The role of the pathologist in diagnosing gynecologic disease includes a broad range of conditions from infectious to congenital and from benign to malignant neoplasms in all parts of the female reproductive tract. The following two cases are typical of those seen in the practice of gynecologic pathology.

The diagnosis for Case 17-1 is adult granulosa cell tumor. Figure 17-1 depicts classic histology: neoplastic cells arranged in sheets with characteristic focal gland-like structures arranged around acellular pink material, known as Call-Exner bodies. The positive immunohistochemical staining confirms via immunofixation that this tumor overexpresses inhibin, which corresponds to the elevated blood level. The granulosa cell is a normal component of the ovarian follicle, which supports the follicle. Their classification will be discussed under tumors of the ovary.

The presentation of this patient with postmenopausal bleeding highlights one of the important clinical implications of this tumor. In addition to producing inhibin, occasionally granulosa cell tumors also produce estrogen. In a postmenopausal woman, unopposed estrogen stimulation can lead to a proliferation of the endometrial lining which can be premalignant or malignant (see section on “Endometrial Hyperplasia“), which can present with abnormal bleeding. Before operating on this patient’s ovarian mass, an endometrial biopsy would be obtained to rule out a concurrent malignancy of the endometrium.

Figure 17-2 shows an ectopic pregnancy, with placental tissue composed of immature chorionic villi, syncytiotrophoblast, and the neural tube of the fetus. This condition arises when a fetus implants at any location other than inside the uterus, with the fallopian tube being the most common site. The incidence increases the most in women who have a history of pelvic inflammatory disease (PID), although women with an intrauterine device also have an increased risk.

Most patients with this condition usually present with severe abdominal pain, which can be a sign that the ectopic pregnancy has ruptured. This can be a life-threatening condition, requiring urgent surgical intervention to prevent excessive blood loss.

A basic knowledge of the development of the female genital tract can be extremely beneficial in the understanding of the pathogenic processes that affect these organs. Of particular importance is that fact that the ovary develops from a different cell type than the fallopian tube and uterus.

The presentation of the patient in Case 17-3 is common, as the majority of Chlamydial infections are asymptomatic. Routine screening for this disease in sexually active women is important due to the potentially grave complications of untreated infections. While some patients have only mild side effects, like urethritis and cervicitis, others may go on to develop PID. PID represents spread of an infection from the lower to the upper reproductive tract, and can lead to life-threatening illness, scarring, and infertility.

Fitz-Hugh–Curtis syndrome is a less common sequela of PID. This syndrome represents spread of the infection to the space around the liver and to the liver capsule (Glisson’s capsule; perihepatitis), which may result in perihepatic adhesions. Perihepatic inflammation will present in women as right-upper quadrant pain, and may be confused with more common causes of pain in that location like cholecystitis.

The organism in Figure 17-5 is Candida albicans, a yeast which is a normal part of the vaginal milieu. Symptomatic candidiasis results when a disturbance of the normal flora permits the overgrowth of this yeast, resulting in vaginal and vulvar redness, itching, and inflammation. A few conditions associated with increased incidence of yeast infection are: diabetes, recent antibiotic therapy, and pregnancy.

Anatomy

The external female genitalia consists superiorly of the mons pubis and clitoris, laterally of the labia majora and more medially of the labia minora. The posterior aspect, referred to as the posterior fourchette, abuts the perineum. The opening to the vagina is termed the vestibule. Bilateral and named glands in the area consist of Skene glands (also known as periurethral glands), which open just lateral to the urethral meatus, and Bartholin glands, present laterally, which empty via ducts that drain into the posterior aspect of the vestibule.

Developmental Anomalies

Clitoromegaly at birth suggests an abnormality of testosterone production, which may be caused by a number of conditions, including adrenogenital syndrome and exogenous maternal ingestion.

