Clinical characteristics and predictive factors of delayed diagnosis in patients with sellar germ cell tumors

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Methods A total of 345 patients with sellar GCTs were retrospectively collected. Patients were classified into a delayed diagnosis group (>6 months from onset to diagnosis) and a non-delayed diagnosis group (≤6 months). We compared general characteristics, clinical symptoms, diagnostic methods, treatment strategies, tumor prognosis, and pituitary function between the two groups. Predictive factors for delayed diagnosis were explored using multivariate logistic regression analysis. Results 225 patients (65.2%) experienced delayed diagnosis. Although there was no association between delayed diagnosis and survival rates or tumor recurrence rates, the delayed diagnosis group had a higher incidence of central diabetes insipidus, central adrenal insufficiency, central hypothyroidism, central hypogonadism, and growth hormone deficiency. Moreover, polyuria/polydipsia (OR 5.46; 95% CI 2.33-12.81), slow growth (OR 5.86; 95% CI 2.61-13.14), amenorrhea (OR 6.82; 95% CI 2.68-17.37), and germinoma (OR 4.99; 95% CI 1.08-3.61) were predictive factors for delayed diagnosis, while older age of onset (OR 0.88; 95% CI 0.84-0.94) and nausea/vomiting (OR 0.31; 95% CI 0.15-0.63) contributed to earlier diagnosis. Conclusion In patients with sellar GCTs, delayed diagnosis is common and linked to increased pituitary dysfunction. Factors predicting delayed diagnosis include slow growth, polyuria /polydipsia, amenorrhea, and germinomas with negative tumor markers. Early diagnosis is crucial to minimize the impact of sellar GCTs on pituitary function. Intracranial germ cell tumors children and adolescents delayed diagnosis pituitary function predictive factors Figures Figure 1 Figure 2 Introduction Intracranial germ cell tumors (iGCTs) are uncommon malignancies that predominantly impact children and adolescents. The peak onset occurs between 10 and 14 years, with 90% of individuals presenting before 20 years [ 1 , 2 ]. In Europe and the United States, iGCTs make up around 3–5% of pediatric intracranial tumors[ 3 , 4 ]. Contrastingly, in Asian regions like Japan and Taiwan, these tumors make up 10–15% of pediatric brain tumors[ 5 , 6 ]. The WHO categorizes iGCTs into two main groups - germinoma and non-germinomatous germ cell tumors (NGGCTs) [ 7 ]. NGGCTs include choriocarcinoma, yolk sac tumor, embryonal carcinoma, mature teratoma, immature teratoma, teratomas with somatic-type malignancy, and mixed germ cell tumors. Some subtypes produce specific tumor markers, and beta-human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (AFP) are the most commonly used in clinical practice. Yolk sac tumors primarily produce AFP, while embryonal carcinoma and immature teratoma may also generate low levels of AFP. β-hCG, on the other hand, is secreted by choriocarcinoma[ 8 ]. However, germinomas with syncytiotrophoblastic giant cells can also produce small amounts of β-hCG, usually less than 100 IU/L[ 9 ]. iGCTs predominantly occur in the pineal gland and sellar region. Some patients can simultaneously have lesions in both areas, a condition known as "bifocal" lesions[ 10 ]. The symptoms of iGCTs vary according to the tumor's size and location. For example, pineal region lesions frequently cause symptoms due to the mass effect, including headaches, nausea, and vomiting, which indicate elevated intracranial pressure [ 11 ]. Lesions in the sellar region primarily manifest endocrinological symptoms, such as polyuria/polydipsia, slow growth, delayed puberty, amenorrhea, precocious puberty, and fatigue[ 12 ]. Visual acuity and visual field disturbances can also occur in these patients when the tumor grows towards the suprasellar region and compresses the optic chiasm. In addition, a minority of individuals with iGCTs occasionally experience neurological symptoms, like motor impairment, cognitive impairment, drowsiness, and even coma[ 8 , 13 ]. Due to their high sensitivity to chemoradiotherapy, germinomas exhibit a 5-year survival rate exceeding 95%[ 9 ]. Even for NGGCTs, it may reach 80% following chemoradiotherapy and surgical resection of residual disease if necessary[ 9 , 14 ]. Given the heterogeneity of iGCTs, diagnosis is challenging. It requires a comprehensive assessment based on the patient's clinical symptoms, neuroimaging features, tumor markers, and histopathological analysis. A definitive diagnosis can be established when patients exhibit typical clinical symptoms and neuroimaging findings, along with positive tumor markers. However, a further biopsy is necessary for a histopathological diagnosis if tumor markers are negative. Prior research has indicated that children with iGCTs typically face a prolonged time to diagnosis than those with other children intracranial neoplasm, with over 50% of the patients encountering delayed diagnosis[ 15 , 16 ]. Sellar GCTs, characterized by the insidious onset of endocrinological symptoms, further add to the complexity of the disease, with delayed diagnosis rates potentially reaching as high as 83%[ 17 ]. Furthermore, a delayed diagnosis may affect the prognosis of individuals with iGCTs. Although several studies with limited sample sizes have not identified a significant relationship between delayed diagnosis and patient survival or recurrence rates, there may be an increased risk of short stature[ 17 – 19 ]. However, the studies above focused on patient survival and recurrence rates without conducting a detailed assessment of hypothalamic-pituitary-target gland axis function. The need for an enhanced quality of life grows as survival time extends. Pituitary dysfunction is a crucial determinant of the quality of life in these individuals and deserves special attention, particularly in individuals with sellar GCTs[ 20 ]. Therefore, we retrospectively collected clinical data from a large sample of sellar GCTs and comprehensively assessed the function of the hypothalamus-pituitary-target gland axis. Our objective was to explore the clinical features and predictive variables of delayed diagnosis in these patients to facilitate early detection. Methods Patients We retrospectively analyzed clinical data from 345 consecutive individuals diagnosed with sellar GCTs at Beijing Tiantan Hospital, Capital Medical University, from January 2018 to May 2023. The collected data included the age of onset, gender, clinical symptoms, time from initial symptoms to definite diagnosis, neuroimaging features (tumor location and size), tumor markers, pathological type, tumor dissemination, diagnostic methods, and treatment strategies. In addition, pituitary function at diagnosis, tumor recurrence, and patient survival were collected. Definitions Previous studies on iGCTs had defined delayed diagnosis as a duration exceeding 6 months from the initial symptoms to the formal diagnosis[ 13 , 17 , 19 ]. For this reason, all patients in this study were categorized into two groups: the delayed diagnosis group (> 6 months) and the non-delayed diagnosis group (≤ 6 months), according to the time from the first symptom to the definite diagnosis. Tumor dissemination was characterized by the existence of non-contiguous lesions in multiple anatomical sites or the detection of tumor cells in the CFS. Typical "bifocal" lesions did not fit into this category. Tumors were categorized as germinomas and NGGCTs. In the absence of a pathological diagnosis, individuals with serum/CSF β-hCG levels surpassing 100 IU/L or AFP elevation were classified as NGGCTs. In contrast, the remaining cases were classified as germinomas. Pituitary function evaluation The assessment of hypothalamic-pituitary-target gland axis function primarily involved evaluating the anterior and posterior pituitary function, including the following aspects. Central adrenal insufficiency (CAI) was diagnosed when the 8:00 am serum cortisol level was below 5µg/dL, accompanied by a low or normal adrenocorticotropic hormone level. Central hypothyroidism (CHT) was defined as having low levels of free thyroxine but normal or slightly elevated levels of thyrotropin. Central hypogonadism (CHG) was characterized by low serum total testosterone and low gonadotropin levels in males older than 14 years or low serum estradiol and low gonadotropin levels in females older than 13 years[ 21 ]. Hypothalamic-pituitary-gonadal function was not assessed in children and early adolescents (boys < 14 years old or girls < 13 years old) with gonadotropin levels below the Tanner stage 2 reference range. Growth hormone deficiency (GHD) was determined by measuring the level of serum insulin-like growth factor I level below the age and sex-matched normal reference range, along with a deficiency of the other three pituitary hormones[ 21 ]. Central diabetes insipidus (CDI) was diagnosed as a serum osmolality > 295 mOsm/kg and urine osmolality < 300 mOsm/kg after water deprivation, along with polyuria and polydipsia improved with administration of vasopressin[ 21 , 22 ]. In addition, CDI was also diagnosed in individuals exhibiting significant polyuria (24-hour urine volume > 50 mL/kg), along with a low urine specific gravity and marked improvement in symptoms after desmopressin treatment. Hyperprolactinemia (HPL) is diagnosed when the serum prolactin level exceeds the laboratory reference range. Statistical analysis Continuous variables were represented by the median (interquartile range), and Categorical variables were presented as numbers and percentages. The Mann–Whitney U test was employed to assess differences in the distribution of continuous variables, while Pearson's χ2 or Fisher's exact test was used for categorical variables. A multivariate logistic regression analysis was conducted to explore the potential predictors for delayed diagnosis, with delayed /non-delayed diagnosis as the dependent variable and significant variables identified through univariate analysis of general characteristics and clinical symptoms as independent variables. All