Cervical Cancer

Epidemiology and Risk Factors

Epidemiology

• Worldwide:
  • > 80% of new cases worldwide occur in less-developed countries.
  • 3rd most common gynecologic cancer diagnosis and cause of death in women
  • 500,000 new cases diagnosed annually
  • > 50% will prove fatal.
• In the United States:
  • 8th most frequent cause of cancer among women
  • Accounts for < 3% of all cancer deaths in women
  • 14,000 new cases of invasive cervical cancer (ICC) are diagnosed annually.
  • Mean age at diagnosis: 50 years
  • > 50% of ICCs are detected in women who did not participate in a regular Regular Insulin cervical cancer screening Screening Preoperative Care program.

Risk factors

High-risk human papillomaviruses (hrHPVs, “oncogenic viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology”) are strongly associated with high-grade lesions and progression to invasive cancer.

• These viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology cause 99% of SCCs and > 85% of adenocarcinomas.
• HPV HPV 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. Papillomavirus (HPV) may also cause cancers in 5 other sites:
  • Vulva Vulva The vulva is the external genitalia of the female and includes the mons pubis, labia majora, labia minora, clitoris, vestibule, vestibular bulb, and greater vestibular glands. Vagina, Vulva, and Pelvic Floor: Anatomy
  • Vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor: Anatomy
  • Anus
  • Oropharynx Oropharynx The middle portion of the pharynx that lies posterior to the mouth, inferior to the soft palate, and superior to the base of the tongue and epiglottis. It has a digestive function as food passes from the mouth into the oropharynx before entering esophagus. Pharynx: Anatomy
  • Penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. Penis: Anatomy
• High-risk HPV HPV 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. Papillomavirus (HPV) types are responsible for most ICCs:
  • HPV-16 (60%)
  • HPV-18 (10%)
  • < 5% for each of the 13 other hrHPVs

HPV-related:

• Early onset of sexual activity
• Multiple sexual partners
• Multiparity and young age at first birth
• History of vulvar or vaginal squamous intraepithelial neoplasia or cancer
• Immunosuppression
• Human immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology ( HIV HIV Anti-HIV Drugs) infection
• Co-infection with Chlamydia trachomatis Chlamydia trachomatis Type species of Chlamydia causing a variety of ocular and urogenital diseases. Chlamydia or herpes simplex Herpes Simplex A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Congenital TORCH Infections virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology

Non–HPV-related:

• Low socioeconomic status
• African American race
• Use of oral contraceptives
• Cigarette smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases (associated with SCC)
• Family history Family History Adult Health Maintenance
• Negative risk factor: circumcised male partners

Pathophysiology

Human papillomavirus Human papillomavirus 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. Papillomavirus (HPV)

• Persistent infection with 1 of the 15 genotypes of hrHPVs causes almost all cases of ICC.
• Most HPV HPV 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. Papillomavirus (HPV) infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease are:
  • Asymptomatic and do not cause tissue changes
  • Detected between 20 and 24 years of age
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency ↓ after the age of 24 years as immunity develops
  • Cleared spontaneously:
    • 50% in < 8 months
    • 90% in < 24 months
    • On average, high-risk HPVs clear in 13 months and low-risk HPVs in 8 months.
• Since only a small proportion of women infected with HPV HPV 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. Papillomavirus (HPV) develop cancer, other risk factors are likely involved.

