Gynecologic Pathology: Infections, Neoplasms and Screening (ENARM)

Syphilis is a bacterial infection caused by the spirochete Treponema pallidum subspecies pallidum (T. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Primary syphilis begins with a chancre, a painless ulcer on the genitals. Progression to secondary syphilis manifests as a generalized maculopapular rash, which includes the palms and soles. The development of tertiary syphilis can cause severe neurologic (neurosyphilis), cardiovascular, and/or gummatous disease. The diagnosis is through both treponemal and nontreponemal testing. Penicillin G is the antibiotic of choice. The duration of management varies based on the stage of the disease.

Genital herpes infections are common sexually transmitted infections caused by herpes simplex virus (HSV) type 1 or 2. Herpes simplex virus type 1 is more commonly associated with non-genital herpes, while HSV-2 is more commonly associated with genital herpes. Primary infection often presents with systemic, prodromal symptoms followed by clusters of painful, fluid-filled vesicles on an erythematous base, dysuria, and painful lymphadenopathy. Primary infection can also be asymptomatic. Herpes infections are unique in that the virus is able to remain dormant in the neuronal ganglia, which allows for recurrent infections. Recurrent outbreaks are usually less severe than the initial infection. Treatment is with antiviral therapy, primarily acyclovir.

Pelvic inflammatory disease (PID) is defined as a polymicrobial infection of the upper female reproductive system. The disease can affect the uterus, fallopian tubes, ovaries, and adjacent structures. Pelvic inflammatory disease is closely linked with sexually transmitted diseases, most commonly caused by Chlamydia trachomatis and Neisseria gonorrhoeae, as well as organisms associated with bacterial vaginosis, such as Gardnerella vaginalis. Common symptoms are lower abdominal pain, cervical discharge, and irregular vaginal bleeding. Complications of PID can include ectopic pregnancy, chronic pelvic pain, and infertility. Diagnosis is primarily clinical in addition to PCR testing of cervical specimens and sometimes imaging or laparoscopy. Due to its polymicrobial nature, PID treatment is with combination antibiotic regimens.

Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic, but it can also be seen in association with chromosomal and genetic defects, including Turner syndrome (45,X karyotype) and FMR1 premutation. Affected individuals present with signs and symptoms of menopause prior to age 40, including oligomenorrhea or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Key laboratory findings include elevated follicle-stimulating hormone (FSH) and low estrogen levels. Once the diagnosis of POI is made, screening for autoimmune adrenal antibodies should be performed and a karyotype, FMR1 premutation screen, and baseline DEXA scan should be obtained. Management includes hormone replacement therapy (HRT), addressing fertility concerns as desired, and psychological support.

Cervical cancer is the 3rd most common gynecologic cancer. More than 90% of cervical cancer cases are associated with high-risk human papillomavirus (hrHPV), which is transmitted by sexual contact. Cervical cancer can be prevented by early detection and treatment of precancerous lesions caused by hrHPV. The methods of detection are cervical cytology and HPV testing. Guidelines vary on when to start screening, with various US societies recommending that screening start between 21 and 25 years of age, while the World Health Organization (WHO) suggests waiting until age 30, especially in resource-limited settings. Guidelines also vary on the preferred method of testing, though HPV testing (with or without cytology) is universally preferred starting at age 30.  Since the screening program was initiated, there has been a 75% decline in the incidence of and mortality from cervical cancer.

Antiestrogens are medications decreasing the estrogenic effects in the body. The antiestrogens include selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), aromatase inhibitors, and several others, which include medications suppressing the gonadotropins or counteracting the effects of estrogen. Antiestrogens are most commonly used in the treatment of breast cancer but also treat precocious puberty, gynecomastia, anovulatory infertility, and several gynecologic complaints. Adverse effects include hot flashes, venous thromboembolic events, bone mineral density loss, and ischemic cardiovascular events. Antiestrogens are contraindicated in individuals with known hypersensitivity reactions and pregnancy.

Genital herpes infections are common sexually transmitted infections caused by herpes simplex virus (HSV) type 1 or 2. Herpes simplex virus type 1 is more commonly associated with non-genital herpes, while HSV-2 is more commonly associated with genital herpes. Primary infection often presents with systemic, prodromal symptoms followed by clusters of painful, fluid-filled vesicles on an erythematous base, dysuria, and painful lymphadenopathy. Primary infection can also be asymptomatic. Herpes infections are unique in that the virus is able to remain dormant in the neuronal ganglia, which allows for recurrent infections. Recurrent outbreaks are usually less severe than the initial infection. Treatment is with antiviral therapy, primarily acyclovir.

The human immunodeficiency virus (HIV) is a species of Lentivirus, a genus of the family Retroviridae, which causes HIV infections and acquired immunodeficiency syndrome (AIDS). The virus has high genetic variability and is divided into 2 major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). The human immunodeficiency virus is a single-stranded, positive-sense, enveloped RNA virus, which targets and destroys WBCs, leading to frequent opportunistic infections and, eventually, death.

Cervical cancer is the 3rd most common gynecologic cancer. More than 90% of cervical cancer cases are associated with high-risk human papillomavirus (hrHPV), which is transmitted by sexual contact. Cervical cancer can be prevented by early detection and treatment of precancerous lesions caused by hrHPV. The methods of detection are cervical cytology and HPV testing. Screening is recommended by the age of 21 and is generally repeated every 3 years up to the age of 29 in an average-risk individual. By age 30, HPV testing with cytology is obtained. Since the screening program was initiated, there has been a 75% decline in the incidence of and mortality from cervical cancer.

Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Currently, reverse transcriptase, protease, integrase, and entry inhibitors are used in combined ART (cART) regimens. Combination therapy (3-drug regimen) is used to prevent drug resistance and cross-resistance, which develop through genetic mutations.

Sexually transmitted infections (STIs) or sexually transmitted diseases (STDs) are infections that spread either by vaginal intercourse, anal sex, or oral sex. Symptoms and signs may include vaginal discharge, penile discharge, dysuria, skin lesions (e.g., warts, ulcers) on or around the genitals, and pelvic pain. Some infections can lead to infertility and chronic debilitating disease. And some STIs can affect infants by vertical transmission. Diagnosis of STIs includes a combination of comprehensive medical and sexual history, assessing risk factors, focused genitourinary physical exam, and disease-specific laboratory tests/cultures. Treatment and prevention include a combination of antibiotic/antiviral agents and patient education on safe sex practices.

Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. There are > 200 serotypes that can cause several conditions, including cutaneous warts, anogenital warts, and neoplasms.

Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Primary syphilis begins with a chancre, a painless ulcer on the genitals. Progression to secondary syphilis manifests as a generalized maculopapular rash, which includes the palms and soles. The development of tertiary syphilis can cause severe neurologic (neurosyphilis), cardiovascular, and/or gummatous disease. The diagnosis is through both treponemal and nontreponemal testing. Penicillin G is the antibiotic of choice. The duration of management varies based on the stage of the disease.

Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. During the menopausal transition, reproductive hormones can fluctuate significantly, leading to symptoms that include hot flushes, sleep and mood disturbances, and vaginal dryness. In postmenopausal woman, low estrogen levels contribute to an increased risk for cardiovascular disease, osteoporosis, and sexual dysfunction due to vulvovaginal atrophy. For some women, symptoms negatively affect their quality of life and treatment is warranted. Management usually involves hormone replacement therapy (HRT), but other treatment options also exist.

Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic, but it can also be seen in association with chromosomal and genetic defects, including Turner syndrome (45,X karyotype) and FMR1 premutation. Patients present with signs and symptoms of menopause prior to age 40, including oligomenorrhea or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Key laboratory findings include elevated follicle-stimulating hormone (FSH) and low estrogen levels. Once the diagnosis of POI is made, the patient should be screened for autoimmune adrenal antibodies, and a karyotype, FMR1 premutation screen, and baseline DEXA scan should be obtained. Management includes hormone replacement therapy (HRT), addressing fertility concerns as desired, and psychological support.

Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. There are 2 major histologic types of ICC: squamous cell carcinoma (SCC) and adenocarcinoma. High-risk human papillomaviruses (hrHPVs) cause > 99% of SCCs and > 85% of adenocarcinomas. Early cervical neoplasia is asymptomatic, and diagnosis is made using routine screening methods, including the cervical Papanicolaou test with cytology, hrHPV testing, and biopsy. Treatment of precursor or dysplastic lesions depends on the severity of the dysplasia and the age of the patient. Management of ICCs depends on the stage and varies from excisional biopsy by cervical cone biopsy for microinvasive ICC to radical hysterectomy for more advanced cases. If there is extracervical spread, radiation and chemotherapy would be recommended.

Pelvic inflammatory disease (PID) is defined as a polymicrobial infection of the upper female reproductive system. The disease can affect the uterus, fallopian tubes, ovaries, and adjacent structures. Pelvic inflammatory disease is closely linked with sexually transmitted diseases, most commonly caused by Chlamydia trachomatis and Neisseria gonorrhoeae, as well as organisms associated with bacterial vaginosis, such as Gardnerella vaginalis. Common symptoms are lower abdominal pain, cervical discharge, and irregular vaginal bleeding. Complications of PID can include ectopic pregnancy, chronic pelvic pain, and infertility. Diagnosis is primarily clinical in addition to PCR testing of cervical specimens and sometimes imaging or laparoscopy. Due to its polymicrobial nature, PID treatment is with combination antibiotic regimens.

The term vulvovaginitis is used to describe an acute inflammation of the vulva and vagina. Vulvovaginitis can be caused by several infectious and non-infectious etiologies, and results from disruption of the normal vaginal environment. Common signs and symptoms include pain, pruritis, erythema, and edema of the affected region, as well as vaginal discharge and dyspareunia. The diagnosis is based on the clinical presentation, physical examination findings, and inspection of vaginal secretions. Management depends on the etiology, including antimicrobials for infectious causes.

Human immunodeficiency virus (HIV), a single-stranded RNA virus belonging to the Retroviridae family, is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus is a sexually transmitted or blood-borne infection that attacks CD4+ T lymphocyte cells, macrophages, and dendritic cells, leading to eventual immunodeficiency. The presentation is marked by constitutional symptoms such as lymphadenopathy and fever. Further progression predisposes to opportunistic infections and malignancies. Diagnosis is by enzyme immunoassay for HIV-1 and -2. Additional tests include HIV viral load, genotyping, and CD4+ T lymphocyte count to determine therapy and evaluate treatment response and disease progression. Immediate treatment with combination antiretroviral therapy is recommended.

Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Genetic factors, age, and hormonal and environmental influence contribute to the progression of the disease. The most common histologic type is infiltrating ductal carcinoma, which is > 75% of all breast cancers. Screening mammography is recommended for early disease detection. Diagnosis is by core needle biopsy, with biologic factors determined by immunohistochemical testing. Surgery, systemic treatment (chemotherapy, biologic therapy, endocrine therapy), and radiation therapy (RT) are part of the early-stage and locally advanced disease management. In metastatic breast cancer, systemic treatment is utilized with palliative measures.