P values < 0.05 were considered statistically significant. Statistical analyses were performed using SPSS 25.0 (SPSS Inc.). Results General characteristics of patients with delayed diagnosis Among the 345 individuals with GCTs, 169 (49%) were female. The median age of onset was 12 (8–15) years. Of the total cases, 252 (73%) exhibited isolated sellar lesions, and 93 (27%) had "bifocal" lesions. Categorically, 258 cases (74.8%) were classified as germinomas, and 87 cases (25.2%) as NGGCTs. At diagnosis, the median maximum tumor size was 20 (12–31) mm. The median time from first symptoms to diagnosis was 12 (4–24) months. Based on the aforementioned criteria, 225 patients (65.2%) were categorized into the delayed-diagnosis group, while 120 patients (34.8%) fell into the non-delayed diagnosis group. Compared to the without delayed diagnosis group, patients in the delayed diagnosis group exhibited a younger age of onset, a higher proportion of females, more isolated sellar lesions, a greater prevalence of germinomas, and a larger maximum tumor size (Table 1 ). Table 1 General characteristics and clinical symptoms of sellar GCTs with and without a delay in diagnosis. All (N = 345) n(%) Delayed (N = 225) n(%) Non-delayed(N = 120) n(%) P value Age at onset(year) 12(8–15) 10(7–14) 13(9–17) <0.001 Female sex 169(49) 129(57.3) 40(33.3) <0.001 Tumor location <0.001 Isolated sellar 252(73.0) 180(80.0) 72(60.0) Bifocal 93(27.0) 45(20.0) 48(40.0) Tumor type 0.002 Germinoma 258(74.8) 180(80.0) 78(65.0) NGGCT 87(25.2) 45(20.0) 42(35.5) Maximum tumor size at diagnosis (mm) 20(12–31) 22(15–32) 18(10–30) 0.005 Endocrinological symptoms Polyuria/ polydipsia 305(88.4) 214(95.1) 91(75.8) <0.001 Slow growth 89(25.8) 80(35.6) 9(7.5) <0.001 Fatigue 76(22.0) 57(25.3) 19(15.8) 0.043 Amenorrhea 50(14.5) 40(17.8) 10(8.3) 0.018 Delay puberty 26(7.5) 23(10.2) 3(2.5) 0.01 Precocious puberty 14(4.1) 6(2.7) 8(6.7) 0.073 Mass effects Visual acuity /field changes 123(35.7) 82(36.4) 41(34.2) 0.674 Headache 100(29.0) 44(19.6) 56(46.7) <0.001 Nausea/vomiting 54(15.7) 21(9.3) 33(27.5) <0.001 Neurological symptoms Drowsiness or coma 27(7.8) 19(8.4) 8(6.7) 0.558 Cognitive impairment 9(2.6) 8(3.6) 1(0.8) 0.131 Motor impairment 7(2.0) 5(2.2) 2(1.7) 0.727 Epilepsy 5(1.4) 3(1.3) 2(1.7) 0.805 Abbreviations: GCTs, germ cell tumor; NGGCT, non-germinomatous germ cell tumor. Symptoms in patients with delayed diagnosis The most prevalent endocrinological symptom was polyuria/polydipsia, accounting for 88.4%, followed by slow growth, fatigue, amenorrhea, delayed puberty, and precocious puberty, with percentages of 25.8%, 22%, 14.5%, 7.5%, and 4.1%, respectively. Concerning mass effects, symptoms like visual acuity/field changes, headache, nausea, or vomiting accounted for 35.7%, 29.0%, and 15.7%, respectively. Neurological symptoms were relatively less common (Table 1 ). The duration of each symptom at the time of diagnosis exhibited variability (Fig. 1 ). Slow growth showed the lengthiest median duration, persisting for 24 months, succeeded by polyuria/polydipsia, amenorrhea, and delayed puberty, each lasting 12 months. Symptoms related to mass effects and neurological impairment, such as headache, nausea/vomiting, and epilepsy, demonstrated shorter median durations, specifically 0.5, 0.5, and 0.28 months, respectively. Compared to the non-delayed diagnosis group, patients with delayed diagnosis had more symptoms such as polyuria/polydipsia, slow growth, fatigue, amenorrhea, and delayed puberty while showing a lower occurrence of headache and nausea/vomiting. There were no discernible differences between the two groups regarding neurological symptoms, precocious puberty, and changes in visual acuity/field (Table 1 ). Diagnostic methods and treatment strategies in patients with delayed diagnosis In the present study, 169 cases (49.0%) were diagnosed through histopathology, 150 cases (44.9%) based on positive β-hCG and/or AFP, and 21 cases (6.1%) through diagnostic radiotherapy (typical clinical symptoms and imaging features with a reduction of the lesion's maximum diameter by over 80% after low-dose local radiotherapy). Among the 258 germinoma patients, 134 cases (51.9%) tested negative for tumor markers, while 124 (48.1%) tested positive for tumor markers. Notably, among the positive cases, 40 patients (32.2%) had positive β-hCG only in CSF and not in serum. Among the 86 cases with NGGCTs, tumor markers were positive in 84 cases (97.7%) and negative in 2 cases (2.3%). Upon histopathological confirmation, these 2 cases were identified as mixed germ cell tumors with a predominant teratoma component. All patients in this study received radiotherapy, and 327 (91.8%) also received platinum-based chemotherapy. A total of 195 patients underwent surgery, including 111 (32.2%) with biopsy, 58 (16.8%) with surgical resection of the lesion, 12 (3.5%) with ventriculoperitoneal shunt (VPS) or endoscopic third ventriculostomy (ETV), and 14 (4.0%) with biopsy + VPS/ETV. Patients with delayed diagnoses had a higher rate of undergoing biopsy than those without delayed diagnoses (37.3% vs 22.5%, p = 0.005). However, there were no significant differences in diagnostic methods and treatment strategies between the two groups. Pituitary function and tumor prognosis in patients with delayed diagnosis Regarding pituitary dysfunction, the most common was CDI, followed by CHG, GHD, HPL, CAI, and CHT, accounting for 96.2%, 83.5%, 67.7%, 67.7%, 64.9%, and 62.3%, respectively. Patients with delayed diagnosis had a higher incidence of CDI, CAI, CHT, CHG, and GHD than those without a delayed diagnosis, with no discernible statistically significant variations in HPL between the two groups. At the time of diagnosis, 58 patients (16.8%) had tumor dissemination. All patients survived during a median follow-up period of 18 (10–30) months, and 9 (2.6%) experienced tumor recurrence. The recurrence duration was a median of 24 (7.5–60) months. There was no statistically significant difference between the two groups in tumor dissemination and recurrence (Table 2 ). Table 2 Pituitary dysfunction and tumor prognosis of sellar GCTs with and without a delay in diagnosis. All (N = 345) n(%) Delayed(N = 225) n(%) Non-delayed(N = 120) n(%) P value Pituitary dysfunction CDI 329/342(96.2) 221/22(99.1) 108/119(90.8) <0.001 CAI 222/342(64.9) 164/22(73.5) 58/119(48.7) <0.001 CHT 213/342(62.3) 151/22(67.7) 62/119(52.1) 0.005 CHG 193/231(83.5) 131/14(87.9) 62/82(75.6) 0.016 GHD 215/318(67.7) 153/20(74.3) 62/112(55.3) 0.001 HPL 229/341(67.7) 156/22(70.3) 73/119(61.3) 0.094 Tumor prognosis Tumor dissemination 58(16.8) 36(16.0) 22(18.3) 0.581 Tumor relapse 9(2.6) 6(2.7) 3(2.5) 0.926 Abbreviations: GCTs, germ cell tumor; CDI, central diabetes insipidus; CAI, central adrenal insufficiency; CHT, central hypothyroidism; CHG, central hypogonadism; GHD, growth hormone deficiency; HPL, hyperprolactinemia. Clinical characteristics of patients with initially negative tumor markers and small lesions Among all 345 patients, 47 cases (13.6%) initially presented with negative tumor markers and either small or indistinct lesions during the first visit, which made the biopsy inappropriate. These cases were ultimately diagnosed as sellar GCTs through regular follow-up examinations. The median age of onset in these patients was 9 (7–13) years, with 28 (59.6%) females and 19 (40.4%) males. The initial symptoms included polyuria/polydipsia in 38 cases (80.9%), polydipsia/polyuria with slow growth in 4 cases (8.5%), polyuria/polydipsia with amenorrhea in 1 case (2.1%), slow growth in 3 cases (6.4%), and amenorrhea in 1 case (2.1%). Upon the first visit, neuroimaging revealed pituitary stalk thickening in 29 cases (61.7%) and no apparent lesions in 18 cases (38.3%). All patients had negative tumor markers in both serum and CSF. All patients showed radiological progression after a median follow-up of 16 (10–22) months. Ultimately, 24 cases (51.1%) were diagnosed based on positive tumor markers, 17 cases (36.2%) through biopsy, and 6 cases (12.8%) via diagnostic radiotherapy. Patients diagnosed through diagnostic radiotherapy had a significantly shorter median time from the initial visit to a definitive diagnosis than those diagnosed based on positive tumor markers and biopsy (6 months vs 18 months vs 18 months, p = 0.013). Categorically, 44 cases (93.6%) were germinomas, and 3 cases (6.4%) were NGGCTs. The median time from the initial symptom to the first consultation and final diagnosis was 7 (4–12) months and 24 (18–32) months, respectively. Figure 3 shows dynamic neuroimaging changes in a patient with initially negative tumor markers and a thickened pituitary stalk. Predictive factors for delayed diagnosis A multivariate logistic regression analysis was conducted to investigate predictive factors for delayed diagnosis in patients with sellar GCTs. The final results revealed that polyuria/polydipsia (OR 5.46; 95% CI 2.33–12.81), slow growth (OR 5.86; 95% CI 2.61–13.14), amenorrhea (OR 6.82; 95% CI 2.68–17.37), and germinoma (OR 4.99; 95% CI 1.08–3.61) were predictive factors for delayed diagnosis, while older age of onset (OR 0.88; 95% CI 0.84–0.94) and nausea/vomiting (OR 0.31; 95% CI 0.15–0.63) contributed to earlier diagnosis (Table 3 ). Table 3 Multivariate logistic regression of the predictive factors for delayed diagnosis in patients with sellar GCTs. OR 95% CL P value Polyuria/polydipsia 5.46 2.33–12.81 <0.001 Slow growth 5.86 2.61–13.14 <0.001 Amenorrhea 6.82 2.68–17.37 <0.001 Germinoma 4.99 1.08–3.61 0.025 Age onset(year) 0.88 0.84–0.94 <0.001 Nausea/vomiting 0.31 0.15–0.63 0.001 Abbreviations: GCTs, germ cell tumor. Discussion Based on a large sample size, this study examined the clinical characteristics of delayed diagnosis and explored predictive factors for delayed diagnosis in patients with sellar GCTs. The results demonstrated that 64.4% of individuals experienced delayed diagnosis. Delayed diagnosis had no significant association with survival rates or tumor recurrence rates. However, individuals with delayed diagnosis