgrowth 996 C H A P T E R 22 The Female Genital Tract can also detect low-stage, highly curable cancers. The acces- sibility of the cervix to Pap testing and visual examination (colposcopy) as well as the slow progression from precursor lesions to invasive carcinoma (typically over the course of decades) provides ample time for screening, detection, and preventive treatment. Pathogenesis High-risk HPVs are by far the most important factor in the development of cervical cancer. HPVs are DNA viruses that are grouped into those of high and low oncogenic risk based on their genotypes. There are 15 high-risk HPVs that are Figure 22.13 Endocervical polyp composed of a dense fibrous stroma currently identified, but HP -16 alone accounts for almost covered with endocervical columnar epithelium. 60% of cervical cancer cases, and HPV-18 accounts for another 10% of cases; other HPV types contribute to less than 5% of cases, individually. High-risk HPVs are also implicated of other microorganisms, which may result in cervicitis or in squamous cell carcinomas arising at many other sites, vaginitis. Some degree of cervical inflammation may be including the vagina, vulva, penis, anus, tonsil, and other found in virtually all women, and it is usually of little clinical oropharyngeal locations. As noted earlier, low oncogenic risk consequence. However, infections by gonococci, chlamydiae, HPVs are the cause of sexually transmitted vulvar, perineal, mycoplasmas, and HS may produce significant acute or and perianal warts (condyloma acuminatum). chronic cervicitis and are important to identify due to their Genital HPV infections are extremely common; most of association with upper genital tract disease, complications them are asymptomatic, do not cause any tissue changes, during pregnancy, and sexual transmission. Marked cervical and therefore are not detected on Pap test. The prevalence inflammation produces reparative and reactive changes of of HPV in cervical smears in women with normal Pap test the epithelium and shedding of atypical-appearing squamous results peaks between 20 and 24 years of age, around the cells, and therefore may cause an abnormal Pap test result. onset of sexual activity, and subsequently declines as protec- tive immunity is established and women enter into monoga- mous relationships. Most HPV infections are transient; ENDOCERVICAL POLYPS overall, 50% of HPV infections are cleared within 8 months, and 90% of infections are cleared within 2 years. The duration Endocervical polyps are common benign exophytic growths of the infection is related to HPV type, as infections with that arise within the endocervical canal. They vary from high-risk HPVs take longer to clear on average than infections small, sessile “bumps” to large polypoid masses that may with low-risk HPVs (13 months vs. 8 months, respectively). protrude through the cervical os. Histologically, they are Persistent infection increases the risk of the development composed of a fibrous stroma covered by mucus-secreting of cervical precursor lesions and subsequent carcinoma. endocervical glands, often accompanied by inflammation Productive, persistent HP infection requires viral entry (Fig. 22.13). Their main significance is that they may be the into immature basal epithelial cells. As a result, surfaces source of irregular vaginal “spotting” or bleeding that arouses covered with mature, intact squamous epithelium, such as suspicion of some more ominous lesion. Simple curettage the ectocervix, vagina, vulva, penis, and oropharynx, are or surgical excision is curative. normally resistant to HPV infection. Sites in the female genital tract that are susceptible to infection include areas of squamous epithelial trauma and repair, where the virus PREMALIGNANT AND MALIGNANT may access basal cells, and the immature metaplastic NEOPLASMS OF THE CERVIX squamous cells that are present at the squamocolumnar junction of the cervix (see Fig. 22.12). The cervix, with its Worldwide, cervical carcinoma is the fourth most common relatively large areas of immature squamous metaplastic cancer in women, with an estimated 570,000 new cases in epithelium, is particularly vulnerable to HPV infection. Other 2018, of which more than one-half will prove fatal. In the sites in the body that are vulnerable to HPV infection include United States, it was estimated in 2019 that 13,179 women the squamocolumnar junction of the anus and the squamous would be diagnosed with cervical cancer and that 4250 cells of oropharyngeal tonsillar crypts, both relatively women would die of the