Efficacy of 18F-FDG-PETCT Scanning in Accurately Detecting Metastases in Patients with Undetected Primary Cancer

To assess the feasibility of 18F-FDG-PET/CT in patients with metastases from an unknown primary carcinoma (UPC) and to evaluate its efficacy in identifying a primary tumor focus in UPC patients with a histologically confirmed diagnosis. A retrospective analysis comprised 187 individuals with UPC metastases diagnosed between September 2018 and December 2022: 64 females (34.2%) and 123 men (65.8%). Patients were 61.9±7.5 years old. All patients underwent a needle biopsy of at least one metastatic lesion, histological confirmation of neoplastic malignancy, and other routine procedures to define the kind of underlying lesion before PET/CT imaging.87 metastatic lymph nodes had squamous cell carcinoma (46.5%), 15 had melanoma (8%), 45 had undifferentiated carcinoma (24.1%), 23 had adenocarcinoma (12.3%), and 17 had undifferentiated malignancy (9.1%). 18F-FDG-PET/CT detected primary tumors with 82.4% sensitivity, 86.5% specificity, and 84% accuracy.18F-FDG-PET/CT accurately stages the neoplastic development in many UPC patients. This method typically locates the main tumor, affecting therapy and prognosis. 18F-FDG-PET/CT is indicated for UPC patient assessment.


INTRODUCTION
Cancer of unknown primary carcinoma (UPC) is connected with a vast diverse collection of tumor forms.The phrase "unknown primary Carcinoma" refers to a primary malignant tumor focus that could not be identified despite intensive diagnostic testing and histologically proven metastatic manifestation [1], [2].Every year, between 5.3 and 19 instances of UPC are reported per 100,000 people.As a consequence, UPC is the seventh to eighth most common kind of cancer, and the fourth leading cause of cancer mortality [3], [4].It also has a poor average survival rate (between 6 and 12 months) [5].
It is critical to identify the main tumor in order to accomplish the optimum treatment strategy, which may improve overall survival time.Positron Emission Tomography/ Computed Tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) has been proven to aid in the identification of the main tumor, with a detection rate of 37% and sensitivity and specificity of 84% [6].
Tomography has become widely used in scientific medical research and industry.This includes a variety of applications in seismic data, digital rock physics, radar imaging, medical modalities such as computed tomography, magnetic resonance, and others, for example, [7][8][9][10][11].Imaging techniques can only detect the main location of the tumor in 10 to 35 percent of cases [12].The tiny size of the lesion, especially if it is smaller than the spatial and contrast resolution of the used diagnostic modalities, might explain the low incidence of identified primary tumors [13].Consistent use of many imaging modalities may be costly and prolong the time it takes to obtain the correct diagnosis and begin the appropriate course of therapy.Some persons are already in an advanced stage of the illness when they are diagnosed [14].
18F-FDG-PET/CT is useful for determining the stage of the tumor process as well as finding the main tumor.The prognosis is dependent to the prevalence of the condition.Conventional staging approaches, such as the Tumor, Lymph node, Metastasis system (TNM) devised by the American Joint Committee on Cancer (AJCC) [15], do not include UPC.Through examination using 18F-FDG-PET/CT, the stage of the illness, and hence treatment methods and the overall prognosis, may be adjusted for these patients.The primary goal of this research was to investigate the predictive usefulness of 18F-FDG-PET/CT in UPC patients.