had higher rates of CDI, CAI, CHT, CHG, and GHD. Slow growth, polyuria/polydipsia, amenorrhea, and germinoma were predictive factors for delayed diagnosis, while an older age of onset and nausea/vomiting contribute to early diagnosis. Delayed diagnosis is common in patients with iGCTs, especially those in the sellar region. Sethi et al. [ 18 ] found that patients with "bifocal" lesions had a delayed diagnosis rate of 55%, while those with isolated sellar lesions had a significantly higher delayed diagnosis rate of 82%. In our study, which included both isolated sellar lesions and "bifocal" lesions, the delayed diagnosis rate was 65.2%, closely aligning with previous research findings. The factors contributing to the delayed diagnosis of sellar GCTs are complex. They may be associated with a younger onset, insidious onset, the inherent complexity of the disease, and psychosocial factors. Sellar GCTs mainly present with endocrinological symptoms, especially polyuria/polydipsia, and slow growth. These symptoms often emerge early, have an insidious onset, progress slowly, and are particularly difficult to detect in children and adolescents. Due to these factors, patients and their families may not easily recognize the symptoms, resulting in a significant delay at the initial medical consultation. This study revealed that the duration of slow growth before the definitive diagnosis was the longest, lasting 24 months, followed by polyuria/polydipsia and amenorrhea, each lasting 12 months. These endocrinological symptoms, along with an earlier age of onset, were more prevalent in patients with delayed diagnosis. Furthermore, slow growth, polyuria/polydipsia, and amenorrhea are independent risk factors for delayed diagnosis, while increasing age is helpful for early diagnosis. Similar to our study, previous research demonstrated that endocrinological symptoms may contribute to delayed diagnosis in patients with iGCTs[ 17 , 23 ]. Additionally, in other pediatric intracranial tumors, a younger age at onset was associated with a higher likelihood of delayed diagnosis[ 24 ]. The above findings indicate that when patients present with endocrinological symptoms, especially in children and adolescents, it is crucial to promptly conduct neuroimaging examinations and tumor marker assessments for early diagnosis. On the contrary, when patients exhibited symptoms of mass effects, like headaches and nausea/vomiting, these manifestations were frequently more pronounced and severe, drawing significant attention from both patients and their families. This study also confirmed this phenomenon. iGCTs were diagnosed only 0.5 months following the first signs of headache and nausea/vomiting, with the latter symptom contributing to the early diagnosis. Consistent with the study by Zhang et al. [ 17 ], the present study also found that germinoma was an independent risk factor for delayed diagnosis in patients with sellar GCTs. This may be related to the complexity and clinical heterogeneity of the disease. Although a tiny number of patients with NGGCTs may have negative tumor markers, the majority typically exhibit varying degrees of tumor marker secretion, making diagnosis easier[ 25 ]. Similarly, germinomas with syncytiotrophoblastic giant cells may also secrete low levels of β-hCG, making the diagnosis relatively straightforward. Notably, among these patients, some have only CSF β-hCG positive, while serum β-hCG is negative. In the present study, among the 124 cases of germinomas with positive tumor markers, 40 cases (32.2%) showed elevated CSF β-hCG only. Previous studies also confirmed that levels of β-hCG in the CSF were generally higher than in the serum[ 26 – 28 ]. This suggests that both serum and CSF tumor markers should be recommended for screening in patients with suspected iGCTs when available. However, pure germinomas generally do not secrete β-hCG and AFP. Diagnosis can be challenging for these patients, especially when the lesions are too small to biopsy, potentially further prolonging the diagnostic timeline[ 9 , 29 ]. In this study, it was observed that 47 patients (13.6%) had negative tumor markers during the initial visit, and neuroimaging revealed either mild pituitary stalk thickening or an absence of apparent lesions. The median duration from the initial symptoms to the first visit for these individuals was 7 months. Subsequently, after a median follow-up of 16 months, the final diagnosis was established as sellar GCTs, significantly prolonging the diagnostic timeline. The majority of these patients (91.5%) were classified as germinomas. A significant finding was that among these 47 patients who initially had negative tumor markers and small lesions, the median time from the first visit to a definitive diagnosis was significantly shorter for those diagnosed through diagnostic radiotherapy compared to those diagnosed through biopsy and positive tumor markers (6 months vs 18 months). This suggests that in patients highly suspected of having iGCTs, with negative tumor markers and lesions too small for biopsy, diagnostic radiotherapy may be a potential approach for early diagnosis. However, the following issues cannot be ignored. First, patients with smaller lesions were often in the disease's initial phases, simply displaying pituitary dysfunction symptoms without evident mass effects. These symptoms were significantly alleviated with appropriate hormone replacement therapy. In such cases, the parents of children and adolescents were reluctant to accept diagnostic radiotherapy, fearing potential irreversible adverse reactions. Secondly, in a complex medical environment, Physicians were cautious in using diagnostic radiotherapy without pathology or positive tumor markers. This caution stemmed from the fact that some patients suspected of having germinomas may not exhibit a significant reduction or any reduction in the tumor size after undergoing diagnostic radiotherapy. Ultimately, these patients received a pathological diagnosis of teratoma or other non-tumor conditions, such as Langerhans cell histiocytosis[ 30 , 31 ]. Although diagnostic radiotherapy facilitated early diagnosis, addressing the existing issues required improved biological, psychological, and social coordination. Similar to prior investigations, our findings showed no correlation between delayed diagnosis and survival or tumor recurrence rates[ 17 , 18 ]. However, it cannot be denied that the follow-up period in the present study was relatively short, lasting only 18 months. In addition to survival and tumor recurrence rates, this study thoroughly evaluated the pituitary function in patients with sellar GCTs. The results indicated that patients with delayed diagnoses exhibited more significant pituitary dysfunction. Presently, the reason remains unclear, but it may be associated with a larger tumor size, prolonged compression of the pituitary and pituitary stalk, and severe ischemic necrosis observed in the delayed diagnosis group. Since pituitary dysfunction was a primary factor influencing patients' long-term quality of life, assessing pituitary function and appropriate hormone replacement therapy was crucial in managing sellar GCTs. This was particularly challenging, especially in addressing growth and developmental issues in pediatric patients[ 29 ]. Our study has several limitations. The estimation of symptom duration was susceptible to recall bias. Additionally, the median follow-up time in this study was only 18 months, potentially inadequately representing the actual survival and recurrence rates. Extending the follow-up period is necessary for a more comprehensive assessment. Furthermore, being a retrospective single-center study, the generalization of the results may be constrained. To enhance the validity of the findings, multi-center prospective studies are warranted for further verification. Conclusion Delayed diagnosis occurred in up to 65.2% of patients with sellar GCTs. Although delayed diagnosis did not impact the survival rate or tumor recurrence rate, patients with delayed diagnosis displayed a higher incidence of hypothalamic-pituitary-target axis dysfunction. Slow growth, polyuria/polydipsia, amenorrhea, and germinoma were predictive factors for delayed diagnosis, while an older age of onset and nausea/vomiting contribute to early diagnosis. Therefore, early recognition and attention to endocrinological symptoms are paramount in children and adolescents. For those with negative tumor markers and challenges in biopsy due to small lesions, dynamic follow-ups are essential to achieve early diagnosis and ultimately minimize unnecessary pituitary dysfunction. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Ethical approval This study protocol was approved by the institutional review board of Beijing Tiantan Hospital, Capital Medical University. Informed consent The requirement for written informed consent from patients was waived owing to the retrospective study design. Acknowledgements We would like to thank all the participants of this study for their contribution to this research. 