Dermatologic Diseases/Benign Tumors

A common benign lesion in this part of the body, the Bartholin cyst, actually represents the accumulation of secretions from the corresponding glands due to plugging of duct outflow, and characteristically presents with a palpable mass located in the lateral aspect of the vestibular orifice. Although they may recur, these cysts are benign, and may require excision when draining alone is not curative. A common cause of infection in a Bartholin gland cyst is N. gonorrhoeae.

The diagnosis associated with Figure 17-6 is lichen sclerosus et atrophicus. This is an inflammatory skin disorder that is more common in postmenopausal women. It is characterized by all of the physical exam findings present in this patient. Microscopically, the epidermis is thinned by almost complete loss of the basal layer, with loss of rete pegs, and superficial hyperkeratosis (Figure 17-6). The superficial dermis is characterized by homogenization and edema, often with a band of pink, subepithelial collagen. There may be chronic inflammatory cells at the junction of the dermis and epidermis. Although it is not considered a premalignant lesion, patients with lichen sclerosus have a slightly increased risk of developing squamous cell carcinoma.

Inflammatory skin disorders that affect other areas of the body can also affect the vulva, including lichen planus, psoriasis, seborrheic dermatitis, and spongiotic dermatitis. For a more thorough discussion of these diseases, please see Chapter 20.

Premalignant and Malignant Tumors

The diagnosis of the biopsy illustrated in Figure 17-7 is vulvar intraepithelial neoplasia (VIN), which represents a spectrum of dysplasia from low grade (VIN1) to high grade (VIN3). Changes in the squamous cells include: increased nuclear to cytoplasmic ratios, nuclear pleomorphism, and a lack of maturation as the cells move toward the surface. Because the nuclear abnormalities are confined to the lower third in this patient’s epithelium, this represents VIN1. The diagnosis of VIN2 is used when the abnormalities are confined to the lower two thirds, and when they are fully thick, VIN3.

There are three types of VIN. The first two: warty and basaloid, are associated with high-risk human papillomavirus (HPV) infection, most commonly HPV 16. This is the type of VIN present in this patient (pictured in Figure 17-7). Many women with these types of VIN have concurrent neoplasia of the genital tract, making this patient’s history of cervical dysplasia (also caused by infection with high-risk HPV) not surprising.

The third type of VIN is termed differentiated VIN (or VIN, simplex type), and while not associated with HPV infections, its incidence is increased in women with inflammatory dermatitis of the vulva, most notable lichen sclerosus. Though their causative agents are not the same, all three subtypes of VIN represent precursor lesions for vulvar squamous cell carcinoma.

The biopsy illustrated in Figure 17-8 demonstrates extramammary Paget disease. The Paget cells are distinct from surrounding epithelium, with paler cytoplasm and more prominent nuclei. They are present in large numbers at the junction of the epidermis and dermis, sometimes in nests and rarely small glands, and other times as single cells. Paget disease can present as a solitary finding of primary cutaneous origin (primary cutaneous Paget disease), or may be a manifestation of an underlying malignancy of the surrounding skin, the anal–rectal region, or the bladder (secondary Paget disease or Paget disease of noncutaneous origin).

Microscopically, the cells of Paget disease mimic those of a cutaneous malignancy, which can present in this part of the body, malignant melanoma. Immunohistochemistry can help to differentiate between these two entities. As shown in Figure 17-6, the neoplastic cells are epithelial in origin, staining positively with low molecular weight cytokeratins CK7 and CAM5.2, and do not stain for the melanoma markers, S100, HMB-45, and MART-1.

Benign Lesions and Malformations

Developmental abnormalities include a septate (doubled) vagina, which is often accompanied by a duplicate uterus (uterus didelphys).

Infectious organism of the external genitalia often affects the vagina. For details, see Table 17-1. In addition, systemic inflammatory diseases, such as Crohn disease and Stevens–Johnson syndrome, may also affect the vagina.

