Incidental 68Ga-DOTATATE uptake in thyroid nodules: Is guideline-directed management still appropriate?

BACKGROUND: Fluorodeoxyglucose uptake on positron emission tomography imaging has been shown to be an independent risk factor for malignancy in thyroid nodules. More recently, a new positron emission tomography radiotracer-Gallium-68 DOTATATE-has gained popularity as a sensitive method to detect neuroendocrine tumors. With greater availability of this imaging, incidental Gallium-68 DOTATATE uptake in the thyroid gland has increased. It is unclear whether current guideline-directed management of thyroid nodules remains appropriate in those that are Gallium-68 DOTATATE avid. METHODS: We retrospectively reviewed Gallium-68 DOTATATE positron emission tomography scans performed at our institution from 2012 to 2022. Patients with incidental focal Gallium-68 DOTATATE uptake in the thyroid gland were included. Fine needle aspiration biopsies were characterized via the Bethesda System for Reporting Thyroid Cytopathology. Bethesda III/IV nodules underwent molecular testing (ThyroSeq v3), and malignancy risk ≥50% was considered positive. RESULTS: In total, 1,176 Gallium-68 DOTATATE PET scans were reviewed across 837 unique patients. Fifty-three (6.3%) patients demonstrated focal Gallium-68 DOTATATE thyroid uptake. Nine patients were imaged for known medullary thyroid cancer. Forty-four patients had incidental radiotracer uptake in the thyroid and were included in our study. Patients included in the study were predominantly female sex (75%), with an average age of 62.9 ± 13.9 years and a maximum standardized uptake value in the thyroid of 7.3 ± 5.3. Frequent indications for imaging included neuroendocrine tumors of the small bowel (n = 17), lung (n = 8), and pancreas (n = 7). Thirty-three patients underwent subsequent thyroid ultrasound. Sonographic findings warranted biopsy in 24 patients, of which 3 were lost to follow-up. Cytopathology and molecular testing results are as follows: 12 Bethesda II (57.1%), 6 Bethesda III/ThyroSeq-negative (28.6%), 1 Bethesda III/ThyroSeq-positive (4.8%), 2 Bethesda V/VI (9.5%). Four nodules were resected, revealing 2 papillary thyroid cancers, 1 neoplasm with papillary-like nuclear features, and 1 follicular adenoma. There was no difference in maximum standardized uptake value between benign and malignant nodules (7.0 ± 4.6 vs 13.1 ± 5.7, P = .106). Overall, the malignancy rate among patients with sonography and appropriate follow-up was 6.7% (2/30). Among patients with cyto- or histopathology, the malignancy rate was 9.5% (2/21). There were no incidental cases of medullary thyroid cancer. CONCLUSION: The malignancy rate among thyroid nodules with incidental Gallium-68 DOTATATE uptake is comparable to rates reported among thyroid nodules in the general population. Guideline-directed management of thyroid nodules remains appropriate in those with incidental Gallium-68 DOTATATE uptake.

Clinicopathological characteristics of gastric neuroendocrine neoplasms: A comprehensive analysis.

OBJECTIVE: This study aimed to explore the clinicopathological characteristics and prognostic implications of gastric neuroendocrine neoplasms (g-NENs). METHODS: A retrospective enrollment of 142 patients diagnosed with g-NENs was conducted at Zhejiang Cancer Hospital between January 1, 2007 and December 31, 2021. The study compared essential clinicopathological features and survival rates. Additionally, the prognosis of gastric neuroendocrine carcinomas/mixed neuroendocrine-non-neuroendocrine neoplasms (g-NEC/MiNEN) were contrasted with those of gastric adenocarcinoma (GAC) and signet ring cell carcinoma (SRCC). RESULTS: The study comprised a total of 142 g-NENs cases, with a male-to-female ratio of approximately 2:1. The 5-year survival rates for g-NEC and g-MiNEN were 26.7% and 35.2%, respectively. Corresponding 5-year survival rates for G1 and G2 were observed at 100% and 80.0%, respectively. g-NEC/MiNEN showed a significantly worse prognosis compared to g-NET (p < 0.001). g-NEC/MiNEN exhibited a poor prognosis compared to GAC (p < 0.001), and within poorly differentiated GAC, g-NEC/MiNEN demonstrated a worse prognosis (p = 0.007). Additionally, patients receiving postoperative adjuvant therapy exhibited notably prolonged overall survival (OS) in the case of g-NEC/MiNEN (p = 0.010). CONCLUSION: In short, the prognosis of g-NEC/MiNEN was worse than that of g-NET, GAC and poorly differentiated GAC, but this group benefit from postoperative adjuvant therapy.