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Journal of pediatric hematology/oncology 31: 541-544 doi:10.1097/MPH.0b013e3181983af5 Villano JL, Propp JM, Porter KR, Stewart AK, Valyi-Nagy T, Li X, Engelhard HH, McCarthy BJ (2008) Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro-oncology 10: 121-130 doi:10.1215/15228517-2007-054 Zhang Y, Zhu H, Deng K, Ma W, Wang Y, Sun J, Lian X, Pan H, Wang R, Yao Y (2018) Results of Biopsy-Proven Sellar Germ Cell Tumors: Nine Years' Experience in a Single Center. World neurosurgery 112: e229-e239 doi:10.1016/j.wneu.2018.01.028 Jabłońska I, Goławski M, Nowicka E, Drosik-Rutowicz K, Trybus A, Tarnawski R, Miszczyk M (2023) Intracranial Germinoma-Association between Delayed Diagnosis, Altered Clinical Manifestations, and Prognosis. Cancers 15 doi:10.3390/cancers15102789 Calaminus G, Frappaz D, Kortmann RD, Krefeld B, Saran F, Pietsch T, Vasiljevic A, Garre ML, Ricardi U, Mann JR, Göbel U, Alapetite C, Murray MJ, Nicholson JC (2017) Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial. Neuro-oncology 19: 1661-1672 doi:10.1093/neuonc/nox122 MacDonald SM, Trofimov A, Safai S, Adams J, Fullerton B, Ebb D, Tarbell NJ, Yock TI (2011) Proton radiotherapy for pediatric central nervous system germ cell tumors: early clinical outcomes. International journal of radiation oncology, biology, physics 79: 121-129 doi:10.1016/j.ijrobp.2009.10.069 Jennings MT, Gelman R, Hochberg F (1985) Intracranial germ-cell tumors: natural history and pathogenesis. Journal of neurosurgery 63: 155-167 doi:10.3171/jns.1985.63.2.0155 Zhang Y, Deng K, Zhu H, Lu L, Pan H, Ma W, Wang R, Yao Y (2019) Delays in Diagnosis of Pediatric Histologically Confirmed Sellar Germ Cell Tumors in China: A Retrospective Risk Factor Analysis. World neurosurgery 122: e472-e479 doi:10.1016/j.wneu.2018.10.082 Sethi RV, Marino R, Niemierko A, Tarbell NJ, Yock TI, MacDonald SM (2013) Delayed diagnosis in children with intracranial germ cell tumors. The Journal of pediatrics 163: 1448-1453 doi:10.1016/j.jpeds.2013.06.024 Hayden J, Murray MJ, Bartels U, Ajithkumar T, Muthusamy B, Penn A, Calaminus G, Nicholson J (2020) Symptom interval and treatment burden for patients with malignant central nervous system germ cell tumours. Archives of disease in childhood 105: 247-252 doi:10.1136/archdischild-2019-317245 Liang SY, Yang TF, Chen YW, Liang ML, Chen HH, Chang KP, Shan IK, Chen YS, Wong TT (2013) Neuropsychological functions and quality of life in survived patients with intracranial germ cell tumors after treatment. Neuro-oncology 15: 1543-1551 doi:10.1093/neuonc/not127 Higham CE, Johannsson G, Shalet SM (2016) Hypopituitarism. Lancet (London, England) 388: 2403-2415 doi:10.1016/s0140-6736(16)30053-8 Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH (2016) Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism 101: 3888-3921 doi:10.1210/jc.2016-2118 Crawford JR, Santi MR, Vezina G, Myseros JS, Keating RF, LaFond DA, Rood BR, MacDonald TJ, Packer RJ (2007) CNS germ cell tumor (CNSGCT) of childhood: presentation and delayed diagnosis. Neurology 68: 1668-1673 doi:10.1212/01.wnl.0000261908.36803.ac Dobrovoljac M, Hengartner H, Boltshauser E, Grotzer MA (2002) Delay in the diagnosis of paediatric brain tumours. European journal of pediatrics 161: 663-667 doi:10.1007/s00431-002-1088-4 Kanamori M, Takami H, Yamaguchi S, Sasayama T, Yoshimoto K, Tominaga T, Inoue A, Ikeda N, Kambe A, Kumabe T, Matsuda M, Tanaka S, Natsumeda M, Matsuda KI, Nonaka M, Kurihara J, Yamaoka M, Kagawa N, Shinojima N, Negoto T, Nakahara Y, Arakawa Y, Hatazaki S, Shimizu H, Yoshino A, Abe H, Akimoto J, Kawanishi Y, Suzuki T, Natsume A, Nagane M, Akiyama Y, Keino D, Fukami T, Tomita T, Kanaya K, Tokuyama T, Izumoto S, Nakada M, Kuga D, Yamamoto S, Anei R, Uzuka T, Fukai J, Kijima N, Terashima K, Ichimura K, Nishikawa R (2021) So-called bifocal tumors with diabetes insipidus and negative tumor markers: are they all germinoma? Neuro-oncology 23: 295-303 doi:10.1093/neuonc/noaa199 Fujimaki T, Mishima K, Asai A, Tabuchi K, Kobayashi M, Suzuki I, Kirino T (2000) Levels of beta-human chorionic gonadotropin in cerebrospinal fluid of patients with malignant germ cell tumor can be used to detect early recurrence and monitor the response to treatment. Japanese journal of clinical oncology 30: 291-294 doi:10.1093/jjco/hyd076 Kong Z, Wang Y, Dai C, Yao Y, Ma W, Wang Y (2018) Central Nervous System Germ Cell Tumors: A Review of the Literature. Journal of child neurology 33: 610-620 doi:10.1177/0883073818772470 Allen J, Chacko J, Donahue B, Dhall G, Kretschmar C, Jakacki R, Holmes E, Pollack I (2012) Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatric blood & cancer 59: 1180-1182 doi:10.1002/pbc.24097 Tong T, Zhong LY (2023) Intracranial germ cell tumors: a view of the endocrinologist. Journal of pediatric endocrinology & metabolism : JPEM 36: 1115-1127 doi:10.1515/jpem-2023-0368 Krooks J, Minkov M, Weatherall AG (2018) Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis. Journal of the American Academy of Dermatology 78: 1035-1044 doi:10.1016/j.jaad.2017.05.059 Leung AKC, Lam JM, Leong KF (2019) Childhood Langerhans cell histiocytosis: a disease with many faces. World journal of pediatrics : WJP 15: 536-545 doi:10.1007/s12519-019-00304-9 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Mar, 2024 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 15 Feb, 2024 Reviews received at journal 07 Feb, 2024 Reviewers agreed at journal 31 Jan, 2024 Reviewers invited by journal 30 Jan, 2024 Submission checks completed at journal 30 Jan, 2024 Editor assigned by journal 30 Jan, 2024 First submitted to journal 30 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3910252","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":270328497,"identity":"0f4bfbc2-9f00-4568-aa8f-63fe179c04cc","order_by":0,"name":"Tao Tong","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Tong","suffix":""},{"id":270328498,"identity":"744573e1-5ce9-43a7-946e-ad04a6988f5d","order_by":1,"name":"Han Chen","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Chen","suffix":""},{"id":270328499,"identity":"c665d403-0afa-4dd1-bbcb-00e8bd6867bf","order_by":2,"name":"Caiyan Mo","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Caiyan","middleName":"","lastName":"Mo","suffix":""},{"id":270328500,"identity":"a6a0543f-2b15-4066-a1b3-1bf0fd809d8e","order_by":3,"name":"Liyong Zhong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYDACCRBRACYZHzPwMDAYEKfFAEwyGzPwGEgQqwXMZJMGaSaoRX5287GHXwwsEvul269VF8j8qTNnYD728QseLYxzjqUbyxhIJM6cc6bs9gygwywb2JJny+DRwiyRYyYtAdSy4UZO2m0ekF8O8BgzS+DRwoaspZgoLTxALZIfwFrSjzHDtDB+wKNFQiItTRoYTsYzZ+QwS8/gMZbccJgtmRmPDgb5GcnHJH9U1Mn2S6Q//FzYI8dvcLz5MOMPfHqAgBkY544NwGhkYOwBcSEieAHITHsGBvYHDAw/ECKjYBSMglEwCmAAACMnQ/tMAK3sAAAAAElFTkSuQmCC","orcid":"","institution":"Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Liyong","middleName":"","lastName":"Zhong","suffix":""}],"badges":[],"createdAt":"2024-01-30 10:17:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3910252/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3910252/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11060-024-04626-1","type":"published","date":"2024-03-04T15:00:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50510725,"identity":"8c31541e-9da1-4424-8de4-c2a41011a53d","added_by":"auto","created_at":"2024-02-01 16:09:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":227722,"visible":true,"origin":"","legend":"\u003cp\u003eDuration of symptoms at the time of diagnosis.\u003c/p\u003e","description":"","filename":"floatimage1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3910252/v1/587089f4c17ecbd2959af71e.jpg"},{"id":50509736,"identity":"dc12a495-9c35-47cc-a0fd-b270a598afb1","added_by":"auto","created_at":"2024-02-01 16:01:35","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":421138,"visible":true,"origin":"","legend":"\u003cp\u003eTypical neuroimaging dynamic changes of sellar germinomawith the initial presentation of pituitary stalk thickening. A 9-year-old girl presented with polyuria and polydipsia as the initial symptoms. Upon the first medical examination, neuroimaging only revealed mild pituitary stalk thickening (A: April 2021), and serum and cerebrospinal fluid tumor markers were negative. Through follow-up, the lesion gradually enlarged (B: December 2021, C: March 2022, D: June 2022), but tumor markers consistently remained negative. Eventually, a definitive diagnosis of a germinoma was made through a biopsy. The time from the onset of symptoms to the first visit and the final diagnosis was 10 months and 24 months, respectively.\u003c/p\u003e","description":"","filename":"floatimage2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3910252/v1/1bfb004fea9555880e280083.jpg"},{"id":52432048,"identity":"0302ea4f-ca01-48d9-b922-80660dfe3e79","added_by":"auto","created_at":"2024-03-11 15:10:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":615627,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3910252/v1/c8dec410-9586-41e3-8cc2-6d79535b2d7c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics and predictive factors of delayed diagnosis in patients with sellar germ cell tumors","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIntracranial germ cell tumors (iGCTs) are uncommon malignancies that predominantly impact children and adolescents. The peak onset occurs between 10 and 14 years, with 90% of individuals presenting before 20 years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In Europe and the United States, iGCTs make up around 3\u0026ndash;5% of pediatric intracranial tumors[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Contrastingly, in Asian regions like Japan and Taiwan, these tumors make up 10\u0026ndash;15% of pediatric brain tumors[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The WHO categorizes iGCTs into two main groups - germinoma and non-germinomatous germ cell tumors (NGGCTs) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. NGGCTs include choriocarcinoma, yolk sac tumor, embryonal carcinoma, mature teratoma, immature teratoma, teratomas with somatic-type malignancy, and mixed germ cell tumors. Some subtypes produce specific tumor markers, and beta-human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (AFP) are the most commonly used in clinical practice. Yolk sac tumors primarily produce AFP, while embryonal carcinoma and immature teratoma may also generate low levels of AFP. β-hCG, on the other hand, is secreted by choriocarcinoma[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, germinomas with syncytiotrophoblastic giant cells can also produce small amounts of β-hCG, usually less than 100 IU/L[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. iGCTs predominantly occur in the pineal gland and sellar region. Some patients can simultaneously have lesions in both areas, a condition known as \"bifocal\" lesions[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The symptoms of iGCTs vary according to the tumor's size and