Cervical Carcinoma

Todd M. Blodgett, MD

Alex Ryan, MD

Omar Almusa, MD

Key Facts

Imaging Findings

PET/CT: Intense FDG activity in primary cervical mass, vagina, uterus, parametria; ± lymphadenopathy, visceral metastases
Primary tumor: CEMR
Most cervical SCCA is avid on FDG → high sensitivity for sizable lesions
Evaluation of pelvic and para-aortic LN
LN detection on PET: Sensitivity 75-91%, specificity 93-100%
When PET/CT is performed with diagnostic quality CT, including IV and oral contrast, quality of the overall procedure is improved
Sensitivity and specificity for post-therapy of patients with cervical cancer: 90-93%, 91-100%

Top Differential Diagnoses

Other Female Reproductive Tract Malignancy
Ovarian Cancer
Leiomyoma
Physiologic FDG Activity in Female Reproductive Organs
Urine Contamination

Clinical Issues

Often asymptomatic
Clinical staging accurate in ˜ 60% of patients

Diagnostic Checklist

PET/CT for optimal staging
Physical exam, MR for evaluation of primary tumor

Graphic shows an irregular mass in the uterine cervix

, compatible with cervical carcinoma.

Coronal PET shows multiple periaortic lymph nodes

and a left pelvic lymph node

, not previously identified. An additional IMRT plan was performed for the left pelvic lymph node.

TERMINOLOGY

Abbreviations and Synonyms

Cervical cancer
Cervical carcinoma
Carcinoma of the cervix
Squamous cell carcinoma of the uterine cervix
Locally advanced cervical cancer (LACC)

Definitions

Primary cancer that arises from intraepithelial neoplasia of cervical cells
- Squamous cell carcinoma (SCCA): 80%
- Adenocarcinoma: 15%
- Adenosquamous: 3-5%
- Rare: Lymphoma and sarcoma

IMAGING FINDINGS

General Features

Best diagnostic clue
- PET/CT
  - Intense FDG activity in primary cervical mass, vagina, uterus, parametria
  - ± Lymphadenopathy, visceral metastases
- CT/MR
  - Enhancing mass in expected location of cervix
  - ± Extension into vagina, uterus, parametria
  - ± Lymphadenopathy, visceral metastases
Location
- Primary
  - Cervix
- Local
  - Vaginal mucosa
  - Extension into endometrium or myometrium
  - Direct extension into parametrium or adjacent structures
- Regional LN
  - Para-aortic
  - Common iliac
  - External iliac
- Metastatic
  - Distant nodes
  - Organs
Size
- Varies, from microscopic to several centimeters
- Many small cervical masses will not be apparent on CT

Imaging Recommendations

Best imaging tool
- Primary tumor
  - CEMR probably best modality for evaluating the primary lesion
- Local and distant metastases
  - PET/CT (consider with contrast-enhanced CT)
  - CT reveals ˜ 1/3 para-aortic mets
  - MR and CT: Moderate sensitivity and specificity for detecting pelvic, para-aortic lymphadenopathy; may fail to identify small metastases
- MR for detecting cervical cancer lymphadenopathy: Sensitivity 36-71%, specificity 76-100%
- Combination of tumor markers and PET/CT may be highly efficient for detecting recurrence
Protocol advice
- FDG excretion through urinary tract and bladder can cause false positive
  - Bladder voiding prior to imaging important to minimize FDG accumulation within the bladder (may cause artifact in pelvis)
  - However, primary tumor likely well characterized on anatomic imaging modality (MR)
  - Image from thighs toward head to minimize excretory FDG within the bladder
  - Can repeat a bed position after voiding if unclear on initial PET scan
  - Lasix may be useful, although not routinely used

