Neuroendocrine Tumors Research Articles

Clinical and Genomic Landscape of Neuroendocrine Prostate Cancer (NEC) vs. Prostate Adenocarcinoma (AdenoK)

Clinical and Genomic Landscape of Neuroendocrine Prostate Cancer (NEC) vs. Prostate Adenocarcinoma (AdenoK)

Epigenetic regulation of p63 blocks squamous-to-neuroendocrine transdifferentiation in esophageal development and malignancy.

While cell fate determination and maintenance are important in establishing and preserving tissue identity and function during development, aberrant cell fate transition leads to cancer cell heterogeneity and resistance to treatment. Here, we report an unexpected role for the transcription factor p63 (Trp63/TP63) in the fate choice of the squamous versus neuroendocrine lineage in esophageal development and malignancy. Deletion of p63 results in extensive neuroendocrine differentiation in the developing mouse esophagus and esophageal progenitors derived from human embryonic stem cells. In human esophageal neuroendocrine carcinoma (eNEC) cells, p63 is transcriptionally silenced by EZH2-mediated H3K27 trimethylation (H3K27me3). Up-regulation of the major p63 isoform ΔNp63α, through either ectopic expression or EZH2 inhibition, promotes squamous transdifferentiation of eNEC cells. Together, these findings uncover p63 as a rheostat in coordinating the transition between squamous and neuroendocrine cell fates during esophageal development and tumor progression.

Changes in WHO classification of adrenal tumors and new ideas for multi-dimensional diagnosis and treatment

In 2022, WHO updated the classification and concept of adrenal cortical and medullary tumors. In terms of adrenal cortical tumors, the WHO classification further standardizes the nomenclature of nodular adrenal cortical disease and refines the pathological classification of primary aldosteronism. In terms of adrenal medullary tumors, the WHO classification unifies the concepts of pheochromocytoma and paraganglioma, and reclassifies various concepts, including paraganglioma-like neuroendocrine tumors. The new standards not only cover the clinical manifestations of the disease, but also include other multiple aspects such as the histological origin of the disease, immunohistochemical manifestations, physiological mechanisms of the disease, hereditary susceptibility and prognostic factors. This article intends to explore how to improve the diagnostic and therapeutic level of adrenal tumors.

Fluorescence detection of pituitary neuroendocrine tumour during endoscopic transsphenoidal surgery using bevacizumab-800CW: a non-randomised, non-blinded, single centre feasibility and dose finding trial [DEPARTURE trial

Achieving endocrine remission by gross total resection is challenging in pituitary neuroendocrine tumours (PitNETs) with cavernous sinus invasion. This study aims to assess the safety, feasibility, and optimal dose for intraoperative fluorescence imaging as an added instrument to discriminate PitNET from surrounding tissue using bevacizumab-800CW, targeting vascular endothelial growth factor A (VEGF-A). In part I, dose-escalation (0-4∙5-10-25mg) was performed in 4 groups of 3 patients with PitNETs Knosp grade 3-4. In part II, after interim analysis, the 10mg and 25mg groups were expanded to a total of 6 patients. Quantitative fluoroscence molecular endoscopy consisted of wide field fluorescence molecular endoscopy and multi-diameter single fiber reflectance / single fiber fluorescence spectroscopy. Mean fluorescence intensity (MFI) of the fresh surgical specimen was calculated and VEGF-staining was performed. Eighteen patients were included. All doses were well tolerated. Three serious adverse events were registered, but none were tracer-related. Part I showed an adequate in-vivo tumour-to-background ratio for both 10mg (TBR 2∙00 [1∙86, 2∙19]) and 25mg (TBR 2∙10, [1∙86, 2∙58]). Part II revealed a substantially higher MFI in the 25mg group. With both 10mg and 25mg a statistically significant difference between tumour and surrounding tissue was detected (p < 0∙0001). All surgical specimens had VEGF-A expression. This study demonstrates the safety and feasibility of quantitative fluorescence molecular endoscopy during PitNET surgery. Both 10mg and 25mg bevacizumab-800CW result in clear differentiation in-vivo, with improved contrast ex-vivo (MFI) in the 25mg group. NCT04212793 / Study Details| Detection of PitNET Tissue During TSS Using Bevacizumab800CW| ClinicalTrials.gov.