location. For example, pineal region lesions frequently cause symptoms due to the mass effect, including headaches, nausea, and vomiting, which indicate elevated intracranial pressure [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Lesions in the sellar region primarily manifest endocrinological symptoms, such as polyuria/polydipsia, slow growth, delayed puberty, amenorrhea, precocious puberty, and fatigue[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Visual acuity and visual field disturbances can also occur in these patients when the tumor grows towards the suprasellar region and compresses the optic chiasm. In addition, a minority of individuals with iGCTs occasionally experience neurological symptoms, like motor impairment, cognitive impairment, drowsiness, and even coma[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Due to their high sensitivity to chemoradiotherapy, germinomas exhibit a 5-year survival rate exceeding 95%[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Even for NGGCTs, it may reach 80% following chemoradiotherapy and surgical resection of residual disease if necessary[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the heterogeneity of iGCTs, diagnosis is challenging. It requires a comprehensive assessment based on the patient's clinical symptoms, neuroimaging features, tumor markers, and histopathological analysis. A definitive diagnosis can be established when patients exhibit typical clinical symptoms and neuroimaging findings, along with positive tumor markers. However, a further biopsy is necessary for a histopathological diagnosis if tumor markers are negative. Prior research has indicated that children with iGCTs typically face a prolonged time to diagnosis than those with other children intracranial neoplasm, with over 50% of the patients encountering delayed diagnosis[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Sellar GCTs, characterized by the insidious onset of endocrinological symptoms, further add to the complexity of the disease, with delayed diagnosis rates potentially reaching as high as 83%[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Furthermore, a delayed diagnosis may affect the prognosis of individuals with iGCTs. Although several studies with limited sample sizes have not identified a significant relationship between delayed diagnosis and patient survival or recurrence rates, there may be an increased risk of short stature[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, the studies above focused on patient survival and recurrence rates without conducting a detailed assessment of hypothalamic-pituitary-target gland axis function. The need for an enhanced quality of life grows as survival time extends. Pituitary dysfunction is a crucial determinant of the quality of life in these individuals and deserves special attention, particularly in individuals with sellar GCTs[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, we retrospectively collected clinical data from a large sample of sellar GCTs and comprehensively assessed the function of the hypothalamus-pituitary-target gland axis. Our objective was to explore the clinical features and predictive variables of delayed diagnosis in these patients to facilitate early detection.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed clinical data from 345 consecutive individuals diagnosed with sellar GCTs at Beijing Tiantan Hospital, Capital Medical University, from January 2018 to May 2023. The collected data included the age of onset, gender, clinical symptoms, time from initial symptoms to definite diagnosis, neuroimaging features (tumor location and size), tumor markers, pathological type, tumor dissemination, diagnostic methods, and treatment strategies. In addition, pituitary function at diagnosis, tumor recurrence, and patient survival were collected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003ePrevious studies on iGCTs had defined delayed diagnosis as a duration exceeding 6 months from the initial symptoms to the formal diagnosis[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. For this reason, all patients in this study were categorized into two groups: the delayed diagnosis group (\u0026gt;\u0026thinsp;6 months) and the non-delayed diagnosis group (\u0026le;\u0026thinsp;6 months), according to the time from the first symptom to the definite diagnosis. Tumor dissemination was characterized by the existence of non-contiguous lesions in multiple anatomical sites or the detection of tumor cells in the CFS. Typical \"bifocal\" lesions did not fit into this category. Tumors were categorized as germinomas and NGGCTs. In the absence of a pathological diagnosis, individuals with serum/CSF β-hCG levels surpassing 100 IU/L or AFP elevation were classified as NGGCTs. In contrast, the remaining cases were classified as germinomas.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePituitary function evaluation\u003c/h2\u003e \u003cp\u003eThe assessment of hypothalamic-pituitary-target gland axis function primarily involved evaluating the anterior and posterior pituitary function, including the following aspects. Central adrenal insufficiency (CAI) was diagnosed when the 8:00 am serum cortisol level was below 5\u0026micro;g/dL, accompanied by a low or normal adrenocorticotropic hormone level. Central hypothyroidism (CHT) was defined as having low levels of free thyroxine but normal or slightly elevated levels of thyrotropin. Central hypogonadism (CHG) was characterized by low serum total testosterone and low gonadotropin levels in males older than 14 years or low serum estradiol and low gonadotropin levels in females older than 13 years[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Hypothalamic-pituitary-gonadal function was not assessed in children and early adolescents (boys\u0026thinsp;\u0026lt;\u0026thinsp;14 years old or girls\u0026thinsp;\u0026lt;\u0026thinsp;13 years old) with gonadotropin levels below the Tanner stage 2 reference range. Growth hormone deficiency (GHD) was determined by measuring the level of serum insulin-like growth factor I level below the age and sex-matched normal reference range, along with a deficiency of the other three pituitary hormones[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Central diabetes insipidus (CDI) was diagnosed as a serum osmolality\u0026thinsp;\u0026gt;\u0026thinsp;295 mOsm/kg and urine osmolality\u0026thinsp;\u0026lt;\u0026thinsp;300 mOsm/kg after water deprivation, along with polyuria and polydipsia improved with administration of vasopressin[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In addition, CDI was also diagnosed in individuals exhibiting significant polyuria (24-hour urine volume\u0026thinsp;\u0026gt;\u0026thinsp;50 mL/kg), along with a low urine specific gravity and marked improvement in symptoms after desmopressin treatment. Hyperprolactinemia (HPL) is diagnosed when the serum prolactin level exceeds the laboratory reference range.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were represented by the median (interquartile range), and Categorical variables were presented as numbers and percentages. The Mann\u0026ndash;Whitney U test was employed to assess differences in the distribution of continuous variables, while Pearson's χ2 or Fisher's exact test was used for categorical variables. A multivariate logistic regression analysis was conducted to explore the potential predictors for delayed diagnosis, with delayed /non-delayed diagnosis as the dependent variable and significant variables identified through univariate analysis of general characteristics and clinical symptoms as independent variables. All P values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. Statistical analyses were performed using SPSS 25.0 (SPSS Inc.).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGeneral characteristics of patients with delayed diagnosis\u003c/h2\u003e \u003cp\u003eAmong the 345 individuals with GCTs, 169 (49%) were female. The median age of onset was 12 (8\u0026ndash;15) years. Of the total cases, 252 (73%) exhibited isolated sellar lesions, and 93 (27%) had \"bifocal\" lesions. Categorically, 258 cases (74.8%) were classified as germinomas, and 87 cases (25.2%) as NGGCTs. At diagnosis, the median maximum tumor size was 20 (12\u0026ndash;31) mm. The median time from first symptoms to diagnosis was 12 (4\u0026ndash;24) months. Based on the aforementioned criteria, 225 patients (65.2%) were categorized into the delayed-diagnosis group, while 120 patients (34.8%) fell into the non-delayed diagnosis group. Compared to the without delayed diagnosis group, patients in the delayed diagnosis group exhibited a younger age of onset, a higher proportion of females, more isolated sellar lesions, a greater prevalence of germinomas, and a larger maximum tumor size (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGeneral characteristics and clinical symptoms of sellar GCTs with and without a delay in diagnosis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (N\u0026thinsp;=\u0026thinsp;345)\u003c/p\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelayed (N\u0026thinsp;=\u0026thinsp;225)\u003c/p\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-delayed(N\u0026thinsp;=\u0026thinsp;120)\u003c/p\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at onset(year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12(8\u0026ndash;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(7\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13(9\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale sex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e169(49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e129(57.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsolated sellar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e252(73.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e180(80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72(60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBifocal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93(27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGerminoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e258(74.