CT Findings

Local tumor
- Primary tumor arises in cervical canal
  - Extension into peripheral parenchyma can be evaluated with CT
- Compared to normal cervical stroma, primary tumor may be hypo- or isoattenuating
  - Stage IB tumors frequently are isoattenuating to normal cervical tissue (50%)
  - May not be apparent on CT
- Larger lesions will show variable diffuse enhancement pattern seen in delayed images of normal cervix
- Tumor extension outside cervix is less likely when cervical margins are smooth and well defined
- Enlargement of endometrial cavity with blood, serous fluid, or pus can follow obstruction of endocervical canal status post radiotherapy
- Necrosis or prior biopsy of lesion may produce intratumoral gas
- Poorer outcome associated with cervical enlargement > 3.5 cm and an AP size > 6 cm
Extension/metastasis
- CT useful for the depiction of
  - Adenopathy
  - Pelvic side wall extension
  - Advanced bladder and rectal invasion
  - Ureteral obstruction
  - Extrapelvic spread of disease
- Tumor extension within 3 mm of pelvic side wall fulfills criterion for invasion
- Tumor extension into uterine body careful evaluation for metastic spread
- Ureteral encasement may result secondary to tumor extension into parametrium
  - Ureteral encasement is specific for parametrial invasion
  - Stage IIIB disease indicated by presence of hydronephrosis
  - Parametrial invasion may also result in perivascular invasion and uterosacral ligament thickening
- Muscular enlargement and enhancing soft tissue mass may be seen with frank invasion of piriformis and obturator internus
- Direct extension to pelvic bones results in bony destruction
- Tumor may encase and narrow iliac vessels
- Signs of bladder or rectal involvement
  - Intraluminal mass
  - Loss of perivesical or perirectal fat plane
  - Asymmetric nodular thickening of bladder or rectal wall
  - Fistula formation with intravesical air
- Cystic appearance of recurrent pelvic disease can be confused with post-surgical fluid collection
  - Recurrence has minimal soft tissue and generally occurs more than 6 months after surgery
- Distant metastases
  - 30% of patients have liver metastases
  - Appear as solid masses with variable enhancement
  - 15% of patients have adrenal metastases
  - 35-40% of patients with thoracic metastatic disease have this presentation
  - Multiple pulmonary nodules may represent thoracic metastasis
  - Minority of cases demonstrate cavitation
Lymph nodes
- Cutoff for suspicion of malignancy is size > 1 cm in short axis
  - 90% of metastatic retroperitoneal LNs are normalsized
  - Sensitivity for retroperitoneal metastases: 44%
  - Sensitivity for para-aortic metastases: 34%
- Enhancement pattern rarely helps differentiate benign from malignant disease
  - Central necrosis has ˜ 100% PPV
- Parametrial station is usually the first to be infiltrated by disease
- Tumor spreads through 3 lymphatic pathways most commonly
  - Laterally along external iliacs
  - Hypogastric route along internal iliacs
  - Presacrally along uterosacral ligament
  - Each pathway leads to common iliac lymph nodes, then leads to para-aortic nodes

Nuclear Medicine Findings

PET/CT performed with diagnostic CT
- Quality of the overall procedure is improved
- Much easier to identify focal abdominopelvic lesions from opacified bowel if oral contrast is used
Initial diagnosis
- Evaluation of primary cervical tumor
  - Generally not performed to look at primary tumor
  - However, most cervical SCCA is FDG-avid → high sensitivity for sizable lesions
  - PET/CT reliable in advanced disease
  - May help avoid unnecessary operations
  - May help with radiation therapy planning
  - Primary tumor SUV ≥ 10 associated with significantly lower 5 year disease-free survival than tumors with lower SUV (52% vs. 71%)
  - Overall survival comparable whether SUV < or > 10
Staging
- Evaluation of pelvic and para-aortic LN
  - LN detection on PET: Sensitivity 75-91%, specificity 93-100%
  - PET sensitivity for advanced disease 87%, specificity 100%
  - Low sensitivity in LN < 1 cm
  - Pelvic LN: Sensitivity 46%, specificity 91%
  - Para-aortic LN: Sensitivity 40%, specificity 99%
  - Presence or absence of para-aortic LN on PET correlates most significantly with disease-free survival
  - Knowledge of para-aortic lymph node status is crucial for treatment planning
  - Invasive surgery, with laparotomy or laparoscopy, has traditionally been used
- Evaluation of distant metastases
  - In one study, ˜ 8% of patients had distant supraclavicular lymphadenopathy detected only by PET
PET/CT
- Useful supplement to clinical staging procedures
  - Sensitivity of 75% and specificity of 87-96% for detection of nodal metastases in the pelvis
- High sensitivity/specificity for newly diagnosed cervical cancer with FIGO stage IB or higher
- Useful for planning treatment strategy
- Histologic confirmation of results should be obtained prior to change of treatment plan
- Can be used for biopsy guidance
PET/CT vs. conventional imaging for detecting metastatic lymph nodes
- Sensitivity 97% vs. 40%
- Specificity 94% vs. 65%
- PPV 97% vs. 70%
- NPV 94% vs. 34%
False positives
- Inflammatory/infectious lesions
  - Pulmonary tuberculosis
  - Acute cholangitis
- Physiologic uptake
  - Physiologic uptake in bowel, vessels, ureter
  - Ovarian uptake, depending on phase of cycle: Around ovulation and early luteal phase
  - Functional ovarian cysts, such as hemorrhagic corpus luteum cyst, may mimic lymph node metastases
- Other
  - Post-operative changes
  - Benign thyroid tumor
False negatives
- Low tumor volumes
Restaging
- Sensitivity and specificity for post-therapy of patients with cervical cancer: 90-93%, 91-100%