ESR Essentials: role of PET/CT in neuroendocrine tumors-practice recommendations by the European Society for Hybrid, Molecular and Translational Imaging.

Neuroendocrine neoplasms (NEN) originate from the secretory cells of the neuroendocrine system, with the majority arising in the gastrointestinal tract and pancreas. Given the heterogeneity in the biological behavior and morphological differentiation of these tumors, advanced imaging techniques are crucial for supporting the suspected diagnosis, accurate staging, and monitoring therapy. As most well-differentiated NEN demonstrate overexpression of somatostatin receptors (SSR) on the cell surface, SSR-directed PET/CT is considered the reference standard for imaging of this particular entity. SSR-PET/CT should be the imaging method of choice in every NEN G1 or G2 and considered for re-staging after both potentially curative and non-curative surgeries. The extent of SSR expression is also crucial for determining a patient's eligibility for peptide receptor radionuclide therapy (PRRT). PRRT utilizes [177Lu]Lu-DOTA-TATE to target the SSR receptor and can significantly prolong progression-free survival in patients with advanced, progressive neuroendocrine tumor of the gastroenteropancreatic system (GEP-NET). PET/CT is a central component of the multidisciplinary management of NEN. Variable follow-up intervals are recommended, considering that tumors with higher proliferation rates or advanced metastatic disease require more frequent assessments. The combination with other imaging modalities, like MRI, complements SSR-PET/CT, further enhancing overall diagnostic accuracy. KEY POINTS: Somatostatin receptor-PET/CT (SSR-PET/CT) is the guideline-recommended reference standard for imaging well-differentiated neuroendocrine tumors (NET). SSR-PET/CT should be the diagnostic imaging of choice for staging and post-therapy re-staging of grade 1 or 2 NET (G1 or G2). Variable follow-up intervals are recommended for NET G1 and G2. Tumors with higher proliferation rates or advanced metastatic disease necessitate more frequent assessments.

Focal Pancreatitis Mimicking Neuroendocrine Tumor on DOTATATE PET/CT With Radiology-Pathology Correlation.

A 54-year-old man presented with left lower quadrant pain. CT showed no cause for his pain but identified an incidental 2.0-cm enhancing lesion in the pancreatic tail. On MRI, this lesion was hyperenhancing and diffusion-restricting, suspicious for a neuroendocrine tumor. However, EUS-guided biopsy yielded only benign pancreatic tissue. Due to this discordance, 64 Cu-DOTATATE PET/CT was performed. The pancreatic tail lesion was tracer-avid, suggesting a well-differentiated neuroendocrine tumor. Based on the PET findings, the patient underwent distal pancreatectomy. Surgical pathology revealed only focal chronic pancreatitis with islet aggregation, a previously undescribed mimic of neuroendocrine tumor on DOTATATE PET/CT.

ASCL1 restrains ERK1/2 to promote survival of a subset of neuroendocrine lung cancers.