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e180(80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78(65.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNGGCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87(25.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42(35.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum tumor size at diagnosis (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(12\u0026ndash;31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(15\u0026ndash;32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18(10\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndocrinological symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolyuria/ polydipsia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e305(88.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e214(95.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91(75.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow growth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89(25.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80(35.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9(7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76(22.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57(25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19(15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmenorrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50(14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40(17.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10(8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelay puberty\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26(7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23(10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrecocious puberty\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMass effects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual acuity\u003c/p\u003e \u003cp\u003e/field changes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123(35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82(36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41(34.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.674\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100(29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44(19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56(46.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea/vomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54(15.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21(9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33(27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeurological symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrowsiness or coma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(8.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCognitive impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.131\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMotor impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.727\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.805\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: GCTs, germ cell tumor; NGGCT, non-germinomatous germ cell tumor.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSymptoms in patients with delayed diagnosis\u003c/h2\u003e \u003cp\u003eThe most prevalent endocrinological symptom was polyuria/polydipsia, accounting for 88.4%, followed by slow growth, fatigue, amenorrhea, delayed puberty, and precocious puberty, with percentages of 25.8%, 22%, 14.5%, 7.5%, and 4.1%, respectively. Concerning mass effects, symptoms like visual acuity/field changes, headache, nausea, or vomiting accounted for 35.7%, 29.0%, and 15.7%, respectively. Neurological symptoms were relatively less common (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The duration of each symptom at the time of diagnosis exhibited variability (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Slow growth showed the lengthiest median duration, persisting for 24 months, succeeded by polyuria/polydipsia, amenorrhea, and delayed puberty, each lasting 12 months. Symptoms related to mass effects and neurological impairment, such as headache, nausea/vomiting, and epilepsy, demonstrated shorter median durations, specifically 0.5, 0.5, and 0.28 months, respectively. Compared to the non-delayed diagnosis group, patients with delayed diagnosis had more symptoms such as polyuria/polydipsia, slow growth, fatigue, amenorrhea, and delayed puberty while showing a lower occurrence of headache and nausea/vomiting. There were no discernible differences between the two groups regarding neurological symptoms, precocious puberty, and changes in visual acuity/field (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic methods and treatment strategies in patients with delayed diagnosis\u003c/h2\u003e \u003cp\u003eIn the present study, 169 cases (49.0%) were diagnosed through histopathology, 150 cases (44.9%) based on positive β-hCG and/or AFP, and 21 cases (6.1%) through diagnostic radiotherapy (typical clinical symptoms and imaging features with a reduction of the lesion's maximum diameter by over 80% after low-dose local radiotherapy). Among the 258 germinoma patients, 134 cases (51.9%) tested negative for tumor markers, while 124 (48.1%) tested positive for tumor markers. Notably, among the positive cases, 40 patients (32.2%) had positive β-hCG only in CSF and not in serum. Among the 86 cases with NGGCTs, tumor markers were positive in 84 cases (97.7%) and negative in 2 cases (2.3%). Upon histopathological confirmation, these 2 cases were identified as mixed germ cell tumors with a predominant teratoma component.\u003c/p\u003e \u003cp\u003eAll patients in this study received radiotherapy, and 327 (91.8%) also received platinum-based chemotherapy. A total of 195 patients underwent surgery, including 111 (32.2%) with biopsy, 58 (16.8%) with surgical resection of the lesion, 12 (3.5%) with ventriculoperitoneal shunt (VPS) or endoscopic third ventriculostomy (ETV), and 14 (4.0%) with biopsy\u0026thinsp;+\u0026thinsp;VPS/ETV. Patients with delayed diagnoses had a higher rate of undergoing biopsy than those without delayed diagnoses (37.3% vs 22.5%, p\u0026thinsp;=\u0026thinsp;0.005). However, there were no significant differences in diagnostic methods and treatment strategies between the two groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePituitary function and tumor prognosis in patients with delayed diagnosis\u003c/h2\u003e \u003cp\u003eRegarding pituitary dysfunction, the most common was CDI, followed by CHG, GHD, HPL, CAI, and CHT, accounting for 96.2%, 83.5%, 67.7%, 67.7%, 64.9%, and 62.3%, respectively. Patients with delayed diagnosis had a higher incidence of CDI, CAI, CHT, CHG, and GHD than those without a delayed diagnosis, with no discernible statistically significant variations in HPL between the two groups. At the time of diagnosis, 58 patients (16.8%) had tumor dissemination. All patients survived during a median follow-up period of 18 (10\u0026ndash;30) months, and 9 (2.6%) experienced tumor recurrence. The recurrence duration was a median of 24 (7.5\u0026ndash;60) months. There was no statistically significant difference between the two groups in tumor dissemination and recurrence (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePituitary dysfunction and tumor prognosis of sellar GCTs with and without a delay in diagnosis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll (N\u0026thinsp;=\u0026thinsp;345)\u003c/p\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelayed(N\u0026thinsp;=\u0026thinsp;225)\u003c/p\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-delayed(N\u0026thinsp;=\u0026thinsp;120)\u003c/p\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePituitary dysfunction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCDI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e329/342(96.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e221/22(99.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e108/119(90.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e222/342(64.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e164/22(73.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e58/119(48.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e213/342(62.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e151/22(67.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e62/119(52.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e193/231(83.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e131/14(87.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e62/82(75.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e215/318(67.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e153/20(74.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e62/112(55.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHPL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e229/341(67.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e156/22(70.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e73/119(61.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor prognosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor dissemination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58(16.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36(16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22(18.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.581\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor relapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9(2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6(2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3(2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.926\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: GCTs, germ cell tumor; CDI, central diabetes insipidus; CAI, central adrenal insufficiency; CHT, central hypothyroidism; CHG, central hypogonadism; GHD, growth hormone deficiency; HPL, hyperprolactinemia.