MATERIALS AND METHODS
The retrospective study comprised 187 patients between September 2018 and December 2022, with 64 female (34.2%) and 123 male (65.8%) having metastases from UPC.The patients' average age was 61.9 7.5 years.Patients were diagnosed with UPC using the European Society of Medical Oncology (ESMO) diagnostic technique for determining the main location of the tumor [16].
Prior to PET/CT imaging, all patients had at least one metastatic lesion biopsied, and the tumors' aggressiveness was established histologically.To determine the type of primary tumor lesion, 175 patients underwent magnetic resonance imaging (MRI), 21 patients underwent computed tomography (CT) of the abdominal cavity and chest, 10 patients underwent chest radiography, and three patients underwent mammography.This research excluded participants having a history of cancer during the preceding 5 years, claustrophobia, significant obesity, diabetes mellitus.
PET/CT was performed on all patients (using the Philips Gemini 64 PET CT equipment).The CT study results were obtained using the following parameters: tube voltage 120 KeV, tube current 120 mAs, detector collimation 10 mm, pitch 0.83, and gantry rotation time 0.8 s.The slice thickness of the reconstructed axial images is 1.25 mm, and the discriminator is 0.938 mm.The PET data collection field of view and spatial step were 40 mm and 5 mm, respectively.The PET findings were edited using iterative techniques.PET was done 45-60 minutes after administering 5 MBq/kg of 18F-FDG.Before the assessment, all patients fasted for six hours.Before the examination, the patient's blood sugar level was measured to check that it was within the normal range (200mg/dL).
A nuclear medicine specialist with over 10 years of experience in cancer diagnoses did the image analysis.The primary tumor, metastases, and lymph nodes were all examined using the standard uptake value (SUVmax).SUVmax has normally calculated as the body weight-normalized ratio of the total amount of radiopharmaceutical administered to the patient to the amount accumulated in the target area.An elliptical area of interest (ROI) was used to assess lymph nodes, metastases, and source tumors.SUVmax was calculated by mapping the ROI with 1mm2 and determining the 18F-FDG of malignant lesions.The lesion with the greatest SUVmax was used for predictive analysis since it was thought to be the most aggressive.Using the Petra et al. method, lymph nodes with SUVmax values more than 2.5 were categorized as malignant [17].
Standard statistical formulas were used to calculate sensitivity, specificity, and accuracy of PET/CT image: Sensitivity= TPR / (TPR + FNR) Specificity= TNR / (TNR + FPR) Accuracy= (TPR + TNR)/ (TPR + FPR + TNR + FNR) Where: TPR is true positive ratio when patient detected a lesion in PET/CT image and confirmed by histopathology; TNR is true negative ratio when patient has a lesion but the image doesn't detect it; FPR is false positive proportion for patients who don't have any lesion in their body but PET/CT shows a lesion in their study; and FNR is false negative ratio when patients don't have any primary cancer and PET/CT scan showed no other abnormalities.

