INTRODUCTION
A 54-year-old woman notes a 6-month history of progressive vaginal discharge with an odor. She also has noted vaginal spotting after intercourse. She had gone through menopause 2 years earlier and took an oral contraceptive for 10 years. She has smoked one pack of cigarettes per day for 20 years. She denies a cough or dyspnea. She complains of right back pain and right leg swelling. The speculum examination shows a 4-cm irregular fungating mass arising from the cervix.
· What is the most likely
diagnosis?
· What is the next
step?
· What is the likely
pathophysiology for this condition?
Summary: A 54-year-old postmenopausal woman has a
6-month history of an odiferous vaginal discharge and postcoital spotting. She
has smoked one pack of cigarettes per day for 20 years. She complains also of
right back pain and right leg swelling. The speculum examination shows a 4-cm
irregular fungating mass arising from the cervix.
· Most likely
diagnosis: Cervical cancer.
· Next step: Biopsy of
the lesion to confirm the diagnosis, followed by staging to assess the extent of
the disease.
· Likely
pathophysiology: Human papillomavirus.
CLINICAL
CORRELATION
Introduction
This patient most likely has cervical cancer.
Indications leading the clinician to the diagnosis in this case include the
patient's risk factors and presenting symptoms. Her risk factors for cervical
cancer include age, a history of oral contraceptive use, and a history of
smoking. The presenting symptoms of malodorous vaginal discharge and postcoital
bleeding are characteristic of cervical cancer. The history should guide the
clinician to examine the cervix. In this case, a grossly visible lesion was seen
on the cervix during speculum examination. The next step in management is to
biopsy the lesion for a definitive diagnosis.
Approach to
Cervical Dysplasia and Cancer
Definitions
Cervical intraepithelial neoplasia (CIN):
Dysplastic growth and development of the epithelial cells of the cervix. Lesions
may be defined by mild, moderate, or severe, or CIN I, CIN II, or CIN III (see
Figure
9-1).
Human papillomavirus (HPV): A double-stranded
DNA virus associated with condyloma, cervical intraepithelial lesions, and
cervical cancer. Cellular changes seen in HPV infection include an expanded
parabasal cell layer and koilocytes but normal maturation and mitoses. There are
over 70 types of HPV, which have varying oncogenic capacities. High-risk HPV
types are those most often associated with high-grade lesions and invasive
cancer. These types include 16,18, 31, 39, 45, 56, 58, and 68.
Koilocyte: A viral expression of E4 protein that
disrupts cytoplasmic keratin matrix in squamous cells and causes pleomorphism,
hyperchromasia, perinuclear halos, and nuclear changes, including enlarged
nuclei with abnormal edges, multinucleation, and variations in nuclear
size.
Discussion
Cervical cancer is the third most common
cancer of the female lower reproductive system. More than 80 percent of
cervical dysplasias and more than 90 percent of cervical cancers are associated
with HPV infection. Because HPV is transmitted through sexual
contact, many of the risk factors for cervical cancer involve behaviors that
increase the risk of all sexually transmitted diseases. These risk factors
include early intercourse, many sexual partners, high-risk sexual partners,
infection with other sexually transmitted diseases, and immunosuppression by HIV
infection. Relative risk factors may include oral contraceptive use, tobacco
use, and immunodeficiency. Other possible risk factors are under
investigation.
Cervical dysplasia is found most often in
females in their twenties, whereas cervical cancers usually become
evident in the fifth decade of life. The classic presentation of cervical
malignancies includes abnormal bleeding and leukorrhea. The bleeding can
range from blood streaking in a discharge or spotting to heavy bright red blood.
Foul-smelling purulent leukorrhea is often present. Other symptoms, such as
pelvic or leg pain, urinary or fecal material in the vagina, weight loss, and
generalized weakness, are suggestive of advanced disease.
The squamocolumnar junction is where the
squamous ectocervix abuts the columnar endocervix. Just distal to this junction
there is an area of squamous metaplasia that is influenced by factors such
menarche, pregnancy, local hormonal influences, infection, and trauma. As
columnar epithelium is replaced by squamous cells, a new squamocolumnar junction
is formed. The area between the old junction and the new junction is called the
transformation zone. It is in this transformation zone that most cervical
cancers arise.
Cervical cancer begins with infection of cervical
epithelium by human papillomavirus. Most infections resolve spontaneously
without progression to cancer. This suggests that viral infection alone is not
responsible for cervical cancer and that other, undefined factors are involved
in the pathogenesis. Additionally, there are many types of HPV that vary in
oncogenic potential, with subtypes 16 and 18 being found most commonly in
cervical caner.
Progression to dysplasia will occur if the viral genome
is integrated into the nucleus of the cell under the influence of other factors
that contribute to a favorable environment. Distinct cellular changes will
occur, representing malignant transformation to low-grade cervical
intraepithelial neoplasia (CIN I). A typical lesion will appear slightly raised
or thickened with koilocytes in the upper and middle epithelial layers.
Koilocytes are cells that have undergone cellular changes because of the
presence of a virus. These cells are pleomorphic, hyperchromic, and
multinucleated and have perinuclear halos. There are few if any mitotic
figures and no atypical mitotic figures in CIN I, usually involving the lower
third of the epithelium.