Pathogenesis

• Entry of hrHPV into immature basal epithelial cells at points of access:
  • Squamocolumnar junction Squamocolumnar junction Esophagus: Anatomy ( transformation zone Transformation zone Diagnostic Procedures in Gynecology): between the squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology of the ectocervix and the glandular epithelium Glandular epithelium Glandular epithelia, composed of epithelial tissue, are specialized structures that play a role in the production and release of enzymes, hormones, sweat, oil, and mucus in organisms. The secretion and release of these substances are prompted by either external or internal stimuli. Glandular Epithelium: Histology of the endocervical canal
  • Any area where there is squamous epithelial trauma and repair
  • Surfaces covered with mature, intact squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology are resistant to HPV HPV 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. Papillomavirus (HPV) infection. 
• Persistence of HPV HPV 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. Papillomavirus (HPV) infection in the maturing squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology
• Progression of a clone of epithelial cells from persistent viral infection to precancerous Precancerous Pathological conditions that tend eventually to become malignant. Barrett Esophagus lesions via E6 and E7 proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis from hrHPV:
  • In 70% of ICCs, HPV HPV 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. Papillomavirus (HPV) is integrated into the host cell genome Genome The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics.
    • ↑ The expression of E6 and E7 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure 
    • May dysregulate oncogenes Oncogenes Genes whose gain-of-function alterations lead to neoplastic cell transformation. They include, for example, genes for activators or stimulators of cell proliferation such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of ‘v-‘ before oncogene symbols indicates oncogenes captured and transmitted by retroviruses; the prefix ‘c-‘ before the gene symbol of an oncogene indicates it is the cellular homolog (proto-oncogenes) of a v-oncogene. Carcinogenesis near sites of viral insertion
  • E6 protein:
    • Binds p53 → degradation of p53 → ↓ ability to keep cells with damaged DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure in G1 phase G1 Phase The period of the cell cycle preceding DNA replication in s phase. Subphases of g1 include ‘competence’ (to respond to growth factors), g1a (entry into g1), g1b (progression), and g1c (assembly). Progression through the g1 subphases is effected by limiting growth factors, nutrients, or inhibitors. Cell Cycle and ↓ ability to initiate apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage 
    • More mutations are likely → ↑ the likelihood of cancer
    • Also ↑ the expression of telomerase Telomerase An essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. DNA Replication → cellular immortalization
  • E7 protein:
    • Binds retinoblastoma Retinoblastoma Retinoblastoma is a rare tumor but the most common primary intraocular malignancy of childhood. It is believed that the condition arises from a neuronal progenitor cell. Retinoblastoma can be heritable or non-heritable. Retinoblastoma ( RB RB Chlamydia) protein → RB RB Chlamydia degradation → releases control of the transcription factor Transcription factor Generic term for proteins necessary for transcription Regulation of Transcription, E2F → uncontrolled proliferation
    • Binds and inhibits the cyclin-dependent kinase inhibitors Cyclin-Dependent Kinase Inhibitors Targeted and Other Nontraditional Antineoplastic Therapy (p21 and p27) → uncontrolled proliferation 
• Development of invasive carcinoma
  • After additional mutations occur
  • Typically occurs after many years in a minority of women with precursor lesions

Pathology of precursor lesions

• Squamous intraepithelial lesions (SILs) are premalignant (preinvasive) lesions of invasive squamous cell cervical cancer.
  • The SIL terminology is part of the Bethesda System Bethesda system A standardized reporting of results of PAP test, which includes the specimen adequacy, general categorization of findings, and results Cervical Cancer Screening of Nomenclature.
  • SIL is also called cervical intraepithelial neoplasia ( CIN CIN An increased tendency to acquire chromosome aberrations when various processes involved in chromosome replication, repair, or segregation are dysfunctional. Colorectal Cancer), or dysplasia.
• Adenocarcinoma in situ ( AIS AIS Scoliosis) is the less commonly seen premalignant lesion of invasive adenocarcinoma of the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy.

SIL classification:

• Low grade (LSIL):
  • Corresponds with CIN CIN An increased tendency to acquire chromosome aberrations when various processes involved in chromosome replication, repair, or segregation are dysfunctional. Colorectal Cancer 1 (low grade dysplasia)
  • Usually regresses on its own
  • Only a small minority proceed to HSIL.
• High grade (HSIL):
  • Corresponds with CIN CIN An increased tendency to acquire chromosome aberrations when various processes involved in chromosome replication, repair, or segregation are dysfunctional. Colorectal Cancer 2 or CIN CIN An increased tendency to acquire chromosome aberrations when various processes involved in chromosome replication, repair, or segregation are dysfunctional. Colorectal Cancer 3 (moderate or high grade dysplasia)
  • ↑ Risk for progression to carcinoma (compared to LSIL) 
  • Due to progressive deregulation of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle, usually by an hrHPV

Gross appearance of HSIL: 

• Most common on anterior lip of cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy
• Seen best when they become white after application of acetic acid

Microscopic appearance: 

• LSIL:
  • Immature squamous cells are confined to the lower 3rd of the epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology
  • Koilocytic atypia Atypia Fibrocystic Change (perinuclear halos)
• HSIL/ CIN CIN An increased tendency to acquire chromosome aberrations when various processes involved in chromosome replication, repair, or segregation are dysfunctional. Colorectal Cancer 2:
  • More atypia Atypia Fibrocystic Change and expansion of immature basal cells involving two-thirds of the epithelial thickness
• HSIL/ CIN CIN An increased tendency to acquire chromosome aberrations when various processes involved in chromosome replication, repair, or segregation are dysfunctional. Colorectal Cancer 3:
  • Also called carcinoma in situ Carcinoma in situ A lesion with cytological characteristics associated with invasive carcinoma but the tumor cells are confined to the epithelium of origin, without invasion of the basement membrane. Leukoplakia
  • Diffuse atypia Atypia Fibrocystic Change and loss of maturation
  • Expansion of the immature basal cells to the epithelial surface