Treatment of poorly differentiated neuroendocrine carcinomas of rectum and anus with chemoradiotherapy: a single-centre evaluation.

PURPOSE: Poorly differentiated neuroendocrine carcinoma (PDNEC) of the rectum and anus is a rare disease exhibiting aggressive biological behaviour, even if diagnosed early. Currently, there are no agreed standard treatment approaches and management of locally advanced (LA) and metastatic PDNEC usually follows treatments used in pulmonary neuroendocrine carcinomas because of the similarities with small cell lung cancer. The role of surgery in PDNEC is still debated and the benefit of chemoradiotherapy (CRT) is unknown. This report summarises the experiences of CRT application in anorectal PDNEC in a single Danish institution. METHODS: All patients with PDNEC treated with concomitant CRT between May 2019 and January 2021 at a University hospital in Denmark were evaluated. Demographics, treatment and survival outcomes were collected and analysed. RESULTS: Six patients were identified. Five patients received radiotherapy with 50.4 Gy/28 fractions, and four were eligible for curative resection after the CRT. Distant metastasis was observed in four patients at diagnosis. Two patients with synchronous liver metastases were treated with RFA, and one received a liver resection. The treatment was well tolerated with limited side effects. The median follow-up time was 17 months (range 10-36 months), and the median duration of response was 11.2 months (range 8.1 to 24.2 months). One patient achieved a complete response. CONCLUSION: A multimodal treatment approach with CRT in advanced stages of PDNEC in a highly selected patient group is well tolerated and with a high chance of achieving local control and, combined with surgery, even complete response in a single case.

Single-Cell Transcriptome Analysis of Small Cell Neuroendocrine Carcinoma of the Endometrium Reveals ISL1 as a Potential Biomarker for Diagnosis and Treatment.

BACKGROUND: As a dedifferentiated tumor, small cell endometrial neuroendocrine tumors (NETs) are rare and frequently diagnosed at an advanced stage with a poor prognosis. Current treatment recommendations are often extrapolated from histologically similar tumors in other sites or based on retrospective studies. The exploration for diagnostic and therapeutic markers in small cell NETs is of great significance. METHODS: In this study, we conducted single-cell RNA sequencing on a specimen obtained from a patient diagnosed with small cell endometrial neuroendocrine carcinoma (SCNEC) based on pathology. We revealed the cell map and intratumoral heterogeneity of the cancer cells through data analysis. Further, we validated the function of ISL LIM Homeobox 1 (ISL1) in vitro in an established neuroendocrine cell line. Finally, we examined the association between ISL1 and tumor staging in small cell lung cancer (SCLC) patient samples. RESULTS: We observed the significant upregulation of ISL1 expression in tumor cells that showed high expression of the neuroepithelial markers. Additionally, in vitro cell function experiments demonstrated that the high ISL1 expression group exhibited markedly higher cell proliferation and migration abilities compared to the low expression group. Finally, we showed that the expression level of ISL1 was correlated with SCLC stages. CONCLUSIONS: ISL1 protein in NETs shows promise as a potential biomarker for diagnosis and treatment.

Colorectal neuroendocrine carcinoma and mixed neuroendocrine-non-neuroendocrine neoplasm: Prognostic factors and PD-L1 expression.

