Globally, cervical cancer is the second most serious gynecological malignancy in terms of mortality in patients under 35 years of age ^[1][2]. As a result, numerous ones have been conducted in order to characterize its epidemiology and possible etiology ^[3][4][5]. A main consideration in the management of cervical cancer is the appropriate staging of access to effective treatment methods and patients’ prognosis ^[2]. One such consideration is that the detection resolution of tomography/computer tomography (PET/CT) for staging of primary tumors of cervical cancers is limited ^[2]. Consequently, the use of MRI for imaging tumor volume, size, and the extent of parametrial invasion may be superior, acting as a gold standard for evaluating the locoregional extension of cervical cancer ^[2][6]. Nevertheless, [¹⁸F]FDG PET, provides metabolic information by depicting glycolytic tumor activity, and it can also obtain additional information in the staging of primary cervical cancers ^[6]. Pawar et al. assessed the success rate of PET/CT in a retrospective one of 56 patients with gynecological malignancy including cervix carcinomas (23 patients). It was shown that PET/CT offers a high diagnostic accuracy, both in the evaluation of suspected tumor recurrence and in persistent disease ^[7]. It was concluded that PET/CT has particular value in primary cervical cancer, which is related to the diagnosis of extra-pelvic abnormalities, the detection of recurrence, and the monitoring of patients after treatment ^[7]. In another retrospective analysis of the accuracy of [¹⁸F]FDG PET/CT, the rate of success in the initial stages of cervical tumors was estimated to be 100% ^[8]. Further and clinical observations have demonstrated that the combined PET/CT has greater accuracy compared to PET imaging alone ^[9][10]. Generally, it has been concluded that [¹⁸F]FDG PET/CT is a choice modality for investigations of pretreatment staging and post-treatment surveillance of cervical cancer ^[11]. One of the most considerable and adverse criteria of cervical cancer is tumor hypoxia ^[12][13]. Hypoxia is defined as oxygen insufficiency in cells, and it can be used as a prognostic indicator. Hypoxia has shown particular utility in therapeutic cancer management, including responses to chemotherapy or radiation therapy ^{[14][15][16][17]}. Another noteworthy aspect of hypoxia is the prediction of metastases in tumor cells which are related to hypoxia’s role in deoxyribonucleic acid (DNA) mutations and malignant, atypical cells ^[18]. Given these observations, the evaluation of hypoxia in treatment management is essential, particularly for locally advanced stages and local recurrences, which occur more than expected in cervical cancer ^[19].

In recent years, ovarian cancer has become the fifth most common cause of death among women worldwide ^[20]. Early detection of ovarian cancer (stage I) leads to successful treatment in more than 90% of cases. However, this percentage dramatically decreases to 20–25% in later stages (III, IV) ^[21]. Various diagnostic modalities provide diverse clinical information for the diagnosis of the disease ^[20]. Molecular imaging modalities including SPECT/CT and PET/CT possess functional information about the biochemistry of tissues ^[20]. Molecular PET imaging agents reflect general information about energy consumption through glucose metabolism ([¹⁸F]FDG) or the proliferation of DNA synthesis ([¹⁸F]F-fluorodeoxythymidine ([¹⁸F]FLT)) ^[22]. For more specific targeting of the cell surface, components like hormone receptors, receptor tyrosine kinases, angiogenesis components, and immunotherapy components would be invaluable ^[22]. Many have been conducted to optimize the effective diagnosis and treatment of ovarian cancer. A comparison of 51 patients with peritoneal lesions arising from ovarian cancer demonstrated that obtained visual results of [¹⁸F]FDG PET/CT in association with other semi-quantitative parameters were effective in the detection of ovarian cancer ^[23]. This result was based on the observed differentiation potency of [¹⁸F]FDG PET/CT in malignant and benign lesions ^[23]. In another, results showed that carcinoma antigen 125 (CA125) acted as a sensitive tumor marker of recurrent ovarian cancer in 175 patients with recurrent refractory ovarian cancer and increased CA125. Specifically, it was demonstrated that the detection rate of [¹⁸F]FDG PET/CT scan is 90% for elevated CA125 and 53% for a low (<30) but measurable amount of CA125 ^[24]. These findings show that [¹⁸F]FDG PET/CT can detect active lesions despite a low level of CA125, and this can be useful for the early detection and treatment of recurrent cases ^[24]. Undoubtedly, with increased CA125 (≥35) the diagnostic value of [¹⁸F]FDG PET/CT has been well established in numerous on ovarian cancer ^[25][26]. Generally, it can be argued that [¹⁸F]FDG PET/CT is a valuable detection method in suspected recurrent situations, and it acts as a viable prediction tool for the progression of advanced ovarian cancer ^{[27][28][29][30][31]}. Despite these beneficial aspects of [¹⁸F]FDG PET/CT, however, this procedure doesn’t show reliable diagnostic value in the primary stages of ovarian cancer ^[22].