disease. Fifty years ago, carcinoma common sites of HPV-associated cancers in individuals who of the cervix was the leading cause of cancer death in women practice anal or oral sex, respectively. in the United States, but the death rate has declined by 75% The ability of HPV to act as a carcinogen depends on to its present rank as the thirteenth cause of cancer mortality. the viral E6 and E7 proteins, which interfere with the No form of cancer better documents the remarkable benefits activity of the key tumor suppressor proteins, p53 and of effective screening, early diagnosis, and curative therapy RB, respectively. Although HP infects immature squamous than does cancer of the cervix. Most credit for these dramatic cells, viral replication occurs in maturing squamous cells. gains belongs to the effectiveness of the Pap test in detecting Normally, these more mature cells are arrested in the G1 cervical precursor lesions, some of which would have phase of the cell cycle, but they continue to actively progress progressed to cancer if not treated; in addition, the Pap test through the cell cycle when infected with HPV, which uses  Cervix 997 the host cell DNA synthesis machinery to replicate its own Table 22.1 Classification Systems for Squamous Cervical genome. As you will recall from Chapter 7, viral E7 protein Precursor Lesions binds the hypophosphorylated (active) form of RB and Dysplasia/Carcinoma SIL, Current promotes its degradation via the proteasome pathway, and in situ CIN Classification also binds and inhibits p21 and p27, two important cyclin- Mild dysplasia CIN I Low-grade SIL (LSIL) dependent kinase inhibitors. Removal of these controls not Moderate dysplasia CIN II High-grade SIL (HSIL) only enhances cell cycle progression, but also impairs the Severe dysplasia CIN III High-grade SIL (HSIL) ability of cells to repair DNA damage. The DNA repair defect in infected cells is exacerbated by E6 proteins encoded Carcinoma in situ CIN III High-grade SIL (HSIL) by high-risk HPV subtypes, which bind p53 and promote CIN, Cervical intraepithelial neoplasia; SIL, squamous intraepithelial lesion. its degradation by the proteasome. In addition, E6 up- regulates the expression of telomerase, which leads to cellular immortalization. The net effect is increased proliferation of cells that are prone to acquire additional mutations that replication, but only mild alterations in the growth of host may lead to cancer development. By contrast to high-risk cells. For these reasons, LSIL is not treated like a premalignant HPVs, the E7 proteins of low-risk HPVs bind RB with lower lesion. LSIL is approximately ten times more common affinity, while the E6 proteins of low-risk HP s fail to bind than HSIL. p53 altogether and instead appear to dysregulate growth By contrast to LSIL, HSIL is considered to be at high and survival by interfering with the Notch signaling pathway. risk for progression to carcinoma. In HSIL, there is a progres- Another factor that contributes to malignant transforma- sive deregulation of the cell cycle by HPV, which results in tion by HPV is the physical state of the virus. The viral increased cellular proliferation, decreased or arrested epi- DNA is integrated into the host cell genome in most cancers. thelial maturation, and a lower rate of viral replication as This configuration increases the expression of E6 and E7 compared with LSIL. Derangement of the cell cycle in HSIL genes, and may also dysregulate oncogenes near the sites may become irreversible and lead to a fully transformed of viral insertion, such as MYC. By contrast, viral DNA is malignant phenotype. extrachromosomal (episomal) in precursor lesions associated with high-risk HPVs and in condylomata associated with low-risk HPVs. MORPHOLOGY Even though HP is firmly established as the major cause of cervical cancer, it is worth remembering that although a The diagnosis of SIL is based on identification of nuclear high percentage of young women are infected with one or atypia characterized by nuclear enlargement, hyperchro- more HPV types during their reproductive years, only a masia (dark staining), coarse chromatin granules, and few develop cancer. Thus, other factors, such as exposure variation in nuclear size and shape (Fig. 22.14). The nuclear to co-carcinogens and host immune status, influence whether changes are often accompanied by cytoplasmic “halos.” At an an HPV infection regresses or persists and eventually leads ultrastructural level, these “halos” consist of perinuclear vacuoles, to cancer. a cytopathic change created in part by an HPV-encoded