Pathology of invasive carcinomas

Gross appearance: 

• Exophytic Exophytic Retinoblastoma 
• Infiltrating

Microscopic appearance:

• SCC:
  • 75% of cases 
  • Composed of nests and tongues of malignant squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology 
  • Either keratinizing or nonkeratinizing
  • Invades the underlying cervical stroma
• Adenocarcinoma
  • 20% of cases
  • Composed of malignant endocervical cells with large, hyperchromatic nuclei 
  • Smaller amounts of mucin than normal glands
• Adenosquamous carcinoma
  • < 3% of cases 
  • Composed of intermixed malignant glandular and squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology 
• Neuroendocrine cervical carcinoma (< 2% of cases)
  • Appearance is similar to that of small-cell carcinoma of the lung.
  • Positive for hrHPVs

Clinical Presentation

General

• Usually asymptomatic in the early stages 
• Often discovered as a result of:
  • Routine cervical cancer screening Screening Preoperative Care
  • Pelvic examination, with visible lesion identified on the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy
• Symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may have:
  • Vaginal bleeding
    • Irregular and/or abnormally heavy menstrual periods
    • Postcoital bleeding
  • Vaginal discharge
    • Foul-smelling
    • Watery, mucoid, or purulent
    • More commonly seen in large cancers
    • Frequently mistaken for cervicitis Cervicitis Inflammation of the uterine cervix. Gonorrhea

Advanced disease

Signs and symptoms caused by tumor Tumor Inflammation extension Extension Examination of the Upper Limbs and invasion:

• Pelvic or lower back pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways that may radiate to the legs
• Palpable lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy in the groin Groin The external junctural region between the lower part of the abdomen and the thigh. Male Genitourinary Examination
• Lymphedema Lymphedema Edema due to obstruction of lymph vessels or disorders of the lymph nodes. Lymphatic Filariasis (Elephantiasis) of the legs
• Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
• Hydronephrosis Hydronephrosis Hydronephrosis is dilation of the renal collecting system as a result of the obstruction of urine outflow. Hydronephrosis can be unilateral or bilateral. Nephrolithiasis is the most common cause of hydronephrosis in young adults, while prostatic hyperplasia and neoplasm are seen in older patients. Hydronephrosis
• Vaginal passage of urine or stool caused by fistulization of the bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess or bowel
• Pressure on the bowel or bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess can cause local ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage.
  • Hematochezia Hematochezia Gastrointestinal Bleeding 
  • Hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma 
• Sites of distant metastases:
  • Supraclavicular lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
  • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types

Pelvic exam findings

• Friable cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy
• Erosions Erosions Corneal Abrasions, Erosion, and Ulcers
• Cervical mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
• Bleeding
• Fixed adnexa

Diagnosis

The diagnosis of ICC is made by histologic examination of a cervical biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.

• Pap testing and cytologic evaluation
  • Used for cervical cancer screening Screening Preoperative Care
  • Ectocervical and endocervical cells are collected to evaluate the transformation zone Transformation zone Diagnostic Procedures in Gynecology (area at risk for cervical cancer). 
  • May be done in conjunction with hrHPV testing
  • Results are reported using a standardized system ( Bethesda system Bethesda system A standardized reporting of results of PAP test, which includes the specimen adequacy, general categorization of findings, and results Cervical Cancer Screening).
• Colposcopy Colposcopy The examination, therapy or surgery of the cervix and vagina by means of a specially designed endoscope introduced vaginally. Cervical Cancer Screening with biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
  • A procedure in which a colposcope Colposcope Instruments inserted into the vagina for examination of the tissues of the vagina and cervix by means of a magnifying lens. Diagnostic Procedures in Gynecology ( magnifying device magnifying device Instruments inserted into the vagina for examination of the tissues of the vagina and cervix by means of a magnifying lens. Diagnostic Procedures in Gynecology) is used to enhance visualization of the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy, identify macroscopic abnormal areas, and guide biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
  • This procedure may be done as a follow-up after an abnormal Pap test or as part of the initial evaluation (e.g., for a pelvic exam with grossly abnormal results).
• Conization (cone biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma)
  • Diagnostic excisional procedure that removes a cone-shaped portion of the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy around the endocervical canal
  • Allows pathologic review of the entire transformation zone Transformation zone Diagnostic Procedures in Gynecology
  • May be required if malignancy Malignancy Hemothorax is suspected but not found on colposcopy-directed biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
  • Technique options:
    • Scalpel (cold knife)
    • Laser
    • Loop electrosurgical excision procedure Loop Electrosurgical Excision Procedure Diagnostic Procedures in Gynecology