Colorectal neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) are rare malignancies with unclear boundaries and poor prognoses. Our study aimed to conduct a comparative analysis of these diseases, identify prognostic factors, and explore potential therapeutic targets. We collected and analyzed clinicopathological data of NEC and MiNEN in our hospital from 2011 to 2020. Immunohistochemical staining for PD-L1, BRAF V600E, and mismatch repair proteins was performed. We identified 14 NEC and 7 MiNEN cases. Demographic data, including median overall survival (17.1 months for NEC and 18.5 months for MiNEN), did not significantly differ. NEC showed a higher tendency to occur in the rectum and sigmoid colon (p = 0.025) and had fewer cases with metastatic adenocarcinoma components in lymph nodes (p = 0.009) compared to MiNEN. Adverse prognostic factors were age ≥70 years (p = 0.012), N2 nodal status (p = 0.032), and stage IV disease (p = 0.013) based on multivariate Cox regression analysis. We identified five PD-L1 positive cases, two BRAF V600E mutated cases, and one Lynch syndrome case with MSH2 and MSH6 loss. Patients with colorectal NEC or MiNEN exhibited poor survival rates. Adverse prognostic factors included older age, N2 nodal status, and distant metastasis. Potential therapeutic avenues such as immune checkpoint and BRAF inhibitors were suggested for patients with these carcinomas.

Gastroenteropancreatic neuroendocrine carcinoma in children and adolescents: a population-based study.

PURPOSE: Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC) in children is an exceptionally rare and aggressive form of cancer. We aimed to conduct a population-based cohort study to predict overall survival (OS) in pediatric patients with GEP-NEC. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was employed to identify all pediatric patients with GEP-NEC diagnosed between 2000 and 2019. To create survival curves based on various criteria, Kaplane-Meier estimations were utilized. The log-rank test was used to compare survival curves. The variables associated with OS were determined using Cox proportional-hazards regression. Furthermore, we developed a nomogram to predict overall survival in pediatric GEP-NEC patients. RESULTS: A total of 103 pediatric GEP-NEC patients were identified. The tumors primarily affected females (62.2%). The majority of GEP-NEC was found in the appendix (63.1%), followed by the pancreas (23.3%) and the intestinal tract (13.6%). The highest rates of localized stage (76.9%) and surgery (98.5%) were found in the NEC of appendix origin. However, pancreatic origins had the largest proportion of distant disease (66.7%) but the lowest percentage of surgery (37.5%). Overall 1-year, 3-year, and 5-year survival rates for all patients were 94.4%, 85.4%, and 85.4%, respectively. Tumors of pancreatic origin had the worst survival compared with those of the appendix and intestinal tract. The Cox proportional hazard regression revealed that only site was an important independent predictor of survival. CONCLUSIONS: Our study revealed that only the primary site was found to be the most important predictor of the OS in pediatric GEP-NEC. It's important to work closely with a multidisciplinary team, including oncologists, surgeons, and other specialists, to determine the most appropriate treatment plan for pediatric GEP-NEC.

[A case of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) diagnosed by re-biopsy of the enlarged primary tumor during chemotherapy for gastric adenocarcinoma].

Gastric mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) is an extremely rare form of gastric neoplasm, and its prognosis is often poor. This is a case report wherein the primary site increased during chemotherapy against gastric adenocarcinoma and was diagnosed with gastric MiNEN after total gastrectomy. A 71-year-old man was diagnosed with gastric adenocarcinoma complicated with liver and para-aortic lymph node metastasis. Chemotherapy with S-1, oxaliplatin, and trastuzumab was initiated. Although the size of metastatic lesions was reduced after six courses of treatment, a part of the primary site of gastric tumor rapidly. Pathological rebiopsy of the primary site suggested a neuroendocrine carcinoma, and he was finally diagnosed with gastric MiNEN after total gastrectomy. Thus, second-line chemotherapy was then initiated showing good response. We herein report a case of MiNEN with a rare diagnostic process.