protein E5 that localizes to the membranes of the endoplasmic reticulum. Cervical Intraepithelial Neoplasia (Squamous Nuclear alterations associated with perinuclear halos are termed koilocytic atypia. The grading of SIL into low or high grade is Intraepithelial Lesions) based on expansion of the immature cell layer from its normal, The classification of cervical precursor lesions has evolved basal location. If the immature squamous cells are confined to over time, and the terms from the various classification the lower one-third of the epithelium, the lesion is called LSIL; systems are used interchangeably. Hence a brief review if they expand to the upper two-thirds of the epithelial thickness, of the terminology is warranted. The oldest classification it is called HSIL. system grouped lesions as having mild dysplasia on one The histologic features of LSIL correlate with HPV replication end and severe dysplasia/carcinoma in situ on the other. and changes in host cell growth and gene expression (Fig. 22.15). This was followed by the cervical intraepithelial neoplasia The highest viral loads (assessed by in situ hybridization for HPV (CIN) classification, with mild dysplasia termed CIN I, DNA; see Fig. 22.15B) are found in maturing keratinocytes in the moderate dysplasia termed CIN II, and severe dysplasia upper half of the epithelium. HPV E6 and E7 proteins prevent termed CIN III. Because the decision with regard to patient cell cycle arrest. As a result, cells in the upper portion of the management is two-tiered (observation vs. surgical treat- epithelium express markers of actively dividing cells, such as Ki-67 ment), the three-tier classification system has been recently (see Fig. 22.15C), that are normally confined to the basal layer simplified to a two-tiered system, with CIN I renamed of the epithelium. Disturbed growth regulation also leads to low-grade squamous intraepithelial lesion (LSIL) and overexpression of p16, a cyclin-dependent kinase inhibitor (see CIN II and CIN III combined into one category referred Fig. 22.15D). Both Ki-67 and p16 staining are highly correlated to as high-grade squamous intraepithelial lesion (HSIL) with HPV infection and are useful for confirmation of the diagnosis (Table 22.1). in equivocal cases of SIL. LSIL does not progress directly to invasive carcinoma, and, in fact, most cases regress spontaneously; only a small percentage progress to HSIL. LSIL represents a productive More than 80% of LSILs and 100% of HSILs are associ- HPV infection in which there is a high level of viral ated with high-risk HPVs, with HPV-16 being the most 998 C H A P T E R 22 The Female Genital Tract Normal CIN I CIN II CIN III Figure 22.14 Spectrum of cervical intraepithelial neoplasia: normal squamous epithelium for comparison; low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia [CIN] I) with koilocytic atypia; high-grade squamous intraepithelial lesion (HSIL) (CIN II) with progressive atypia and expansion of the immature basal cells above the lower third of the epithelial thickness; HSIL (CIN III) with diffuse atypia, loss of maturation, and expansion of the immature basal cells to the epithelial surface. common HPV type in both lesions. Table 22.2 shows Cervical Carcinoma rates of regression and progression of SILs within a 2-year follow-up. Although the majority of HSILs develop from The average age of patients with invasive cervical carcinoma LSILs, approximately 20% of cases of HSIL develop de is between 45 and 50 years. Squamous cell carcinoma is the novo, independent of any preexisting LSIL. The rates of most common histologic subtype, accounting for approxi- progression are by no means uniform, and although HPV mately 80% of cases. The second most common tumor type type—especially HPV 16—is associated with increased risk, is adenocarcinoma, which constitutes about 15% of cervical it is difficult to predict the outcome in an individual patient. cancer cases and develops from a precursor lesion called These findings underscore that the risk of precursor lesions adenocarcinoma in situ. Adenosquamous and neuroendocrine and cancer is conferred only in part by HPV type. Progression carcinomas are rare cervical tumors that account for the to invasive carcinoma, when it occurs, on average takes remaining 5% of cases. All of the aforementioned tumor place over several decades. types are caused by high-risk HPVs. The progression time A B C D Figure 22.15 (A) Low-grade squamous intraepithelial lesion: routine hematoxylin and eosin staining shows koilocytic change, seen as nuclear enlargement and perinuclear “halos.” (B) In situ hybridization test for human papillomavirus deoxyribonucleic acid (HPV DNA). The dark granular staining denotes HPV DNA, which is most abundant in the superficial koilocytes. (C) Diffuse positivity for the proliferation marker Ki-67 (seen as brown nuclear staining), illustrates expansion of the proliferating cells from the normal basal location to the superficial layers of the epithelium. (D) Up-regulation of the cyclin- dependent kinase inhibitor p16 (seen here as brown staining) characterizes high-risk HPV infections.  