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eClinical characteristics of patients with initially negative tumor markers and small lesions\u003c/h2\u003e \u003cp\u003eAmong all 345 patients, 47 cases (13.6%) initially presented with negative tumor markers and either small or indistinct lesions during the first visit, which made the biopsy inappropriate. These cases were ultimately diagnosed as sellar GCTs through regular follow-up examinations. The median age of onset in these patients was 9 (7\u0026ndash;13) years, with 28 (59.6%) females and 19 (40.4%) males. The initial symptoms included polyuria/polydipsia in 38 cases (80.9%), polydipsia/polyuria with slow growth in 4 cases (8.5%), polyuria/polydipsia with amenorrhea in 1 case (2.1%), slow growth in 3 cases (6.4%), and amenorrhea in 1 case (2.1%). Upon the first visit, neuroimaging revealed pituitary stalk thickening in 29 cases (61.7%) and no apparent lesions in 18 cases (38.3%). All patients had negative tumor markers in both serum and CSF. All patients showed radiological progression after a median follow-up of 16 (10\u0026ndash;22) months. Ultimately, 24 cases (51.1%) were diagnosed based on positive tumor markers, 17 cases (36.2%) through biopsy, and 6 cases (12.8%) via diagnostic radiotherapy. Patients diagnosed through diagnostic radiotherapy had a significantly shorter median time from the initial visit to a definitive diagnosis than those diagnosed based on positive tumor markers and biopsy (6 months vs 18 months vs 18 months, p\u0026thinsp;=\u0026thinsp;0.013). Categorically, 44 cases (93.6%) were germinomas, and 3 cases (6.4%) were NGGCTs. The median time from the initial symptom to the first consultation and final diagnosis was 7 (4\u0026ndash;12) months and 24 (18\u0026ndash;32) months, respectively. Figure\u0026nbsp;3 shows dynamic neuroimaging changes in a patient with initially negative tumor markers and a thickened pituitary stalk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePredictive factors for delayed diagnosis\u003c/h2\u003e \u003cp\u003eA multivariate logistic regression analysis was conducted to investigate predictive factors for delayed diagnosis in patients with sellar GCTs. The final results revealed that polyuria/polydipsia (OR 5.46; 95% CI 2.33\u0026ndash;12.81), slow growth (OR 5.86; 95% CI 2.61\u0026ndash;13.14), amenorrhea (OR 6.82; 95% CI 2.68\u0026ndash;17.37), and germinoma (OR 4.99; 95% CI 1.08\u0026ndash;3.61) were predictive factors for delayed diagnosis, while older age of onset (OR 0.88; 95% CI 0.84\u0026ndash;0.94) and nausea/vomiting (OR 0.31; 95% CI 0.15\u0026ndash;0.63) contributed to earlier diagnosis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate logistic regression of the predictive factors for delayed diagnosis in patients with sellar GCTs.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolyuria/polydipsia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.33\u0026ndash;12.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSlow growth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.61\u0026ndash;13.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmenorrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.68\u0026ndash;17.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGerminoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.08\u0026ndash;3.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge onset(year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.84\u0026ndash;0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea/vomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.15\u0026ndash;0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: GCTs, germ cell tumor.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eBased on a large sample size, this study examined the clinical characteristics of delayed diagnosis and explored predictive factors for delayed diagnosis in patients with sellar GCTs. The results demonstrated that 64.4% of individuals experienced delayed diagnosis. Delayed diagnosis had no significant association with survival rates or tumor recurrence rates. However, individuals with delayed diagnosis had higher rates of CDI, CAI, CHT, CHG, and GHD. Slow growth, polyuria/polydipsia, amenorrhea, and germinoma were predictive factors for delayed diagnosis, while an older age of onset and nausea/vomiting contribute to early diagnosis.\u003c/p\u003e \u003cp\u003eDelayed diagnosis is common in patients with iGCTs, especially those in the sellar region. Sethi et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] found that patients with \"bifocal\" lesions had a delayed diagnosis rate of 55%, while those with isolated sellar lesions had a significantly higher delayed diagnosis rate of 82%. In our study, which included both isolated sellar lesions and \"bifocal\" lesions, the delayed diagnosis rate was 65.2%, closely aligning with previous research findings. The factors contributing to the delayed diagnosis of sellar GCTs are complex. They may be associated with a younger onset, insidious onset, the inherent complexity of the disease, and psychosocial factors. Sellar GCTs mainly present with endocrinological symptoms, especially polyuria/polydipsia, and slow growth. These symptoms often emerge early, have an insidious onset, progress slowly, and are particularly difficult to detect in children and adolescents. Due to these factors, patients and their families may not easily recognize the symptoms, resulting in a significant delay at the initial medical consultation. This study revealed that the duration of slow growth before the definitive diagnosis was the longest, lasting 24 months, followed by polyuria/polydipsia and amenorrhea, each lasting 12 months. These endocrinological symptoms, along with an earlier age of onset, were more prevalent in patients with delayed diagnosis. Furthermore, slow growth, polyuria/polydipsia, and amenorrhea are independent risk factors for delayed diagnosis, while increasing age is helpful for early diagnosis. Similar to our study, previous research demonstrated that endocrinological symptoms may contribute to delayed diagnosis in patients with iGCTs[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Additionally, in other pediatric intracranial tumors, a younger age at onset was associated with a higher likelihood of delayed diagnosis[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The above findings indicate that when patients present with endocrinological symptoms, especially in children and adolescents, it is crucial to promptly conduct neuroimaging examinations and tumor marker assessments for early diagnosis. On the contrary, when patients exhibited symptoms of mass effects, like headaches and nausea/vomiting, these manifestations were frequently more pronounced and severe, drawing significant attention from both patients and their families. This study also confirmed this phenomenon. iGCTs were diagnosed only 0.5 months following the first signs of headache and nausea/vomiting, with the latter symptom contributing to the early diagnosis.\u003c/p\u003e \u003cp\u003eConsistent with the study by Zhang et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], the present study also found that germinoma was an independent risk factor for delayed diagnosis in patients with sellar GCTs. This may be related to the complexity and clinical heterogeneity of the disease. Although a tiny number of patients with NGGCTs may have negative tumor markers, the majority typically exhibit varying degrees of tumor marker secretion, making diagnosis easier[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Similarly, germinomas with syncytiotrophoblastic giant cells may also secrete low levels of β-hCG, making the diagnosis relatively straightforward. Notably, among these patients, some have only CSF β-hCG positive, while serum β-hCG is negative. In the present study, among the 124 cases of germinomas with positive tumor markers, 40 cases (32.2%) showed elevated CSF β-hCG only. Previous studies also confirmed that levels of β-hCG in the CSF were generally higher than in the serum[\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. This suggests that both serum and CSF tumor markers should be recommended for screening in patients with suspected iGCTs when available. However, pure germinomas generally do not secrete β-hCG and AFP. Diagnosis can be challenging for these patients, especially when the lesions are too small to biopsy, potentially further prolonging the diagnostic timeline[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In this study, it was observed that 47 patients (13.6%) had negative tumor markers during the initial visit, and neuroimaging revealed either mild pituitary stalk thickening or an absence of apparent lesions. The median duration from the initial symptoms to the first visit for these individuals was 7 months. Subsequently, after a median follow-up of 16 months, the final diagnosis was established as sellar GCTs, significantly prolonging the diagnostic timeline. The majority of these patients (91.5%) were classified as germinomas.\u003c/p\u003e \u003cp\u003eA significant finding was that among these 47 patients who initially had negative tumor markers and small lesions, the median time from the first visit to a definitive diagnosis was significantly shorter for those diagnosed through diagnostic radiotherapy compared to those diagnosed through biopsy and positive tumor markers (6 months vs 18 months). This suggests that in patients highly suspected of having iGCTs, with negative tumor markers and lesions too small for biopsy, diagnostic radiotherapy may be a potential approach for early diagnosis. However, the following issues cannot be ignored. First, patients with smaller lesions were often in the disease's initial phases, simply displaying pituitary dysfunction symptoms without evident mass effects. These symptoms were significantly alleviated with appropriate hormone replacement therapy. In such cases, the parents of children and adolescents were reluctant to accept diagnostic radiotherapy, fearing potential irreversible adverse reactions. Secondly, in a complex medical environment, Physicians were cautious in using diagnostic radiotherapy without pathology or positive tumor markers. This caution stemmed from the fact that some patients suspected of having germinomas may not exhibit a significant reduction or any reduction in the tumor size after undergoing diagnostic radiotherapy. Ultimately, these patients received a pathological diagnosis of teratoma or other non-tumor conditions, such as Langerhans cell histiocytosis[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Although diagnostic radiotherapy facilitated early diagnosis, addressing the existing issues required improved biological, psychological, and social coordination.