Staging

• Based on the American Joint Committee on Cancer and Union for International Cancer Control 8th edition
• Provides guidance on prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas and management
• Clinical staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis may be done through:
  • Physical examination
  • Cervical biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
  • Endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD)
    • Hysteroscopy Hysteroscopy Endoscopic examination, therapy or surgery of the interior of the uterus. Diagnostic Procedures in Gynecology
    • Cystoscopy
    • Proctoscopy
  • Imaging studies
    • Intravenous pyelogram (IVP): to evaluate for urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy obstruction
    • CT
    • MRI
    • PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging
• Statistics on the extent of disease at diagnosis (in the United States):
  • Localized disease in 45%
  • Advanced disease:
    • Regional disease in 36%
    • Distant metastases in 15%

TNM staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis

Prognostic staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis

The TNM stage can then be used to determine the prognostic stage group.

Management

Management options

• Conization:
  • Loop electrosurgical excision procedure Loop Electrosurgical Excision Procedure Diagnostic Procedures in Gynecology
  • Cold knife
  • Laser
• Radical cervicectomy: surgical removal of the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy, upper part of the vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor: Anatomy, and adjacent parametrium
• Hysterectomy:
  • Simple:
    • Cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy and uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy are removed.
    • Surrounding structures are spared.
  • Radical:
    • Cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy and uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy are removed.
    • Parts of the vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor: Anatomy and parametrium are also removed.
• Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy:
  • External beam radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy (EBRT)
  • Brachytherapy:
    • Localized radioactive implants to the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy
    • Usually contain cesium
    • Allows a higher dose of radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma and spares surrounding tissue
• Chemotherapy Chemotherapy Osteosarcoma:
  • Platinum therapy:
    • Cisplatin Cisplatin An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These cross links appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the g2 phase of the cell cycle. Alkylating Agents and Platinum
    • Carboplatin Carboplatin An organoplatinum compound that possesses antineoplastic activity. Alkylating Agents and Platinum
  • Paclitaxel Paclitaxel A cyclodecane isolated from the bark of the pacific yew tree, taxus brevifolia. It stabilizes microtubules in their polymerized form leading to cell death. Microtubule and Topoisomerase Inhibitors
  • Fluorouracil Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Bowen Disease and Erythroplasia of Queyrat
  • Gemcitabine Gemcitabine Antimetabolite Chemotherapy
  • Topetecan
• Immunotherapy:
  • Bevacizumab Bevacizumab An anti-vegf humanized murine monoclonal antibody. It inhibits vegf receptors and helps to prevent pathologic angiogenesis. Targeted and Other Nontraditional Antineoplastic Therapy ( vascular endothelial growth factor Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing (VEGF) monoclonal antibody)
  • Pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC) (programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death 1 ( PD-1 PD-1 An inhibitory t-lymphocyte receptor that has specificity for CD274 antigen and programmed cell death 1 ligand 2 protein. Signaling by the receptor limits T cell proliferation and interferon gamma synthesis. The receptor also may play an essential role in the regulatory pathway that induces peripheral tolerance. T cells: Types and Functions) monoclonal antibody)

Management by stage

Management depends on the stage, extension Extension Examination of the Upper Limbs to nearby lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy and tissue, and the patient’s age, pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care status, and desire to maintain fertility.

• LSIL (CIN-1):
  • Observation, especially if the patient is < 25 years old, since most regress
  • Excision of the cervical transformation zone Transformation zone Diagnostic Procedures in Gynecology
    • Loop electrosurgical excision procedure Loop Electrosurgical Excision Procedure Diagnostic Procedures in Gynecology 
    • Laser ablation 
• HSIL (CIN-2, CIN-3):
  • Treatment with loop electrosurgical excision procedure Loop Electrosurgical Excision Procedure Diagnostic Procedures in Gynecology 
  • If CIN-2 and < 25 years old, observation is preferred
• Stage IA:
  • Options to maintain fertility:
    • Conization with or without lymphadenectomy
    • If negative margins, the patient may be monitored closely
    • If positive margins, repeat conization or radical cervicectomy with lymphadenectomy
  • Options if fertility is not an issue:
    • EBRT plus brachytherapy
    • Simple hysterectomy or radical hysterectomy with lymphadenectomy
    • Surgery may be combined with EBRT or brachytherapy.
    • Chemotherapy Chemotherapy Osteosarcoma is added if there is spread to the parametrium.
• Stages IB‒IIA:
  • Radical cervicectomy with lymphadenectomy:
    • Option to maintain fertility 
    • For stage IB only
  • Radical hysterectomy with lymphadenectomy:
    • If spread to the parametrium, EBRT with chemotherapy Chemotherapy Osteosarcoma is added.
    • Brachytherapy may be added.
  • Brachytherapy plus EBRT:
    • For patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who are not surgical candidates
    • Chemotherapy Chemotherapy Osteosarcoma may be added
• Stages IIB‒IVA:
  • Chemotherapy Chemotherapy Osteosarcoma plus radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma (EBRT and brachytherapy)
• Stage IVB:
  • Not considered curable
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma with or without chemotherapy Chemotherapy Osteosarcoma
  • Immunotherapy may be added.