Cervix 999 Table 22.2 Natural History of Squamous Intraepithelial Lesions With Approximate 2-Year Follow-Up Lesion Regress Persist Progress LSIL 60% 30% 10% to HSIL HSIL 30% 60% 10% to carcinomaa HSIL, High-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion. a Progression within 2 to 10 years. from in situ to invasive adenosquamous and neuroendocrine carcinomas is shorter than in squamous cell carcinoma, and patients with these tumors often present with advanced disease and have a less favorable prognosis. MORPHOLOGY A Invasive cervical carcinoma may manifest as fungating (exophytic) or infiltrative masses. Squamous cell carcinoma is composed of nests and tongues of malignant squamous epithelium, either keratinizing or nonkeratinizing, which invade the underlying cervical stroma (Fig. 22.16A–B). Adenocarcinoma is characterized by proliferation of glandular epithelium composed of malignant endocervical cells with large, hyperchromatic nuclei and relatively mucin-depleted cytoplasm, resulting in a dark appearance of the glands, as compared with the normal endocervical epithelium B Figure 22.17 Adenocarcinoma of the cervix. (A) Adenocarcinoma in situ (arrow) showing dark glands with atypical, enlarged nuclei adjacent to a normal, pale endocervical gland. (B) Invasive adenocarcinoma. (Fig. 22.17A–B). Adenosquamous carcinoma is composed of A intermixed malignant glandular and squamous epithelium. Neu- roendocrine cervical carcinoma has an appearance similar to small cell carcinoma of the lung (Chapter 15) but differs in being positive for high-risk HPVs. Advanced cervical carcinoma spreads by direct exten- sion to contiguous tissues, including paracervical soft tissue, urinary bladder, ureters (resulting in hydronephrosis), rectum, and vagina. Lymphovascular invasion results in local and distant lymph nodes metastases. Distant metastases may also be found in the liver, lungs, bone marrow, and other organs. Cervical cancer is staged as follows: Stage 0—Carcinoma in situ (CIN III, HSIL) Stage I—Carcinoma confined to the cervix Ia—Preclinical carcinoma, that is, diagnosed only by microscopy Ia1—Stromal invasion no deeper than 3 mm and no wider B than 7 mm (so-called superficially invasive squamous cell carcinoma) Figure 22.16 Squamous cell carcinoma of the cervix. (A) Early invasion Ia2—Maximum depth of invasion of stroma deeper than 3 mm in squamous cell carcinoma showing an invasive nest breaking through and no deeper than 5 mm taken from base of epithelium; the basement membrane of a high-grade squamous intraepithelial lesion. horizontal invasion no more than 7 mm (B) Invasive squamous cell carcinoma. 1000 C H A P T E R 22 The Female Genital Tract 5-year survival rate is 100% for superficially invasive Ib—Histologically invasive carcinoma confined to the cervix squamous cell carcinomas and less than 20% for tumors and greater than stage Ia2 extending beyond the pelvis. Most patients with advanced Stage II—Carcinoma extends beyond the cervix but not to the cervical cancer die of the consequences of local tumor inva- pelvic wall. Carcinoma involves the vagina but not the lower sion (e.g., ureteral obstruction, pyelonephritis, and uremia) third. rather than distant metastases. Stage III—Carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the CERVICAL CANCER SCREENING vagina. Stage IV—Carcinoma has extended beyond the true pelvis or AND PREVENTION has involved the mucosa of the bladder or rectum. This stage As is well known, cytologic cancer screening has significantly also includes cancers with metastatic dissemination. reduced mortality from cervical cancer. In countries where such screening is not widely practiced, cervical cancer continues to exact a high toll. The reason that cytologic Clinical Features screening is so effective in preventing cervical cancer is that More than one-half of invasive cervical cancers are detected most cancers arise from precursor lesions over the course in women who did not participate in regular screening. of years. These