Prognostic model for survival in patients with neuroendocrine carcinomas of the cervix: SEER database analysis and a single-center retrospective study.

OBJECTIVE: Neuroendocrine carcinoma of the cervix (NECC) is extremely rare in clinical practice. This study aimed to methodologically analyze the clinicopathological factors associated with NECC patients and to develop a validated survival prediction model. METHODS: A total of 535 patients diagnosed with NECC between 2004 and 2016 were identified from the Surveillance, Epidemiology and End Results (SEER) database, while 122 patients diagnosed with NECC at Yunnan Cancer Hospital (YCH) from 2006 to 2019 were also recruited. Patients from the SEER database were divided into a training cohort (n = 376) and a validation cohort (n = 159) in a 7:3 ratio for the construction and internal validation of the nomogram. External validation was performed in a cohort at YCH. The Kaplan-Meier method was used for survival analysis, the Log-rank method test was used for univariate analysis of prognostic influences, and the Cox regression model was used for multivariate analysis. RESULTS: The 3-year and 5-year overall survival (OS) rates for patients with NECC in SEER were 43.6% and 39.7%, respectively. In the training cohort, multivariate analysis showed independent prognostic factors for NECC patients including race, tumor size, distant metastasis, stage, and chemotherapy (p<0.05). For extended application in other cohorts, a nomogram including four factors without race was subsequently created. The consistency index (C-index) of the nomogram predicting survival was 0.736, which was well-validated in the validation cohorts (0.746 for the internal validation cohort and 0.765 for the external validation cohort). In both the training and validation cohorts, the 3-year survival rates predicted by the nomogram were comparable to the actual ones. We then succeeded in dividing patients with NECC into high- and low-risk groups concerning OS using the nomogram we developed. Besides, univariate analysis showed that chemotherapy ≥4 cycles may improve the OS of patients at YCH with NECC. CONCLUSION: We successfully constructed a nomogram that precisely predicts the OS for patients with NECC based on the SEER database and a large single-center retrospective cohort. The visualized and practical model can distinguish high-risk patients for recurrence and death who may benefit from clinical trials of boost therapy effectively. We also found that patients who received more than 4 cycles of chemotherapy acquired survival benefits than those who received less than 4 cycles.

Diagnosis and management of neuroendocrine prostate cancer.

BACKGROUND: Although most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration-resistant disease invariably develops. Progression to treatment-emergent neuroendocrine PC (t-NEPC) represents a unique mechanism of resistance to androgen receptor (AR)-targeted therapy in which lineage plasticity and neuroendocrine differentiation induce a phenotypic switch from an AR-driven adenocarcinoma to an AR-independent NEPC. t-NEPC is characterized by an aggressive clinical course, increased resistance to AR-targeted therapies, and a poor overall prognosis. METHODS: This review provides an overview of our current knowledge of NEPC, with a focus on the unmet needs, diagnosis, and clinical management of t-NEPC. RESULTS: Evidence extrapolated from the literature on small cell lung cancer or data from metastatic castration-resistant PC (mCRPC) cohorts enriched for t-NEPC suggests an increased sensitivity to platinum-based chemotherapy. However, optimal strategies for managing t-NEPC have not been established, and prospective clinical trial data are limited. Intertumoral heterogeneity within a given patient, as well as the lack of robust molecular or clinical biomarkers for early detection, often lead to delays in diagnosis and prolonged treatment with suboptimal strategies (i.e., conventional chemohormonal therapies for mCRPC), which may further contribute to poor outcomes. CONCLUSIONS: Recent advances in genomic and molecular classification of NEPC and the development of novel biomarkers may facilitate an early diagnosis, help to identify promising therapeutic targets, and improve the selection of patients most likely to benefit from NEPC-targeted therapies.

Epidemiology and survival outcomes of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinoma.