These low-grade CIN I lesions may regress spontaneously
without treatment but may progress to higher-grade lesions. When atypical cells
spread to between the lower 1/3 and 2/3 of the epithelium or the majority of the
cells of the keratinizing layers, the lesion is defined as CIN II. These
lesions demonstrate some areas of maturation but have areas of immature atypical
koilocytic cells with a decreased nuclear to cytoplasmic ratio and increased
numbers of mitotic figures (see Figure 9-2).
Progression to CIN III involves the upper 1/3 of the epithelium by
atypical cells with loss of maturation, an increase in hyperchromasia, and more
mitotic figures with atypical mitoses. As the lesion progresses to squamous
carcinoma in situ, the dysplastic cells may lose their cell walls and form
syncytial-like groups. Many small round nuclei with scant cytoplasm can be seen.
The majority of cells are atypical and are more hyperchromatic with coarse
chromatin, a higher degree of pleomorphism, and increased atypical mitoses.
Carcinoma in situ becomes invasive squamous cell carcinoma when
atypical cells invade the basement membrane. Invasive carcinoma has wide
variations of irregularly shaped cells and may have keratin pearls. There
may also be evidence of necrosis, hemorrhage, and inflammatory
cells.
The progression from CIN to cervical cancer is a slow
process that usually occurs over several years. This allows many opportunities
for screening before advanced-stage disease is evident. Most cases of cervical
dysplasia are asymptomatic, and the diagnosis is made when a Pap smear reveals
abnormal cytology. Good screening of asymptomatic patients, including a
thorough history and physical, and routine Pap smears have led to a decreased
incidence of cervical cancer. The role of the Pap smear is paramount in
early detection of cervical dysplasia to afford timely treatment and avoid
progression to invasive cervical cancer. Even after the development of cervical
cancer, a Pap smear has an important role in detection because diagnosis early
in the disease process may offer a better prognosis. Treatment of early cervical
cancer offers a 95 percent cure rate, whereas more advanced stages often lead to
death in more than a third of cases. This underscores the importance of diligent
efforts by the physician in counseling patients to receive an annual Pap
smear.
COMPREHENSION
QUESTIONS
[9.1] A 24-year-old woman is noted to have atypical
cells on a Pap smear. Which of the following features most likely would indicate
the need for further investigation of cervical biopsy?
A. HPV viral subtype revealing that type 16 is
present
B. Presence of diabetes mellitus
C. Presence of endocervical cells
D. Presence of vulvar condylomata
E. Three lifetime sexual partners
[9.2] A 32-year-old woman is noted to have a 2-cm
fungating lesion of the cervix. Which of the following is the best next
step?
A. Application of tricyclic acetic acid
(TCA)
B. Biopsy of the lesion
C. Pap smear of the cervix
D. Repeat examination after 6
months
[9.3] A hysterectomy specimen is performed, and the
cervix is examined by the pathologist. The pathologist determines that the
patient has CIN I. Which of the following is the most likely histologic
finding?
A. Cells with enlarged nuclei and loss of
polarity involving the upper third of the epithelium
B. Cells with enlarged nuclei involving the
middle third of the epithelium
C. Cells with enlarged nuclei and loss of
polarity involving the lower third of the epithelium
D. Cells with large nuclei and mitotic figures
below the basement membrane but not more than 3 mm
ANSWERS
[9.1] A. In the Besthesda system of Papanicolau
cytology reporting, findings can include atypical squamous cells of uncertain
significance (ASCUS), low-grade intraepithelial neoplasia, high-grade
intraepithelial neoplasia, and invasive cancer. ASCUS does not necessarily
translate into a serious condition, and some practitioners will repeat the Pap
smear in 3 to 6 months. However, if a high-risk viral subtype such as 16 or 18
is detected, colposcopic examination with directed cervical biopsies is
recommended to assess the extent of disease.
[9.2] B. The Pap smear is for cytologic
analysis of a normal-appearing cervix and is used as a screening test. An
abnormal cervix (i.e., lesion) should be biopsied.
[9.3] C. CIN I entails mild dysplasia that
involves the lower third of the epithelium. Because the basal cells (those
closest to the basement membrane) are the actively dividing cells, they are the
ones affected by HPV.
PATHOLOGY
PEARLS
· Cervical intraepithelial
neopalsia is a precursor to cervical cancer.
· The vast majority of cases
of cervical dyspasia and cancer are associated with human papillomavirus,
particularly subtypes 16 and 18.
· The best method for
analyzing a visible cervical lesion is biopsy, not a Pap smear.
· The Pap smear has decreased
the incidence of cervical cancer in the United States dramatically.
· The Bethesda classification
for pap smears reports atypical squamous cells of uncertain significance
(ASCUS), low grade squamous intraepithelial lesion (LSIL), high grade squamous
intraepithelial lesion (HSIL), and invasive cancer.
· LSIL includes human
papilloma viral changes and CIN I.
· HSIL includes CIN II and
CIN III and carcinoma in situ.
REFERENCES
Crum CP The female genital tract. In: Kumar V, Assas
AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7 ed.
Philadelphia: Elsevier Saunders, 2004:1072-1079.
DeCherney A, Lauren N. Current obstetric & gynecologic diagnosis and treatment, 9th ed. Chicago:
Mcgraw-Hill, 2003.
Stenchever M, et al. Comprehensive gynecology, 4th ed.
St. Louis: Mosby, 2001.