The radiopharmaceutical, [¹⁸F]c, is a tracer for proliferation activity. After internalization, [¹⁸F]FLT undergoes phosphorylation by thymidine kinase 1, resulting in sequestrated intracellular radioactivity ^[32]. Thymidine kinase participates in DNA synthesis and therefore reflects the proliferation rate in tissues. Evidence from both preclinical and clinical ones shows a decrease in [¹⁸F]FLT uptake after ovarian cancer treatment ^[33][34][35]. Moreover, a pilot one demonstrated that prior to the debulking surgery of ovarian cancer in six patients, [¹⁸F]FLT showed a higher uptake in tumors compared to normal tissues ^[35]. Additionally, clinical ones have reported that, due to a high background in liver and bone marrow, administration of [¹⁸F]FLT for pretreatment assessments would not be recommended given that it may cover the metastases located adjacent to the mentioned organs with a high background ^[36].

Previously it has been shown that in estrogen receptor (ER) positive early breast cancer patients, endocrine therapeutic procedures reduce recurrences and the mortality rate, regardless of whether chemotherapy is also applied ^[37]. Previous clinical trials have also demonstrated that endocrine therapy for ovarian cancer can improve the response to treatment and prolong survival in platinum-resistant ovarian cancer patients ^{[38][39][40][41]}. Based on these findings, ER receptors could be a valuable predictor for patients who may benefit from endocrine hormonal therapy ^[42].

The 16a-[¹⁸F]-fluoro-17b-estradiol ([¹⁸F]FES) PET/CT has been successfully applied in breast and ovarian cancer; and [¹⁸F]FES uptake has shown a high correlation with estrogen receptor (ER) expressions in previous ones ^[43][44]. In a clinical one on estrogen-receptor-positive primary breast cancer patients, hormonal therapy failure in [¹⁸F]FES negative cases was investigated ^[44]: [¹⁸F]FES sensitivity and specificity for detection of ER positive lesions was estimated at 84% to 94% for breast cancer and 79% to 100% for ovarian cancer, respectively ^[20]. Additionally, [¹⁸F]FES has been demonstrated in leiomyoma as well as epithelial ovarian cancer ^[44][45]. In 15 patients with suspected ovarian cancer, 88% exhibited lesions measurable with CT and that could be diagnosed with [¹⁸F]FES PET/CT. The remainder were non-quantifiable due to a high radioactivity uptake of adjacent tissues ^[45]. These findings support the beneficial role of [¹⁸F]FES in hormonal therapy.