lesions shed abnormal cells that can be While superficially invasive squamous cell carcinomas may detected on cytologic examination. Using a spatula or brush, be treated by cervical cone excision alone, most invasive the transformation zone of the cervix is circumferentially cancers are managed by hysterectomy with lymph node scraped and the cells are smeared or spun down onto a dissection and, for advanced lesions, radiation and chemo- slide. Following fixation and staining with the Papanicolaou therapy. The prognosis for invasive carcinomas depends method, the smears are screened microscopically by eye or on the stage of the cancer at diagnosis and to some degree (increasingly) with automated image analysis systems. The on histologic subtype, with small-cell neuroendocrine tumors cellular changes seen on the Pap test, illustrating the spectrum having a very poor prognosis. With current treatments, the from LSIL to HSIL, are shown in Fig. 22.18. A B C D Figure 22.18 The cytology of cervical intraepithelial neoplasia as seen on the Papanicolaou smear. The cytoplasmic staining of desquamated cells may be either red or blue. (A) Normal exfoliated superficial squamous cells. (B) Low-grade squamous intraepithelial lesion—koilocytes. (C) High-grade squamous intraepithelial lesion (HSIL; cervical intraepithelial neoplasia [CIN] II). (D) HSIL (CIN III). Note the reduction in cytoplasm and the increase in the nucleus-to-cytoplasm ratio, which occurs as the grade of the lesion increases. This reflects the progressive loss of cellular differentiation on the surface of the lesions from which these cells are exfoliated. (Courtesy Dr. Edmund S. Cibas, Brigham and Women’s Hospital, Boston, Mass.)  Body of uterus and endometrium 1001 Testing for the presence of HPV DNA in the cervical An additional important aspect of cervical cancer preven- scrape is a molecular method of cervical cancer screening. tion is vaccination against high-risk oncogenic HPV, which HPV testing has a higher sensitivity but lower specificity, is now recommended for all girls and boys by 11 to 12 as compared to the Pap test. HPV DNA testing may be years of age, as well as young men and women up to 26 added to cervical cytology for screening in women 30 years years of age. Two HPV vaccines are now FDA-licensed. of age or older. HPV testing of women younger than 30 Both provide nearly complete protection against high-risk years of age is not recommended because of the high oncogenic HPV types 16 and 18 (together accounting for incidence of infection, and thus the particularly low specific- approximately 70% of cervical cancers), and one also provides ity of HPV test results in this age group. protection against additional five high oncogenic risk HPVs Cervical cancer screening and preventive measures are as well as two low oncogenic risk HPV types 6 and 11, carried out in a stepwise fashion. Recommendations for the which are responsible for genital warts. Vaccination is now frequency of Pap screening vary, but in general the first recommended for boys as well as girls due to the role that smear should be at 21 years of age or within 3 years of males play in the spread of HPV to women and the toll that onset of sexual activity, and thereafter every 3 years. After HPV-related anal and oropharyngeal cancers take in men. 30 years of age, women who have had normal cytology The vaccines offer protection for up to 10 years; longer results and are negative for HPV may be screened every 5 follow-up studies are still pending. Because the HPV vaccines years. Women who have a normal cytology result but test do not protect against all high-risk HPV types, current positive for high-risk HPV DNA should have cervical guidelines recommend that cervical cancer screening be cytology repeated every 6 to 12 months. continued as in the past. When the result of a Pap test is abnormal, a colposcopic examination of the cervix and vagina is performed to identify the lesion. The mucosa is examined with a magnifying glass KEY CONCEPTS following application of acetic acid, which highlights Cervical LSIL is a productive HPV infection that usually regresses abnormal epithelium as white spots (aceto-white areas). spontaneously but occasionally progresses to HSIL. Abnormal appearing areas are biopsied. Women with HSIL is characterized by progressive deregulation of the cell biopsy-confirmed LSIL can be followed in a conservative cycle and increasing cellular atypia. HSIL may progress to invasive fashion. Some gynecologists will perform local ablation (e.g., carcinoma. cryotherapy) of