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasms are a rare subtype of neuroendocrine neoplasm consisting of ≥30% each of neuroendocrine and non-neuroendocrine differentiation. Neuroendocrine carcinomas are poorly differentiated neuroendocrine tumors. The epidemiology and prognosis of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas are not clearly defined in the literature. We sought to examine the presentation, patterns of care, and outcomes of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. METHODS: We identified patients diagnosed with stage I-III colorectal (excluding appendix) mixed neuroendocrine-non-neuroendocrine neoplasms or neuroendocrine carcinomas with only one-lifetime cancer diagnosis who underwent surgical resection between 2010 and 2018 from the National Cancer Database. We performed bidirectional selection to identify variables to include in a multivariable Cox proportional hazards model. RESULTS: We identified 189 patients with a diagnosis of stage I to III colorectal mixed neuroendocrine-non-neuroendocrine neoplasms, 66% of whom had poorly differentiated tumors and 482 with neuroendocrine carcinomas. Among patients with stage III disease, 68% of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and 54% of patients with neuroendocrine carcinomas received adjuvant chemotherapy. The median survival for the overall patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas cohorts were 38 and 42 months, respectively (P = .22), and the median survival for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas with stage III disease were 30 and 25 months, respectively (P = .27). In multivariable analysis, fewer number of positive nodes and receipt of adjuvant chemotherapy were independently associated with decreased risk of mortality for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. CONCLUSION: Adjuvant chemotherapy is associated with improved survival in stage III mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. Future studies are warranted to identify subsets of patients benefiting most from adjuvant therapy.

Diagnostic Challenges and Long-term Outcomes of Neuroendocrine Carcinoma of the Cervix: A Case Series.

Neuroendocrine carcinomas (NECs) of the cervix are rare, aggressive malignancies that are challenging to diagnose and treat. They are high-grade lesions that often share features with poorly differentiated adenocarcinoma and squamous cell carcinoma. NECs are classified into large-cell or small-cell subtypes but can often have a mixed appearance or occur concurrently with a squamous or adenocarcinoma. Diagnosis is dependent on tissue sampling, histomorphology, and immunohistochemistry. Eight cases of NEC were retrieved from the Department of Pathology at our institution from 2008 to 2022. Tumor slides were reviewed and evaluated by 2 independent pathologists. Seven of 8 patients tested positive for neuroendocrine markers, including CD56, synaptophysin, and chromogranin. We discuss the diagnostic challenges, review the histopathology, and describe the treatment courses and clinical outcomes. This case series reveals that traditional markers, such as p16, p63, and p40, may be focally positive in NEC and should not be considered a confirmation of squamous cell carcinoma. Patient outcomes can be affected by delays in diagnosis, misdiagnosis, and inadequate treatment when NEC is not considered in the initial differential diagnosis.

Case series of ovarian neuroendocrine carcinoma: overview of clinicopathological features.

BACKGROUND: Ovarian neuroendocrine carcinoma (O-NEC) is a relatively uncommon neoplasm, and the current knowledge regarding its diagnosis and management is limited. In this series, our objective was to provide an overview of the clinicopathological characteristics of the disease by analyzing clinical case data to establish a theoretical foundation for the diagnosis and management of O-NEC. CASE PRESENTATION: We included three patients in the present case series, all of whom were diagnosed with primary O-NEC based on pathomorphological observation and immunohistochemistry. Patient 1 was a 62-year-old patient diagnosed with small cell carcinoma (SCC) of the pulmonary type. Post-surgery, the patient was diagnosed with stage II SCC of the ovary and underwent standardized chemotherapy; however, imaging examinations conducted at the 16-month follow-up revealed the existence of lymph node metastasis. Unfortunately, she passed away 21 months after the surgery. The other two patients were diagnosed with carcinoid tumors, one at age 39 and the other at age 71. Post-surgery, patient 2 was diagnosed with a carcinoid in the left ovary, whereas patient 3 was diagnosed with a carcinoid in her right ovary based on clinical evaluation. Neither of the cases received adjuvant therapy following surgery; however, they have both survived for 9 and 10 years, respectively, as of date. CONCLUSION: Primary O-NECs are rare and of diverse histological types, each of which has its own unique biological features and prognosis. SCC is a neoplasm characterized by high malignancy and a poor prognosis, whereas carcinoid tumors are of lesser malignancy and have a more favorable prognosis.

