Nuclear Medicine in Gynaecological Cancers

1. The clinical problem

Gynaecological cancers ask nuclear medicine four different questions. In cervical and vulvar squamous cell carcinoma, spread is lymphatic and orderly, so the job is to find nodes: their presence decides between surgery and chemoradiotherapy, and their level decides the radiotherapy field. In endometrial cancer, most women are cured by surgery, staging is surgical and molecular, and imaging matters mainly for high-risk disease and recurrence. In ovarian cancer, spread is peritoneal, the questions are resectability and the site of relapse, and CT carries most of the load.

ESGO (European Society of Gynaecological Oncology) guidelines, written with ESTRO (European Society for Radiotherapy and Oncology) and ESP (European Society of Pathology), grade each recommendation by level of evidence (I, randomised trials, to V, expert opinion) and strength (A, strongly recommended; B, generally recommended; C, optional; D, generally not recommended; E, never recommended). Those gradings are quoted in square brackets throughout.

2. Tracers and why they work

¹⁸F-fluorodeoxyglucose (FDG) enters cells through glucose transporters and is trapped after phosphorylation by hexokinase. Squamous cell carcinomas of the cervix and vulva are usually intensely avid, as are high-grade endometrial carcinomas and high-grade serous ovarian carcinoma. Low-grade and mucinous tumours are less predictable, so a faint primary tumour is not reassuring and a negative scan in these subtypes means less.

FDG positron emission tomography (PET) fails for two physical reasons. The first is size: in uterine cancers, node-based sensitivity was 100% for metastatic nodes of 10 mm or more, 67% for nodes of 5 to 9 mm and 13% for nodes of 4 mm or less. Micrometastases (up to 2 mm) and isolated tumour cells are beyond any PET scanner, which is why early cervical, endometrial and vulvar cancer are staged surgically with the sentinel node. The second is geometry: thin, flat peritoneal implants next to physiological bowel activity are easily missed, and in a meta-analysis of ovarian cancer FDG detected peritoneal metastases with a pooled sensitivity of only 70%.

⁹⁹ᵐTc-nanocolloid is injected into tissue, taken up by lymphatic capillaries and retained by macrophages in the first draining node or nodes. It gives a preoperative map (planar images and single photon emission computed tomography with CT, SPECT/CT) and lets the surgeon find the node with a gamma probe. Indocyanine green (ICG) is a fluorescent dye seen with a near-infrared camera during surgery; it is not a radiotracer and gives no preoperative map. A hybrid ICG-⁹⁹ᵐTc-nanocolloid tracer combines both signals.

3. Indications by clinical scenario

3.1 Cervical cancer

Pelvic magnetic resonance imaging (MRI) is mandatory for local extent [II, A]; FDG PET/CT answers the nodal and distant question. In early disease managed by surgery, surgical and pathological staging of the pelvic nodes is the standard [III, A] and PET adds little, because the nodes that matter are microscopic. In locally advanced cervical cancer (LACC: T1b3 and higher, except T2a1) the risk of disease outside the pelvic radiotherapy field is real, and PET/CT is recommended.

How good is PET for the para-aortic nodes? A meta-analysis of 14 studies found a pooled sensitivity of 71% and specificity of 97%. Specificity is the dependable number: an avid para-aortic node on PET is usually real. Sensitivity is the weak point. In a French prospective series of 237 women with LACC and a negative para-aortic PET/CT, laparoscopic para-aortic lymphadenectomy found nodal metastases in 29 (12%). Three-year event-free survival was 74% with no para-aortic disease, 69% when the metastasis measured 5 mm or less (treated with extended fields), and 17% when it was larger than 5 mm.

Surgical staging versus imaging. The randomised Uterus-11 trial (255 women, FIGO 2009 stage IIB to IVA) compared laparoscopic staging with clinical and CT or MRI staging before chemoradiotherapy. Surgery upstaged 33% but did not improve disease-free survival overall (p=0.084); it did so in stage IIB (hazard ratio 0.51) and improved cancer-specific survival in a post-hoc analysis (hazard ratio 0.61). PET/CT was not mandated in either arm. This is why ESGO states only that para-aortic dissection 'may be considered' [IV, C]: the extra 12% found by the surgeon after a negative PET must be weighed against a surgical procedure that has not been shown to improve survival overall.