LSIL, particularly if there is concern about Almost all cervical precursor lesions and cervical carcinomas the reliability of patient follow-up. HSIL is treated with are caused by high-risk HPV types, most commonly HPV-16. cervical conization (superficial excision). Body of Uterus and Endometrium The uterus has two major components: the myometrium The cycle commences with menses, during which the and the endometrium. The myometrium is composed of superficial portion of the endometrium, referred to as tightly interwoven bundles of smooth muscle that form the the functionalis, is shed. wall of the uterus. The internal cavity of the uterus is lined The proliferative phase is marked by rapid growth of glands by the endometrium, which is composed of glands embedded and stroma arising from the deeper portion of the in a cellular stroma. The uterus is affected by a variety of endometrium (basalis). During the proliferative phase, disorders, the most common of which results from endocrine the glands are straight, tubular structures lined by regular, imbalances, complications of pregnancy, and neoplastic tall, pseudostratified columnar cells. Mitotic figures are proliferation. numerous, and there is no evidence of mucus secretion or vacuolation. The endometrial stroma is composed of spindle cells with scant cytoplasm that are also actively ENDOMETRIAL HISTOLOGY IN THE proliferating (see Fig. 22.19A). MENSTRUAL CYCLE At ovulation, endometrial proliferation ceases and dif- ferentiation commences in response to the effects of The endometrium undergoes dynamic physiologic and progesterone made by the corpus luteum in the ovary. morphologic changes during the menstrual cycle in Postovulation is initially marked by the appearance of response to sex steroid hormones coordinately produced secretory vacuoles beneath the nuclei in the glandular in the ovary. The ovary is influenced by hormones produced epithelium (see Fig. 22.19B). Secretory activity is most by the pituitary gland due to signals from the hypothalamus. prominent during the third week of the menstrual cycle, Together, hypothalamic, pituitary, and ovarian factors and when the basal vacuoles progressively move to the apical their interactions regulate maturation of ovarian follicles, surface. By the fourth week, the glands are tortuous, ovulation, and menstruation. producing a serrated appearance. This serrated or The histologic appearance of the endometrium may be “sawtooth” appearance is accentuated by secretory used to assess hormonal status, document ovulation, and exhaustion and shrinkage of the glands. determine causes of endometrial bleeding and infertility Stromal changes in the late secretory phase, due predomi- (Fig. 22.19). Progression through a normal menstrual cycle nantly to progesterone, are the most significant features. is correlated with the following histologic features: Prominent spiral arterioles appear accompanied by an 1002 C H A P T E R 22 The Female Genital Tract A B C D Figure 22.19 Histology of the menstrual cycle. (A) Proliferative phase with mitoses (arrow). (B) Early secretory phase with subnuclear vacuoles (arrow). (C) Late secretory exhaustion and predecidual changes (arrow). (D) Menstrual endometrium with stromal breakdown (arrow) (see text). increase in ground substance and edema between the down-regulates the expression of estrogen receptor in both stromal cells followed by stromal cell hypertrophy, the glands and the stroma, and as a result endometrial increased cytoplasmic eosinophilia (predecidual change), proliferation is suppressed. Progesterone also promotes the and a resurgence of stromal mitoses (see Fig. 22.19C). differentiation of the glands and causes functional changes Predecidual changes spread throughout the functio- in the stromal cells. Endometrial stem cells have been identi- nalis and are accompanied by a sparse infiltrate of fied that likely have a central role in the regeneration of the neutrophils and lymphocytes, which in this context are endometrium after menses. They may also contribute to considered normal. the development of ectopic endometrial tissue and endo- With the dissolution of the corpus luteum and the metrial cancer. subsequent drop in progesterone levels, the functionalis degenerates and bleeding into the stroma occurs, followed by stromal breakdown and onset of the next menstrual FUNCTIONAL ENDOMETRIAL cycle (see Fig. 22.19D). DISORDERS (DYSFUNCTIONAL The action of the ovarian hormones on the endometrium UTERINE BLEEDING) primarily occurs through their cognate nuclear receptors. During the proliferativ