Population-Based Survival Analysis of Stage IVB Small-Cell Neuroendocrine Carcinoma in Comparison to Major Histological Subtypes of Cervical Cancer.

The aim of the current study is to investigate the survival outcome of stage IVB SCNEC of the uterine cervix in comparison to major histological subtypes of cervical cancer. A population-based retrospective cohort study was conducted using the Osaka Cancer Registry data from 1994 to 2018. All FIGO 2009 stage IVB cervical cancer patients who displayed squamous cell carcinoma (SCC), adenocarcinoma (A), adenosquamous cell carcinoma (AS), or small-cell neuroendocrine carcinoma (SCNEC) were first identified. The patients were classified into groups according to the types of primary treatment. Then, their survival rates were examined using the Kaplan-Meier method. Overall, in a total of 1158 patients, clearly differential survival rates were observed according to the histological subtypes, and SCNEC was associated with shortest survival. When examined according to the types of primary treatments, SCNEC was associated with significantly decreased survival when compared to SCC or A/AS, except for those treated with surgery. In patients with FIGO 2009 stage IVB cervical cancer, SCNEC was associated with decreased survival when compared to SCC or A/AS. Although current treatments with either surgery, chemotherapy or radiotherapy have some therapeutic efficacies, to improve the prognosis, novel effective treatments specifically targeting cervical SCNEC need to be developed.

Role of radiotherapy in the management of rare gynaecological cancers.

There are a large number of gynaecological cancers with rare histologies, for which the available data are limited and usually retrospective. Because of their rarity and poor prognosis, the management of these cancers must be centralized in expert centres, for both histological diagnosis and treatment. With the exception of sarcomas, most endometrial or cervical cancers with rare histologies respond to the same radiation treatment modalities than cancers with more common histologies, although there are some specificities regarding treatments such as neuroendocrine carcinomas (chemotherapy with platinum and etoposide, major role of surgery). For localized or locally advanced ovarian cancer, external beam radiotherapy has a role in the management of hypercalcaemic small cell carcinoma of the ovary. This article summarizes the current role of external beam radiotherapy and brachytherapy in the management of cancers of the uterine cervix, uterine corpus and ovaries, with rare or very rare histologies, and with localized or locally advanced stages.

Clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas.

Objective: We examined the clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas (NECs) to offer additional guidance for the clinical treatment of small-cell lung cancer (SCLC), which is a type of advanced intrapulmonary NEC (IPNECs). Materials and Methods: The clinical data and survival of 123 patients with advanced IPNECs and extrapulmonary NECs (EPNECs) were obtained. We retrospectively examined the corresponding clinical diagnosis and treatment and investigated the significant factors influencing the survival prognosis of patients with NECs. Results: There were 90 cases of IPNECs (including 81 cases of SCLC), and 33 cases of EPNECs. The median overall survival (OS) of IPNECs was significantly longer than that of the EPNECs in the gastrointestinal tract and in the other regions (P < 0.05). The median OS of patients with other IPNECs was longer than that of patients with SCLC (P > 0.05). Multivariate analysis demonstrated that age, liver metastasis, number of cycles of first-line chemotherapy, and chest radiotherapy were risk factors influencing OS in patients with NECs (P < 0.05). Conclusions: The survival of IPNECs was significantly longer than that of EPNECs in the gastrointestinal tract and other regions. Nevertheless, patients with advanced NECs who were older and had liver metastases had a poorer prognosis. Multidisciplinary treatments including multicycle chemotherapy and a combination of chemotherapy and radiotherapy should function significantly in extending the survival of NECs.