The transcription factor achaete-scute complex homolog 1 (ASCL1) is a lineage oncogene that is central in growth and survival of the majority of small cell lung cancers (SCLC) and neuroendocrine non-small cell lung cancers (NSCLC-NE) that express it. Targeting ASCL1, or its downstream pathways, remains a challenge. SCLCs and NSCLC-NE that express ASCL1 exhibit relatively low ERK1/2 activity, in dramatic contrast to NSCLCs in which the ERK pathway has a major role in pathogenesis. ERK1/2 inhibition in ASCL1-expressing lung tumor cells revealed down-regulation of ERK1/2 pathway suppressors SPRY4, SPRED1, DUSP6, and the transcription factor ETV5, which regulates DUSP6. CHIP-seq demonstrated that these genes are bound by ASCL1. Availability of a pharmacological inhibitor directed mechanistic studies towards DUSP6, an ERK1/2-selective phosphatase, in a subset of ASCL1-high NE lung tumors. Inhibition of DUSP6 increased active ERK1/2, which accumulated in the nucleus. Pharmacologic and genetic inhibition of DUSP6 reduced proliferation and survival of these cancers. Resistance developed in DUSP6 KO cells, indicating a bypass mechanism. Although targeting ASCL1 remains a challenge, our findings suggest that expression of ASCL1, DUSP6 and low phospho-ERK1/2 identify neuroendocrine lung cancers for which DUSP6 may be a therapeutic target.

High-Grade Progression, Sarcomatous Transformation, and/or Metastasis of Pituitary Neuroendocrine Neoplasms (PitNENs): The UCSF Experience.

Pituitary neuroendocrine tumors (PitNET) that metastasize comprise ~ 0.2% of adenohypophyseal tumors are aggressive and are challenging to treat. However, many non-metastatic tumors are also aggressive. Herein, we review 21 specimens from 13 patients at UCSF with metastatic PitNETs (CSF or systemic, N = 7 patients), high-grade pituitary neuroendocrine neoplasms (HG-PitNEN, N = 4 patients), and/or PitNETs with sarcomatous transformation (PitNET-ST, N = 5 patients). We subtyped cases using the World Health Organization (WHO) and International Agency for Research on Cancer (IARC) criteria for neuroendocrine neoplasms (NENs). Lineage subtypes included acidophil stem cell, null cell, thyrotroph, corticotroph, lactotroph, and gonadotroph tumors. The median Ki-67 labeling index was 25% (range 5-70%). Lack of p16 was seen in 3 cases, with overexpression in 2. Strong diffuse p53 immunopositivity was present in 3 specimens from 2 patients. Loss of Rb expression was seen in 2 cases, with ATRX loss in one. Molecular analysis in 4 tumors variably revealed TERT alterations, homozygous CDKN2A deletion, aneuploidy, and mutations in PTEN, TP53, PDGFRB, and/or PIK3CA. Eight patients (62%) died of disease, 4 were alive at the last follow-up, and 1 was lost to the follow-up. All primary tumors had worrisome features, including aggressive lineage subtype, high mitotic count, and/or high Ki-67 indices. Additional evidence of high-grade progression included immunohistochemical loss of neuroendocrine, transcription factor, and/or hormone markers. We conclude that metastatic PitNET is not the only high-grade form of pituitary NEN. If further confirmed, these histopathologic and/or molecular features could provide advanced warning of biological aggressiveness and be applied towards a future grading scheme.

Cancer of the paranasal sinuses in Germany: Data on incidence and survival from a population-based cancer registry

PurposeThis study aims to provide a broad overview of the epidemiology of cancer of the paranasal sinuses (PSC) in Germany. The data include information on incidence, staging, clinicopathological features and survival from one of the largest cancer registries in Europe. MethodsPopulation-based data on PSC diagnosed from January 1st, 2009 until December 31st, 2019 were retrieved from the German Centre for Cancer Registry Data (ZfKD). Age standardized incidence was calculated and relative survival estimates were computed by sex, histological subtype, age group and T-, N-, and M-Stage. ResultsIn total, 3975 cases were included in this study. The age-adjusted incidence rate (ASR) for PSC was 0.3/100,000 which remained stable during the observation period. The most frequent tumor localization was the maxillary sinus (41.9 %) and the most common histological subtype was keratinizing squamous cell carcinoma (kSCC) (44.3 %). All subtypes were predominantly found in the maxillary sinus except for adenocarcinoma and neuroendocrine carcinomas (SNEC), which were most frequently located in the ethmoidal sinus. The majority of the patients with a known T stage was diagnosed in tumor stage T4 (60.8 %). The overall 5-year relative survival (RS) for all patients with PSC was 52 %. RS dropped from 93 % for T1 stage tumors to 39 % for T4 tumors. RS was 58 % for N0 and 31 % for N+ cases, 54 % for M0 and 27 % for M1 cases. ConclusionAge-adjusted incidence for PSC is low and has been stable for the observed 11-year period. RS decreases continuously with increasing T-, N- and M-stage.