Premalignant and Malignant Neoplasms

The most common malignant tumor of the vagina is metastatic cervical carcinoma. Although primary squamous cell carcinoma of the vagina is rare when compared to cervical and vulvar carcinoma, it does occur. Like vulvar carcinoma, it is preceded by three levels of dysplasia, and uses the same criteria to differentiate between the grades of vaginal intraepithelial neoplasia. Risk factors include HPV infection, immunosuppression, and a history of ionizing radiation.

Anatomy

The uterine cervix consists of the endocervix, which is contiguous with the uterus, and the outer portion that opens into the vagina, the exocervix. The patent center of the cervix is called the os. The endocervix is lined by mucous-secreting cells, while the exocervix is lined by squamous epithelium. The area where these two meet is called the transformation zone. This zone is pathologically important, as it is the preferred locale for infection by HPV, a known precursor of cervical dysplasia and carcinoma. The transformation zone migrates throughout life as the cervix elongates (Figures 17-4 and 17-11).

Benign Findings of the Cervix

Inflammation: The normal flora of the vagina is dominated by Lactobacilli, which produce acid and maintain the vaginal pH below 4.5. This environment curbs the growth of other organisms, like yeast. However, normal physiologic events, like menstruation, can alter the vaginal pH and result in shifts in vaginal flora. These normal changes lead most women to show signs of inflammation in the cervix. Marked or destructive inflammation, however, must be noted on cervical biopsies, as it may be the harbinger of a more serious upper tract infection like Chlamydia, Herpes Simplex Virus, or gonococcus (see Table 17-1).

Benign Lesions of Cervix: Two benign lesions of the cervix are noted here due to their potential confusion for a malignant condition. Leiomyomas are benign, circumscribed tumors of smooth muscle. Although they occur most frequently in the uterus, cervical leiomyomas can cause reactive atypia of the overlying epithelium. Cervical polyps are relatively common exophytic growths that occur in adult women. Because they can present with vaginal bleeding and a mass, they occasionally cause clinical concern. However, simple excision shows them to be benign fibrous tissue covered by columnar epithelium. Occasionally, entrapped mucous-filled spaces, termed, Nabothian cysts, may present as a cervical polyp as well.

Premalignant and Malignant Neoplasms

Squamous Cell Lesions: The implementation of screening for squamous cell carcinoma of the cervix is an important success story in the history of medicine. Early detection of precursor lesions by Pap smear (named after its creator, Papanicolaou), allows for clinical intervention before carcinoma develops in the vast majority of cases. Once a relatively common condition, invasive squamous cell carcinoma has been decreasing in incidence in the West for some time as a result, although it continues to be a major public health problem in less developed countries throughout the world.

The pathogenesis of cervical carcinoma has been linked to infection with HPV, a DNA virus that has many subtypes. There are known types that are “high risk” for causing cervical carcinoma, namely, HPV 16 and 18, and others that are “low risk,” and tend to cause lesions like genital warts, namely, HPV 6 and 11. Risk factors that increase exposure to HPV infections also increase an individual’s likelihood of developing cervical dysplasia and cancer. Among these are: early age at first intercourse, multiple sexual partners or a male partner with multiple previous partners, persistent infection with high-risk HPV subtypes, and high parity. Other risk factors, like immunosuppression and smoking, compromise the body’s defense against the infecting virus.

HPV infection, even with high-risk serotypes, can be transient. It is known that younger women more often clear the virus. It is, therefore, essential for the treating clinician to take into account a woman’s age when making management decisions for patients with cervical dysplasia. The general trend is to manage younger patients less aggressively, and older patients more vigilantly.

The Pap smear in Figure 17-12 shows benign squamous cells with pink cytoplasm and more atypical cells with blue cytoplasm, called koilocytes. This term is used for squamous cells that show changes due to HPV infection. In addition to the perinuclear halo (seen above as a clear space around the nucleus), nuclear changes present in the koilocytes include enlargement, irregular borders, and clumping of chromatin. The diagnosis in this patient is low-grade squamous intraepithelial lesion.