Sentinel nodes in early disease. In SENTICOL (139 women, stage IA1 with lymphovascular invasion to IB1), combined radiocolloid and blue dye found at least one SLN in 97.8%, with sensitivity 92.0% and negative predictive value 98.2%; there were no false negatives when SLNs were found on both sides. SENTIX then tested SLN biopsy without pelvic lymphadenectomy (FIGO 2018 IA1 with lymphovascular invasion to IB2): of 594 women in the intention-to-treat cohort, 82 (12%) had SLN metastases, 43.9% of them found only by ultrastaging, and the 2-year recurrence rate was 6.1%, non-inferior to the 7% reference.

3.2 Endometrial cancer

The 2025 ESGO/ESTRO/ESP update puts the sentinel node at the centre of staging and molecular classification (POLE-mutated, mismatch-repair deficient, no specific molecular profile or p53-abnormal) at the centre of risk assignment; molecular classification should be done for all endometrial carcinomas [IV, A]. Its printed recommendations contain no PET statement for primary staging. In practice FDG PET/CT is used selectively: high-grade or serous histology, carcinosarcoma, clinically advanced disease, and suspected recurrence.

The evidence for SLN mapping came from two prospective studies. In SENTI-ENDO (125 eligible women, FIGO I to II) cervical injection of ⁹⁹ᵐTc and patent blue detected an SLN in 111; per hemipelvis the negative predictive value was 100%, but per patient sensitivity was 84% and all three false negatives were in type 2 (high-grade) cancers. Ultrastaging found 9 of the 19 node-positive women (47%). FIRES (385 women, cervical ICG, robotic surgery) mapped at least one SLN in 86%, with sensitivity 97.2% and negative predictive value 99.6%. SPECT/CT earns its place because uterine drainage is deep: it localises nodes near the injection site and in the para-aortic region that planar imaging misses.

3.3 Ovarian cancer

Ovarian cancer is staged at surgery. The ESGO-ESMO-ESP (European Society for Medical Oncology) consensus lists contrast-enhanced CT, MRI and PET/CT, with a structured report, as options for the initial evaluation of advanced disease [III, A]; in practice contrast CT is the workhorse and PET/CT is a problem-solving test, for example for suspected disease above the diaphragm. FDG's weakness is the peritoneum: small, flat implants on bowel serosa and mesentery sit next to physiological bowel uptake, and surgical exploration remains the reference standard for peritoneal spread.

The clearest indication is the rising CA-125 with negative or equivocal CT. In a meta-analysis of 34 studies of recurrent ovarian cancer, PET/CT had the highest pooled sensitivity (91%) and CA-125 the highest specificity (93%); the authors singled out women with a rising CA-125 and negative CT or MRI as those most likely to benefit. Before secondary cytoreduction, PET/CT can help to exclude disease beyond the abdomen.

3.4 Vulvar cancer

GROINSS-V I (403 women, 623 groins) established safety: among 259 women with a unifocal tumour and a negative SLN, the groin recurrence rate was 2.3% and 3-year survival 97%, with far less morbidity than lymphadenectomy. GROINSS-V II then treated a positive SLN with inguinofemoral radiotherapy instead of lymphadenectomy. For micrometastases (2 mm or less) the 2-year isolated groin recurrence rate was 1.6%; for macrometastases it was 22% after radiotherapy against 6.9% after lymphadenectomy. The nuclear medicine report therefore feeds a pathology report whose metastasis size decides the next operation.

4. Evidence at a glance

PFS, progression-free survival; EFS, event-free survival; DFS, disease-free survival; HR, hazard ratio; NPV, negative predictive value.

5. Patient preparation and acquisition

Standard FDG preparation applies. What differs in gynaecological practice is the menstrual cycle, the bladder, radiotherapy positioning and the sentinel node protocols.

• Record the menstrual history. Note the first day of the last period, cycle regularity, contraception and hormone therapy on the request. When the timing is elective, a healthy-volunteer study suggested scanning within a week before or a few days after menstrual flow to avoid physiological endometrial and ovarian uptake.
• Exclude pregnancy. ESGO advises that PET/CT be avoided in pregnancy [IV, B]; whole-body diffusion-weighted MRI can stage without ionising radiation.
• Manage urine. Ask the patient to void immediately before the pelvic bed positions. Urine in the bladder, a ureter or a vaginal fornix can mimic or hide disease; late pelvic images after further voiding help when a focus is equivocal.
• Radiotherapy planning scans. Acquire in the treatment position (flat couch, immobilisation) so the images can be registered for contouring, as ESGO recommends for 3D planning.