Short-term outcome of endoscopic submucosal dissection using a clutch cutter for subepithelial lesions within the esophagogastric submucosa: a Japanese prospective observational study.

The efficacy and safety of endoscopic submucosal dissection using a clutch cutter (ESD-CC) for subepithelial lesions within the esophagogastric submucosa (SELEGSM) has not been investigated. This study aimed to assess the efficacy and safety of ESD-CC for the treatment of SELEGSM. This prospective study included 15 consecutive patients with 18 SELEGSMs diagnosed by endoscopic ultrasonography. The primary outcomes were short-term outcomes including en bloc resection rate, R0 resection rate, procedure time, and complication rate. The secondary outcome was final histological diagnosis. Among the participants, 18 lesions were identified: 12 in the stomach (nine patients) and six in the esophagus (six patients). The en bloc resection rate was 94.4% (17/18). The R0 resection rate was 88.9% (16/18). The median operating time was 39 min, and no instances of perforation or bleeding were observed. The final diagnoses of SELEGSM included six neuroendocrine tumors (33.3%), six granular cell tumors (33.3%), two ectopic pancreases (11.1%), one inflammatory fibroid polyp (5.6%), one leiomyoma (5.6%), one lipoma (5.6%), and one leiomyosarcoma (5.6%). ESD-CC appears to be a technically efficient and safe approach for SELEGSM resection, suggesting its potential as a valuable treatment option.

Preoperative Glycosylated Hemoglobin A1C Impacts Long-Term Outcomes Following Curative-Intent Resection of Nonfunctional Gastroenteropancreatic Neuroendocrine Tumors.

To investigate the impact of preoperative glycosylated hemoglobin A1C (HbA1c) among patients following curative-intent resection of nonfunctional gastroentropancreatic neuroendocrine tumors (GEP-NETs). Patients who underwent curative-intent resection for GEP-NETs from 2000 to 2020 were identified from the US Neuroendocrine Tumor Study Group (US-NETSG). Preoperative blood HbA1c levels were defined as high HbA1c (≥ 6.5%) versus low HbA1c group (< 6.5%). Impact of HbA1c level on postoperative short-term and long-term overall (OS) were investigated. A total of 130 patients with HbA1c < 6.5% and 60 patients with HbA1c ≥ 6.5% were included. Patients with HbA1c ≥ 6.5% had higher proportion of comorbidities, such as hypertension, obesity, anemia, and lower preoperative albumin levels versus patients with HbA1c < 6.5% (all p < 0.05). In addition, high level of preoperative HbA1c was associated with increased incidence of wound and infectious complications, as well as decreased long-term OS (median OS: high Hb1Ac 89.8 months vs. low Hb1Ac not reached, HR 3.487, p = 0.004) among patients with nonfunctional GEP-NETs, as well as among the subset of pancreatic NET patients (median OS: high Hb1Ac 74.3 months vs. low Hb1Ac not reached, p = 0.004), and patients with normal fasting blood glucose (< 140 mg/dL) (median OS: high Hb1Ac 75.4 months vs. low Hb1Ac not reached, p = 0.001). Hb1Ac might have value as a screening tool to identify high-risk patients following surgical resection of nonfunctional GEP-NETs for consideration of more strict postoperative surveillance and treatment of elevated Hb1Ac level.