The novel prognostic nomograms for predicting cancer-specific survival and overall survival in mixed medullary and follicular cell carcinoma: A SEER-based study.

BACKGROUND: The aim of this study was to evaluate independent predictors of prognosis in patients with mixed medullary and follicular cell carcinoma (MMFCC) and to establish the novel prognostic nomograms in the academic community for 3-, 5-, and 10 year CSS and OS in patients with MMFCC. METHODS: Demographic information, clinicopathological characteristics, treatment information, and survival status information of 200 patients with MMFCC and 6615 patients with medullary thyroid carcinoma (MTC) from 2000 to 2020 in the SEER database were retrospectively analyzed. Independent predictors of prognosis in MMFCC patients were derived using univariate and multivariate Cox regression analyses after relevant comparisons based on pathologic typing. On this basis, we developed and validated clinical prognostic nomograms and risk-stratified the patient population. RESULTS: In this study, the clinical information of 200 patients with MMFCC was compared with that of 5947 patients with MTC (NOS) and 668 patients with MTC with amyloid stroma, and there was a significant difference in the relevant variables among the three, with the CSS being 88.5%, 87.5%, and 90.9%, and the OS being 76.5%, 75.4%, and 83.8%. Univariate and multivariate Cox regression analyses yielded that age at diagnosis, presence of distant metastases, thyroidectomy scope, and lymph node dissection status were significantly correlated with the prognosis of patients (P < 0.05), and were independent predictors of CSS and OS for patients with MMFCC, and the Kaplan-Meier survival curves plotted by these factors demonstrated their predictive power for the prognosis of patients with MMFCC. The concordance index of the prognostic nomograms of CSS and OS established on this basis was 0.838 and 0.794, respectively, and the time-dependent area under curve, calibration curve, and decision curve analysis curve showed that the model had good discriminative ability, accuracy, and clinical applicability. CONCLUSIONS: In this study, we concluded that there are large differences between MMFCC and MTC in terms of demographic information, clinicopathological characteristics, treatment information, and survival status information, and we constructed the novel prognostic nomograms for 3-, 5-, and 10 year CSS and OS for patients with MMFCC with risk stratification, which will help clinicians to develop individualized protocols for their postoperative treatments and follow-ups.

Exploring the molecular features and genetic prognostic factors of pulmonary high-grade neuroendocrine carcinomas.

Molecular research on large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) has progressed significantly. However, there are still fewer molecular markers related to prognostic/therapeutic strategies for these conditions compared to those for adenocarcinoma. We therefore investigated the molecular characteristics of neuroendocrine carcinomas (NECs). We enrolled patients surgically diagnosed with NECs between 2011 and 2019, with complete follow-up records. All were analyzed using whole exome sequencing and p53/Rb immunohistochemistry (IHC). A total of 92 cases, comprising 45 pure SCLC, 15 combined SCLC, 27 pure LCNEC, and 5 combined LCNEC, were included. TP53 (78.3%) and RB1 (34.8%) were the most common molecular alterations, followed by KMT2D, LRP1B, FAT3, NCOR2, SPTA1, and NOTCH1. The mutation frequency for EGFR was 10.9%. Sixteen patients with LCNEC who had TP53/RB1 co-alterations were SCLC-like, while the remaining were NSCLC-like. There was no statistically significant difference between the groups regarding overall survival (OS; p = 0.458) and progression-free survival (PFS; p = 0.157). The frequency of the loss of Rb expression by IHC in SCLC-like LCNEC was 100%. Significant pathway alterations unique to SCLC included Notch and AMPK, while HIF-1 was enriched exclusively in LCNEC. NCOR2 mutation was linked to worse OS (p = 0.029) and PFS (p = 0.015), while wild-type SPTA1 was associated with poor PFS (p = 0.018). IHC for Rb was reliable for predicting LCNEC molecular subtypes, indicating its clinical value. NCOR2 and SPTA1 alterations were identified as prognostic factors that may provide therapeutic targets for patients with NEC.