Sentinel node lymphoscintigraphy

In a meta-analysis of eight studies in cervical cancer, SPECT/CT detected SLNs in 98.6% against 85.3% with planar imaging. Mark the skin over each node, report each node's basin (external iliac, obturator, common iliac, para-aortic, inguinal) and number, and state plainly when a side has not mapped: in endometrial cancer that side then needs lymphadenectomy if the risk is high-intermediate or high, and in a midline vulvar cancer the unmapped groin needs lymphadenectomy.

6. Interpretation

What to read and how to report it

• Primary tumour. Size, extension to the uterine body, vagina, parametria, bladder or rectum is MRI's job; note it on PET only when it is obvious, and record the maximum standardised uptake value (SUVmax) as a baseline.
• Nodes, by station. Report each avid node by station (external iliac, internal iliac, obturator, common iliac, para-aortic below or above the inferior mesenteric artery and the renal vein, inguinal, supraclavicular), with short-axis size. A node counts when its uptake is clearly above background and it corresponds to a node on CT; there is no validated SUV threshold, and a normal-sized avid node is still abnormal.
• Assign the stage. State the FIGO 2018 stage that the scan supports (for example IIIC2r), give the TNM categories alongside it as ESGO asks, and say which findings, if confirmed, would change the stage.
• Distant disease. Look at supraclavicular nodes, lung, liver, bone and peritoneum. Solitary unexpected findings that would change intent need a biopsy.

Post-treatment categories

The response studies in cervical cancer used simple visual categories rather than numeric thresholds: complete metabolic response (no abnormal FDG uptake), partial metabolic response (persistent abnormal uptake at treated sites, reduced from baseline) and progressive disease (new sites of abnormal uptake). Grigsby separated persistent uptake inside the irradiated region from new uptake outside it, and the distinction mattered: no woman with new sites was alive at 5 years.

Normal variants, pitfalls and mimics

7. Response assessment and follow-up

• Cervix after chemoradiotherapy. Use the same imaging method as at baseline [V, B], no earlier than 3 months after treatment [IV, B]. If complete remission is uncertain at 3 months, repeat after a further 2 to 3 months, with biopsy if indicated [IV, B]. Women with persistent tumour 3 to 6 months after treatment and no regional or distant disease should be referred to a specialist centre to consider salvage surgery [IV, B].
• Why 3 months. Earlier scans are confounded by radiation inflammation. In the prospective JAMA study, PET at 2 to 4 months (mean 3) showed complete response in 70%, partial response in 16% and progression in 13%; partial response carried a hazard ratio for recurrence of 6.3 and progression 32.6.
• Cervix, routine follow-up. Imaging and blood tests are driven by risk of recurrence, symptoms or findings [V, A]; routine surveillance PET is not recommended.
• Vulva after chemoradiotherapy. Assess response at 12 weeks, clinically, with imaging and with biopsy if residual tumour is suspected [III, B].
• Endometrium. No routine surveillance imaging; PET/CT when recurrence is suspected, particularly to decide between local treatment of oligometastatic disease and systemic therapy.
• Ovary. Surveillance is clinical, with CA-125 and CT; PET/CT is for the rising marker with unhelpful conventional imaging and for planning secondary surgery.

8. Theranostics and emerging tracers

No radioligand therapy is approved for a gynaecological cancer. The emerging agents below are diagnostic, and their evidence is early.

9. Structured report example

10. Take-home points

1. In cervical cancer, FDG PET/CT is recommended for locally advanced disease, suspicious nodes and before curative chemoradiotherapy; it is not needed for surgically staged early disease.
2. FIGO 2018 lets imaging assign nodal stage: pelvic nodes IIIC1r, para-aortic nodes IIIC2r. Report nodes by station, because the level sets the radiotherapy field.
3. An avid para-aortic node is usually real (specificity 97%); a negative para-aortic PET still misses about one woman in eight.
4. Scan the response no earlier than 3 months after chemoradiotherapy; new sites of uptake carry the worst prognosis.
5. Sentinel node mapping stages early cervical, endometrial and vulvar cancer. Radiocolloid is mandatory in vulvar cancer, and SPECT/CT maps deep pelvic and para-aortic drainage.
6. Time elective scans in premenopausal women away from menstruation and ovulation; after the menopause, focal ovarian or endometrial uptake is abnormal.
7. In ovarian cancer, PET/CT is the test for a rising CA-125 with negative CT; small peritoneal implants remain its blind spot. FAPI and FES are research tools for now.

Test yourself

5 quick questions. Pick an answer to see the explanation.

References

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