\u003c/p\u003e \u003cp\u003eSimilar to prior investigations, our findings showed no correlation between delayed diagnosis and survival or tumor recurrence rates[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, it cannot be denied that the follow-up period in the present study was relatively short, lasting only 18 months. In addition to survival and tumor recurrence rates, this study thoroughly evaluated the pituitary function in patients with sellar GCTs. The results indicated that patients with delayed diagnoses exhibited more significant pituitary dysfunction. Presently, the reason remains unclear, but it may be associated with a larger tumor size, prolonged compression of the pituitary and pituitary stalk, and severe ischemic necrosis observed in the delayed diagnosis group. Since pituitary dysfunction was a primary factor influencing patients' long-term quality of life, assessing pituitary function and appropriate hormone replacement therapy was crucial in managing sellar GCTs. This was particularly challenging, especially in addressing growth and developmental issues in pediatric patients[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study has several limitations. The estimation of symptom duration was susceptible to recall bias. Additionally, the median follow-up time in this study was only 18 months, potentially inadequately representing the actual survival and recurrence rates. Extending the follow-up period is necessary for a more comprehensive assessment. Furthermore, being a retrospective single-center study, the generalization of the results may be constrained. To enhance the validity of the findings, multi-center prospective studies are warranted for further verification.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDelayed diagnosis occurred in up to 65.2% of patients with sellar GCTs. Although delayed diagnosis did not impact the survival rate or tumor recurrence rate, patients with delayed diagnosis displayed a higher incidence of hypothalamic-pituitary-target axis dysfunction. Slow growth, polyuria/polydipsia, amenorrhea, and germinoma were predictive factors for delayed diagnosis, while an older age of onset and nausea/vomiting contribute to early diagnosis. Therefore, early recognition and attention to endocrinological symptoms are paramount in children and adolescents. For those with negative tumor markers and challenges in biopsy due to small lesions, dynamic follow-ups are essential to achieve early diagnosis and ultimately minimize unnecessary pituitary dysfunction.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u0026nbsp;\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003e\u003cem\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u0026nbsp;\u003c/strong\u003eThis study\u0026nbsp;protocol\u0026nbsp;was approved by the institutional review board of Beijing Tiantan Hospital, Capital Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u0026nbsp;\u003c/strong\u003eThe requirement for written informed consent from patients was waived owing to the retrospective study design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003eWe would like to thank all the participants of this study for their contribution to this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003eT. T. and L. Z. conceived the study, designed the study, and drafted the manuscript. T. T., H. C. and C. M. participated in the data collection and analyses. L.Z. conceived the study and participated in its design and coordination.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVillano JL, Virk IY, Ramirez V, Propp JM, Engelhard HH, McCarthy BJ (2010) Descriptive epidemiology of central nervous system germ cell tumors: nonpineal analysis. Neuro-oncology 12: 257-264 doi:10.1093/neuonc/nop029\u003c/li\u003e\n\u003cli\u003eMurray MJ, Bartels U, Nishikawa R, Fangusaro J, Matsutani M, Nicholson JC (2015) Consensus on the management of intracranial germ-cell tumours. 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Neuro-oncology 23: 295-303 doi:10.1093/neuonc/noaa199\u003c/li\u003e\n\u003cli\u003eFujimaki T, Mishima K, Asai A, Tabuchi K, Kobayashi M, Suzuki I, Kirino T (2000) Levels of beta-human chorionic gonadotropin in cerebrospinal fluid of patients with malignant germ cell tumor can be used to detect early recurrence and monitor the response to treatment. Japanese journal of clinical oncology 30: 291-294 doi:10.1093/jjco/hyd076\u003c/li\u003e\n\u003cli\u003eKong Z, Wang Y, Dai C, Yao Y, Ma W, Wang Y (2018) Central Nervous System Germ Cell Tumors: A Review of the Literature. Journal of child neurology 33: 610-620 doi:10.1177/0883073818772470\u003c/li\u003e\n\u003cli\u003eAllen J, Chacko J, Donahue B, Dhall G, Kretschmar C, Jakacki R, Holmes E, Pollack I (2012) Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatric blood \u0026amp; cancer 59: 1180-1182 doi:10.1002/pbc.24097\u003c/li\u003e\n\u003cli\u003eTong T, Zhong LY (2023) Intracranial germ cell tumors: a view of the endocrinologist. Journal of pediatric endocrinology \u0026amp; metabolism : JPEM 36: 1115-1127 doi:10.1515/jpem-2023-0368\u003c/li\u003e\n\u003cli\u003eKrooks J, Minkov M, Weatherall AG (2018) Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis. Journal of the American Academy of Dermatology 78: 1035-1044 doi:10.1016/j.jaad.2017.05.059\u003c/li\u003e\n\u003cli\u003eLeung AKC, Lam JM, Leong KF (2019) Childhood Langerhans cell histiocytosis: a disease with many faces. World journal of pediatrics : WJP 15: 536-545 doi:10.1007/s12519-019-00304-9\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Intracranial germ cell tumors, children and adolescents, delayed diagnosis, pituitary function, predictive factors","lastPublishedDoi":"10.21203/rs.3.rs-3910252/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3910252/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose \u003c/strong\u003eTo investigate the clinical characteristics and predictive factors associated with delayed diagnosis in patients with sellar germ cell tumors (GCTs), aiming for early diagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e A total of 345 patients with sellar GCTs were retrospectively collected. Patients were classified into a delayed diagnosis group (\u0026gt;6 months from onset to diagnosis) and a non-delayed diagnosis group (≤6 months). We compared general characteristics, clinical symptoms, diagnostic methods, treatment strategies, tumor prognosis, and pituitary function between the two groups. Predictive factors for delayed diagnosis were explored using multivariate logistic regression analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003e225 patients (65.2%) experienced delayed diagnosis. Although there was no association between delayed diagnosis and survival rates or tumor recurrence rates, the delayed diagnosis group had a higher incidence of central diabetes insipidus, central adrenal insufficiency, central hypothyroidism, central hypogonadism, and growth hormone deficiency. Moreover, polyuria/polydipsia (OR 5.46; 95% CI 2.33-12.81), slow growth (OR 5.86; 95% CI 2.61-13.14), amenorrhea (OR 6.82; 95% CI 2.68-17.37), and germinoma (OR 4.99; 95% CI 1.08-3.61) were predictive factors for delayed diagnosis, while older age of onset (OR 0.88; 95% CI 0.84-0.94) and nausea/vomiting (OR 0.31; 95% CI 0.15-0.63) contributed to earlier diagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eIn patients with sellar GCTs, delayed diagnosis is common and linked to increased pituitary dysfunction. Factors predicting delayed diagnosis include slow growth, polyuria /polydipsia, amenorrhea, and germinomas with negative tumor markers. Early diagnosis is crucial to minimize the impact of sellar GCTs on pituitary function.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics and predictive factors of delayed diagnosis in patients with sellar germ cell tumors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-01 16:01:30","doi":"10.21203/rs.3.rs-3910252/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-02-15T22:23:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-07T19:30:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"43353f1e-c56f-49b6-b1d3-6c384cb1c925","date":"2024-01-31T20:20:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-30T15:36:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-30T14:38:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-30T14:38:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2024-01-30T10:06:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"029ab327-486f-40e9-ac55-af6da0092ba6","owner":[],"postedDate":"February 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-11T15:06:42+00:00","versionOfRecord":{"articleIdentity":"rs-3910252","link":"https://doi.org/10.1007/s11060-024-04626-1","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2024-03-04 15:00:58","publishedOnDateReadable":"March 4th, 2024"},"versionCreatedAt":"2024-02-01 16:01:30","video":"","vorDoi":"10.1007/s11060-024-04626-1","vorDoiUrl":"https://doi.org/10.1007/s11060-024-04626-1","workflowStages":[]},"version":"v1","identity":"rs-3910252","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3910252","identity":"rs-3910252","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}