Prognosis

• 5-year survival rates in the United States:
  • Stage I: > 80%
  • Stage II: 60%–80%
  • Stage III: approximately 50%
  • Stage IV: < 30%
• 3-year disease-free survival
  • Adenocarcinoma: 78% 
  • SCC: 57%
• Small-cell neuroendocrine tumors Neuroendocrine tumors Tumors whose cells possess secretory granules and originate from the neuroectoderm, i.e., the cells of the ectoblast or epiblast that program the neuroendocrine system. Common properties across most neuroendocrine tumors include ectopic hormone production (often via apud cells), the presence of tumor-associated antigens, and isozyme composition. Gastrinoma have the worst prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas.
  • Overall survival rate is 29% at 5 years.
  • No patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship survive if the stage is > IB1 or if there are lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node metastases.
• Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with advanced cervical cancer die because of the effects of local tumor Tumor Inflammation invasion (e.g., ureteral obstruction Ureteral obstruction Blockage in any part of the ureter causing obstruction of urine flow from the kidney to the urinary bladder. The obstruction may be congenital, acquired, unilateral, bilateral, complete, partial, acute, or chronic. Depending on the degree and duration of the obstruction, clinical features vary greatly such as hydronephrosis and obstructive nephropathy. Vesicoureteral Reflux and kidney failure) rather than metastases.

Differential Diagnosis

• Endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer: a malignancy Malignancy Hemothorax of the endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development, usually due to adenocarcinoma. This is more commonly seen in women > 50 years of age with a history of unopposed estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy exposure. Postmenopausal vaginal bleeding is a worrisome symptom. Imaging and endometrial biopsy Endometrial Biopsy Diagnostic Procedures in Gynecology will provide the diagnosis. Management depends on the stage but may include hysterectomy, chemotherapy Chemotherapy Osteosarcoma, and radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma.
• Cervicitis Cervicitis Inflammation of the uterine cervix. Gonorrhea: an inflammatory or infectious condition of the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy. Common causes include Chlamydia trachomatis Chlamydia trachomatis Type species of Chlamydia causing a variety of ocular and urogenital diseases. Chlamydia, Neisseria gonorrhoeae Neisseria gonorrhoeae A species of gram-negative, aerobic bacteria primarily found in purulent venereal discharges. It is the causative agent of gonorrhea. Neisseria, gynecologic procedures, and chemical irritants or allergens. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may have vaginal discharge and bleeding. Cervical edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion, and friability may be noted on pelvic exam. Diagnosis is based on this history and testing for sexually transmitted organisms. Management includes antibiotics for infectious causes.
• Pelvic inflammatory disease Pelvic inflammatory disease 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, Neisseria gonorrhoeae, and Gardnerella vaginalis. Pelvic Inflammatory Disease ( PID PID 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, Neisseria gonorrhoeae, and gardnerella vaginalis. Pelvic Inflammatory Disease): an ascending infectious process involving the uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy, fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Uterus, Cervix, and Fallopian Tubes: Anatomy, and ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries: Anatomy. This disease is closely linked with sexually transmitted diseases (especially C. trachomatis and N. gonorrhoeae N. gonorrhoeae A species of gram-negative, aerobic bacteria primarily found in purulent venereal discharges. It is the causative agent of gonorrhea. Neisseria). Pelvic inflammatory disease Pelvic inflammatory disease 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, Neisseria gonorrhoeae, and Gardnerella vaginalis. Pelvic Inflammatory Disease is an acute process that causes extreme tenderness on pelvic exam and a fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. Diagnosis involves identification Identification Defense Mechanisms of the causative organism. Treatment is with antibiotics.
• Endocervical polyp: a common benign Benign Fibroadenoma exophytic Exophytic Retinoblastoma proliferation in the endocervical canal that may have a stalk and protrude through the cervical os. This may cause abnormal vaginal spotting or bleeding (postcoital or contact) or abnormal vaginal discharge. Diagnosis is usually obvious on colposcopic exam (polyps are soft, with smooth and regular Regular Insulin contours).