Endometrial cancer is the most common cancer of the genital tract and the fourth most common malignancy among women in developed countries ^[46]. Endometrial cancer exhibits a more positive prognosis in that it can often be diagnosed earlier and, for localized occurrences, a five-year survival rate is usually expected (96% of cases) ^[47]. Nevertheless, overall survival declines to 57% in patients with regional metastasis in pelvic lymph nodes (PLN), and 49.4% in those with metastasis to para-aortic lymph nodes (PALN), with or without positive PLN ^[48]. Numerous ones have emphasized the unique role of [¹⁸F]FDG PET/CT in the assessments of staging, restaging, monitoring, and planning of therapeutic procedures in uterine cancers ^{[49][50][51][52]}. The reliability of [¹⁸F]FDG PET/CT in the detection of pelvic and/or para aortic lymph nodes metastasis in patients with untreated endometrial cancer was evaluated in several clinical ^{[53][54][55][56]}, generally showing high efficacy. Furthermore, a meta-analysis ^[54] also highlighted the utility of [¹⁸F]FDG PET/CT in the diagnosis of lymph node metastasis (LNM) in pre-operational investigations and post-operative recurrences of endometrial cancers. In order to verify the post-operational effect of [¹⁸F]FDG, 90 patients with endometrial cancer history were involved in a clinical one designed to investigate residual tumors after curettage ^[57]. The results support that [¹⁸F]FDG PET/CT can be used for exact determination of residual tumors in endometrial cancers ^[57]. Furthermore, it was concluded that in patients with low grade carcinomas and lesion sizes <1.35 cm, [¹⁸F]FDG uptake would be low, possibly leading to false negative results ^[57]. In a notable one with coupled [¹⁸F]FES and [¹⁸F]FDG PET, it was shown that both approaches are advantageous for the differentiation of malignant and benign uterine tumors ^[58][59]. It was further demonstrated that the estrogen dependency and the glucose tendency of tumor cells decrease and increase respectively, each correlating with tumor aggression in endometrial carcinomas ^[59]. Moreover, this observation also highlighted the differences in the [¹⁸F]FES and the [¹⁸F]FDG accumulation rates, as related to estrogen expression and glucose consumption ^[59]. Considering these differences, the [¹⁸F]FDG–to–[18F]FES ratio may be the most informative index reflecting tumor aggressiveness ^[59]. Taken together, these findings may assist in developing non-invasive methods for guiding decisions regarding the early detection of and the optimal therapeutic processes for gynecological cancers.

Vulvar cancer is a comparatively rare type of neoplasm accounting for 1–5% of the total cancer types in women, and it is more frequent in older women ^[60]. Distant metastases are very rare in vulvar cancer while lymph node dissemination is observed in 30% of patients ^[61]. Sentinel node biopsy (SNB) is a gold standard method for staging vulvar cancer without lymphatic spread, and it is useful in preventing post-surgical morbidity ^[62]. One pervasive issue, however, is the imaging of metastatic LNs. In a clinical trial carried out by Crivellaro et al., 29 patients (mean age 69 years, range 51–88) with vulvar cancer (clinical apparent stage I-II) underwent a pre-operative [¹⁸F]FDG PET/CT scan ^[63]. The results showed that [¹⁸F]FDG PET/CT had low sensitivity and moderate specificity in nodal staging; and, thus, it was not an optimal tool for nodal status assessment. Furthermore, PET/CT may not be cost-effective in detecting the rare event of distant metastases in early stages. Nevertheless, further on larger samples are essential to clarify the exact role of [¹⁸F]FDG PET/CT scans for this purpose.

Finally, ^99mTc-labeled colloids have been considered for detection of sentinel node (SLN) using planar scintigraphy and, more recently, SPECT or SPECT/CT ^{[64][65][66][67]}. There is evidence in vulvar cancer patients that indocyanine green (ICG)-[^99mTc]Tc-nanocolloid SPECT/CT can be used for personalized lymphatic mapping, possibly providing detailed information about the number and the anatomical location of SNs for adequate surgical guidance ^[64][68][69].

Vaginal cancer accounts for approximately 1–2% of gynecological malignancies, among which squamous cell carcinomas and melanoma (less than 4% of vaginal tumors) are the most common ^[70]. The use of SLN mapping with radiocolloids is beneficial for both diagnosis as well as therapy ^[71][72]. The most common procedure for detection of LNs is preoperative lymphoscintigraphy using [^99mTc]Tc-colloids, following a simultaneous intraoperative blue dye procedure and gamma probe ^[73]. Clinical trials have shown that, in patients undergoing joint lymphoscintigraphy and blue dye procedures, there was a detection rate of 82% SLN, while just 9% of LNs were detected when using each method separately ^[74]. In 14 patients with vaginal cancers (including 7 squamous cell carcinomas, 5 vaginal melanomas, 1 adenocarcinoma, and 1 undifferentiated carcinoma), at least one lesion was detectable in 79% of all patients and in each case ^[74]. Many case reports have also demonstrated that SPECT/CT lymphoscintigraphy is a feasible and an ideal method for pre-operative mapping in vaginal cancer ^{[75][76][77][78][79][80][81][82]}. However, false negative cases have also been reported ^[83][84][85].