Characteristics and Management of Children with Appendiceal Neuroendocrine Neoplasms: A Single-Center Study.

Appendiceal neuroendocrine neoplasms (ANENs) are usually found incidentally during histology examination after appendectomy for appendicitis. Due to their rarity in pediatric populations, there is no consensus on treatment or follow-up. The analysis of patients with ANENs of our and other studies will increase the understanding of this tumor. Pediatric patients with ANENs were uniformly managed at our center between 1998 and 2023. Patients' presenting symptoms, surgery, tumor histology, post-surgical work-up, follow-up and outcome were analyzed. Our report describes 17 patients with a diagnosis of ANEN after appendectomy. The median age was 14 years (range of 4-17 years). Tumors were located at the tip of the appendix in 58.8% of cases and only one had a diameter >1 cm. All were well-differentiated tumors with free resection margins. The submucosa was invaded in five cases, muscularis propria in eight and subserosa in four. Post-appendectomy work-up included tumor marker measurement, abdominal ultrasound and computed tomography or magnetic resonance imaging, chest X-ray and octreotide scintigraphy. No residual tumors or metastases were detected. Additional surgery was not necessary. Follow-up was carried out for a median duration of 6 years (range of 1-10 years). Only one patient was lost to follow-up and all other patients are alive without tumor recurrence. The tumor characteristics of our patients confirmed data from the literature. With the lack of a sufficient number of large prospective trials, it is important to add more information to confirm the benign nature and excellent outcome of this tumor, even without additional surgery. Consensus guidelines are needed for ANENs in pediatric populations.

68Ga-DOTATATE Uptake in Pancreatic Ductal Adenocarcinoma.

We present a case of pancreatic ductal adenocarcinoma showing increased 68Ga-DOTATATE uptake mimicking neuroendocrine tumor on PET/CT. Immunohistochemical analyses of the resected tumor showed the tumor cells were negative for somatostatin receptor subtype 2. The nonneoplastic islets scattered throughout the tumor were positive for somatostatin receptor subtype 2, which may be responsible for the increased 68Ga-DOTATATE uptake. This case indicates that pancreatic ductal adenocarcinoma should be included in the differential diagnosis of the pancreatic lesions showing increased 68Ga-DOTATATE uptake.

To Perform, or Not to Perform Interim PET: Questioning the Impact of Midtherapy Evaluation During PRRT in GEP-NET Patients.

This study aimed to analyze the impact of interim evaluation on the continuation of 177Lu-based peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to survey its usage across German university hospitals. In 119 GEP-NET patients who underwent PRRT, we retrospectively assessed the results and therapeutic impact of restaging performed after 2 cycles using MRI/CT/somatostatin receptor imaging. Therapeutic decisions based on interim PET results were made in multidisciplinary tumor board meetings. Additionally, an online survey was conducted among 37 German university hospitals regarding their interim evaluation practices, focusing on the change in management. Of 119 patients, 83 completed 4 PRRT cycles; 36 stopped after 2: 27 showed PD, 3 had PR leading to surgery, 5 experienced toxicity, and 1 died. Those completing 4 cycles showed a median PFS of 38.0 months (95% confidence interval, 32.2-43.8). Seventeen of 37 surveyed hospitals routinely used interim evaluation. In a survey among 37 German university hospitals, 62% reported offering PRRT for GEP-NET patients, with 74% of these performing a routinely interim evaluation after 2 cycles of PRRT, primarily using PET/CT imaging techniques. Interim PET after 2 PRRT cycles helps to identify early progression in GEP-NET patients. Standardizing interim evaluation practices could enhance the comparability of clinical outcomes and optimize patient management.

Rapid Evolution of Metastases in Patients with Treated G3 Neuroendocrine Tumors Associated with NEC-Like Transformation and TP53 Mutation.