RESULT AND DISCUSSION
During the duration of the study, 187 patients who had UPC were separated into four groups: those who had UPC as a TPR consisted of 93 patients (49.7%), those who did not have UPC as a TNR consisted of 64 patients (34.2%), those who had FPR consisted of 10 patients (5.3%), and those who did not have FPR consisted of 20 patients (10.6%) (Figure 1).It was shown that the 18F-FDG-PET/CT had a sensitivity of 82.4%, a specificity of 86.5%, and an accuracy rate of 84% when it came to identifying primary tumors.According to the outcomes of calculating the t-test independent samples, there was no significant difference between the groups in terms of the age distribution of the patients (p = 0.278), which was the case even while assuming that the Levine variances were equivalent (p = 0.641).As revealed by Pearson's 2 test (p = 0.065), there was no significant difference in the gender distribution of the patients across the groups.
The main locations of the tumors in the individuals who had primary tumor foci are outlined in Table 1.For UPC, the oropharynx had the largest value, representing 52.6%, followed by the lungs, which represented 9.67%, followed by the mammary glands, which represented 6.45%, and the large intestine, which represented 5.37%.Malignancies of the stomach, skin, esophagus, and kidneys all have a ratio of 3.2%, whereas malignancies of the other organs all have a ratio of less than 2%.
Figure 2 depicts a patient who has an example of a situation in which they have an enlarged right cervical lymph node, and the picture displays an axillary lymph node metastasis, but the initial cancer that was discovered via the biopsy was squamous cell carcinoma.
The histological variants of the tumor were divided among the 187 participants in the research based on biopsy of metastatic lesions as follows: Squamous cell carcinoma was discovered in 87 (46.5%) of the patients, melanoma in 15 (8%), undifferentiated carcinoma in 45 (24.1%), adenocarcinoma in 23 (12.3%), and undifferentiated malignant neoplasm in 17 (9.1%).Table 2 displays all of these outcomes.
In 89 individuals, or 47.5% of the overall sample, PET/CT was employed to detect new metastatic lesions.According to Pearson's chi-square test, the likelihood of detecting a new lesion in patients who had previously identified and unexplained UPC is not statistically significant different, with a p-value of 0.273.The  Mann-Whitney test found no statistically significant difference in the frequency of new lesions between patients with identified and undiagnosed UPC (p = 0.827).There were no variations in the total number of lesions between these patient groups, according to the Mann-Whitney test (p = 0.8).
It should be emphasized that a change in tumor stage occurred following PET/CT in 131 patients (70.1%), and this shift was connected to both the detection of the main tumor and the identification of additional metastatic foci.Patients with discovered UPC were significantly more likely than patients without discovered UPC to have a change in stage (100% vs. 40.4%,p-value 0.001).
Tawfeek et al colleagues investigated the efficacy of 18F-FDG-PET/CT in detecting a primary tumor in patients with cancer metastases from UPC [18].The outcomes of the research demonstrated that whole-body PET/CT was superior to traditional imaging approaches in determining the site of the tumor.To avoid unnecessary diagnostic procedures, 18F-FDG-PET/CT should be done in patients with UPC before any further tests.In this study, 18F-FDG-PET/CT may become the recommended approach for patients with cancer metastases from an unknown source tumor.
One of the finest advantages of UPC is the ability of PET/CT to identify a wide range of oncological disorders in patients [19].Another benefit is the ability to do a non-invasive examination of the complete body, which saves the patient from unneeded diagnostic procedures and cuts down on waiting time.
Among the 187 patients diagnosed with UPC based on earlier diagnostic techniques, our findings demonstrated that 18F-FDG-PET/CT had a high sensitivity: the main tumor location was detected in 93 instances (49.7%).These findings matched those of a meta-analysis research done by Woo et al [20].The approach exhibited great effectiveness when employed on patients with head and neck metastases using 18F-FDG-PET/CT.Thus, the nasopharynx was the primary focus in 49 instances, correlating with previous study [13], [21].Using 18F-FDG-PET/CT, Servikal et al [1] demonstrated a sensitivity of 87% and a specificity of 83% for the identification of UPC in patients with cervical lymph node metastases.In a cohort of 187 UPC instances, the present research discovered a detection rate of 82.4% and 86.5%, respectively.
Another study, which agreed with our study, found that 18F-FDG-PET/CT had a sensitivity of 82% and a specificity of 44% in detecting primary tumors in patients with an unknown primary cancer.The diagnostic accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) were 73%, 93%, and 28%, respectively.The specificity rate of 18F-FDG-PET/CT was lower than the literature, indicating a higher rate of false positive results, which may be explained by the higher prevalence of granulomatous pathology [22].
A careful history review and patient clinical examination are extremely important to increase 18F-FDG-PET/CT specificity, according to a study [15], because inflammatory lesions are among the most common non-oncological causes of FDG uptake, with 37% of benign lesions being inflammatory in nature.Furthermore, the high rate of false positive results in inflammatory lesions can be attributed to FDG uptake caused by increased cellular metabolism.Unfortunately, FDG is not a cancer-specific tracer, and it has been observed in a wide range of inflammatory lesions such as tuberculosis, sarcoidosis, fungal infections, and cerebral abscesses [12].However, false negatives can be explained by the fact that tumor cells in metastatic lesions may differ biologically from those in the primary tumor, metastases may uptake higher FDG levels than the primary, and FDG uptake in low grade epithelial tumors can be small or absent [12].Furthermore, the primary tumor size may be smaller than the resolution power of 18F-FDG-PET/CT, particularly in anatomically complicated areas such as the abdomen and pelvis, as well as in breast cancer with low 18F-FDG uptake [23].
A change in the degree of disease in UPC cancer patients who have metastases leads to a change in treatment strategies and, as a result, a better prognosis.This is coherent with Rahmim et al. [24] discovered that 18F-FDG-PET/CT has an impact on the therapeutic treatment of patients with metastases in the lymph nodes of the neck.Furthermore, regardless of the type of primary tumor in all UPC patients, 18F-FDG-PET/CT can be used to provide information on treatment efficacy and assess potential relapses of the underlying disease.

CONCLUSION
In a sizeable portion of UPC patients, the 18F-FDG-PET/CT scan enables a more precise diagnosis of the stage of the oncological process.The process, in many instances, makes it possible to identify the main tumor, which in turn affects the treatment methods and prognosis for these individuals.When assessing individuals who have UPC, 18F-FDG-PET/CT testing should be necessary in all diagnostic strategies.

Figure 1 :
Figure 1: Distribution of patients with undetected and detected UPC patients through 18F-FDG-PET/CT scan.

Figure 2 :
Figure 2: A 23-year-old man presented with enlarged right cervical lymph nodes, epithelial tumor metastasis on biopsy, 18F-FDG PET/CT showed increased uptake in the right axillary lymph node (SUVmax 5.5), and squamous cell carcinoma as the final diagnosis.

Table 1 :
The UPC locations' distribution.

Table 2 :
Quantitative distribution of the histological types of tumors in patients with UPC.