DIFFERENTIAL DIAGNOSIS

Other Female Reproductive Tract Malignancy

Endometrial cancer
Ovarian cancer

Leiomyoma

Variable FDG avidity, ranging from very minimal to intense
Often distinguishable from cervical mass on CT portion of PET/CT

Physiologic FDG Activity in Female Reproductive Organs

Menstruation: FDG activity in endometrial cavity, less frequently in vagina, associated with normal menstruation
- Clinical history of current menstruation important
- May need ultrasound, clinical correlation if patient not currently menstruating
Ovaries: Benign and malignant etiologies
- May need ultrasound to distinguish

Urine Contamination

May need ultrasound to distinguish
Incontinence can cause contamination of external genitalia

Endometrial Carcinoma

Usually spares cervix, though may spread to cervix if diagnosed late
Generally older patient population

PATHOLOGY

General Features

General path comments
- Glut-1: Overexpressed in cervical carcinoma, may be correlated with tumor grade
  - Absence of glut-1 correlated with improved metastasis-free survival
- In women with LN positive cervical carcinoma, 80% of involved LN are < 1.0 cm in greatest dimension
Etiology
- Likely multifactorial
- Associated with human papillomavirus (HPV) infection (strains 16, 18, 31, 33, 45)
- Other risk factors
  - Multiple sexual partners
  - Sex before age 18
  - Tobacco use
  - Diethylstilbestrol
Epidemiology
- In USA: ˜ 10,000 cases per year
  - ˜ 1/3 die of disease
- HPV vaccination programs widely instituted with goal of eradicating cervical cancer
- However, cervical cancer remains an important public health problem
- Worldwide:
  - > 300,000 cases diagnosed per year
  - 2nd most frequently diagnosed gynecologic malignancy in women
  - 50% mortality rate
- 5 year recurrence: 28%
- 5 year overall mortality: 27.8%

Staging, Grading, or Classification Criteria

In contrast to other gynecologic malignancies, cervical cancer is staged clinically
FIGO staging
- Allows only the following diagnostic tests to be used in determining the stage
  - Palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, and intravenous urography
  - X-ray examination of the lungs and skeleton, and cervical conization
- Most important limitation: Does not provide any information about retroperitoneal lymph node status
  - Especially para-aortic nodal metastases
- Discrepancies between FIGO staging and surgical/histopathologic findings
  - Occurs in about 30% of patients with locally advanced cervical cancer
Clinical staging accurate in ˜ 60% of patients
- Undiagnosed lymphadenopathy is a major problem
American Joint Committee on Cancer (AJCC) staging
- Stage 0
  - Carcinoma in situ
- Stage I
  - Confined to uterus
- Stage II
  - Beyond uterus, but not to pelvic side wall, lower third of vagina
- Stage IIIA
  - Extends to pelvic wall, lower third of vagina
  - Causes hydronephrosis/nonfunctioning kidney
  - Negative lymph nodes (LN)
- Stage IIIB
  - Extends to pelvic wall, lower third of vagina
  - Causes hydronephrosis/nonfunctioning kidney
  - Positive LN
- Stage IVA
  - Beyond true pelvis, bladder mucosa, rectal mucosa
  - Positive LN
- Stage IVB
  - Distant metastases
Pre-treatment surgical staging issues
- Risks of laparotomy for nodal staging include
  - Bowel obstruction
  - Infection
  - Vascular damage
  - Ureteral injury
  - Fistula formation
  - Lymphocyst/lymphedema
  - Thrombophlebitis
- Surgical staging results in treatment modification in 18-44% of patients
- Negative sentinal lymph node biopsy accurately predicts negative status of retroperitoneal lymph nodes in early cervical cancer
  - NPV: 92-97%
- Sentinal node biopsy has limited value in locally advanced disease due to high false negative rate
- Many centers defer surgical staging due to high morbidity

CLINICAL ISSUES

Presentation

Most common signs/symptoms
- Often asymptomatic
  - Abnormal cells typically found during a cervical screening test (Pap smear)
- Later symptoms
  - Abnormal vaginal bleeding/discharge
  - Discomfort during/after sexual intercourse
Other signs/symptoms: Smaller lesions often asymptomatic