Little is known about the morphomolecular features of G3 neuroendocrine tumors (G3NETs) under prolonged systemic treatments, although rapid progression is increasingly observed. This longitudinal study aims to elucidate the course and morphomolecular features of metastasized G3NETs with high-grade transformation. Clinical and histological findings in 40 patients with metastasized and treated G3NETs, which were histologically examined at least twice with an interval time of more than 6 months (median 27), were reviewed and the morphomolecular changes recorded and assigned to treatment. Neuroendocrine carcinoma (NEC)-like histology defined by high-grade atypia, diffuse growth pattern, and/or necrosis was identified in nine (22%) G3NETs (seven pancreatic, two rectal) patients. All NEC-like tumors showed a significantly higher Ki67 increase and longer interval time betweenfirst and last examination than non-NEC-like G3NETs (53 vs. 19% and 60 vs. 24 months, respectively). Moreover, all NEC-like G3NETs had TP53 (100%), but rarely RB1 (12%) mutations, and retained NET-typical mutations such as MEN1 or DAXX (five of the pancreatic NETs). The last treatments received prior to the NEC-like transformation included PRRT (n = 3), somatostatin analog, everolimus, sunitinib (n = 1 each), and alkylating agents (n = 2). Abrupt clinical progression in patients with metastasized G3NETs is associated with a significant increase in Ki67, accelerated growth, and NEC-like histology. These findings are most likely attributable to the novel TP53 mutation, which was detected in all nine cases at the last evaluation. However, none of the cases exhibited a complete transformation to a typical NEC, as the tumors retained partial histological and genetic features of NETs.

Surgical microwave ablation of 397 neuroendocrine liver metastases: a retrospective cohort analysis of 16 years of experience.

Neuroendocrine tumors (NET) constitute a heterogeneous group of malignancies whose incidence has been on the rise over the past two decades, currently documented at 5.25 per 100,000. Liver metastasis develops in over 60% of NET patients. Even after resection recurrence rates are high, underscoring the importance of parenchymal-sparing interventions. In this study, we conducted 105 surgical microwave ablations and examined outcomes related to survival and local recurrence. Retrospective review of patients who underwent a surgical microwave ablation (MWA) at a single-center, high-volume institution from September 2007 through December 2022 using a prospective database. Primary outcome was overall survival. A total of 105 operations were performed on 94 patients, with 397 tumors undergoing MWA. Median tumor size was 1.3cm (range 0.3-8.0), and the median number of tumors ablated was 2 (range 1-12). Laparoscopic approach was utilized 69.5% of the time. The most common concomitant procedure performed was hepatectomy (33.3%) and cholecystectomy (23.8%). Clavien-Dindo grade III or IV complications occurred in 9 patients (9.6%). Mortality within 30days occurred in 1 patient (1.1%). The rate of incomplete ablation was 0.3% per tumor. Local recurrence occurred in 2.8% of tumors. Median OS was 9.43years [95% CI 4.23-14.63years], with a 5- and 10-year survival probability of 70.2% and 48.2%, respectively. Surgical MWA offers an efficacious, parenchymal-sparing treatment of hepatic metastasis of NET, with low rates of incomplete ablation and local recurrence per tumor.

Endoscopic ultrasound‐guided tissue acquisition allows a reliable proliferation assessment of small (≤20 mm) pancreatic neuroendocrine tumors

Endoscopic ultrasound‐guided tissue acquisition allows a reliable proliferation assessment of small (≤20 mm) pancreatic neuroendocrine tumors

TTF-1 is a highly sensitive but not fully specific marker for pulmonary and thyroidal cancer: a tissue microarray study evaluating more than 17,000 tumors from 152 different tumor entities.

Thyroid transcription factor 1 (TTF-1) immunohistochemistry (IHC) is routinely used for the distinction of primary pulmonary adenocarcinomas. However, TTF-1 can also occur in other malignancies. A tissue microarray containing 17,772 samples from 152 different tumor types was analyzed. Napsin-A, CK20, SATB2, FABP1, and Villin-1 IHC data were available from previous studies. TTF-1 staining was seen in 82 of 152 tumor categories including thyroidal cancers (19-100%), adenocarcinomas (94%), neuroendocrine tumors (67%) of the lung, small cell neuroendocrine carcinomas (71-80%), mesenchymal tumors (up to 42%), and thymomas (39%). Comparative analysis of TTF-1 and Napsin-A revealed a sensitivity/specificity of 94%/86% (TTF-1), 87%/98% (Napsin-A), and 85%/99.1% (TTF-1 and Napsin-A) for the distinction of pulmonary adenocarcinomas. Combined analysis of TTF-1 and enteric markers revealed a positivity for TTF-1 and at least one enteric marker in 22% of pulmonary adenocarcinomas but also a TTF-1 positivity in 6% of colorectal, 2% of pancreatic, and 3% of gastric adenocarcinomas. TTF-1 is a marker of high sensitivity but insufficient specificity for pulmonary adenocarcinomas. A small fraction of TTF-1-positive gastrointestinal adenocarcinomas represents a pitfall mimicking enteric-type pulmonary adenocarcinoma. Combined analysis of TTF-1 and Napsin-A improves the specificity of pulmonary adenocarcinoma diagnosis.

Challenges in Managing Insulinomas and Hyperparathyroidism in MEN1: A Clinical Case Study

Pancreatic insulinoma is an uncommon neuroendocrine tumor with an incidence of approximately 1 per million people annually. While the majority of insulinomas are sporadic, a minority are associated with Multiple Endocrine Neoplasia type 1 (MEN1), a rare genetic disorder transmitted in an autosomal dominant pattern. MEN1 is characterized by the presence of hyperplastic or adenomatous parathyroid glands, pancreatic islet cell tumors, and pituitary tumors. The disorder can also involve lesions in the duodenum, adrenal glands, thymus, and bronchi. We report a case of MEN1 presenting with multiple insulinomas in a 37-year-old male, who exhibited symptoms of intermittent hypoglycemia over a decade. Diagnostic workup included biochemical assays , and imaging studies that revealed elevated insulin and C-peptide levels and hypervascular pancreatic lesions, , and pathological findings consistent with MEN1. Surgical intervention involved the enucleation of insulinomas and distal pancreatectomy, followed by removal of parathyroid adenomas. The postoperative evolution was marked by the resolution of hypoglycemic episodes and the persistence of primary hyperparathyroidism. This case underscores the complexity of diagnosing and managing insulinomas within the context of MEN1. It highlights the importance of a multidisciplinary approach to treatment and the need for ongoing surveillance to address both endocrine manifestations and psychological impacts. The findings advocate for comprehensive management strategies and support systems to improve patient outcomes and quality of life.

HER2 amplification and PD-L1 expression in invasive stratified mucin-producing carcinoma of the cervix: a clinicopathological analysis of eighteen cases

Objective: To investigate the clinicopathological features, prognosis and the expression of HER2 and PD-L1 in invasive stratified mucin-producing carcinoma of the cervix (ISMC). Methods: The clinicopathological data of 18 ISMC cases with radical resection of the cervix diagnosed in the Daping Hospital, Army Medical University from January 2018 to December 2023 were collected and retrospectively analyzed. PD-L1 and HER2 immunohistochemical staining and HER2 FISH were conducted. Results: The patient ages ranged from 31 to 72 years, with an average of 45 years. Approximately 8% of cervical adenocarcinoma cases in our hospital during the same period. Eleven cases were pure ISMC, and 7 cases were mixed-type ISMC, with the component of squamous cell carcinoma or usual-type adenocarcinoma. One case showed concurrent small cell neuroendocrine carcinoma (SCNEC). Three cases were diagnosed through biopsy (3/18). Five cases were of Silva pattern B and 13 cases of Silva pattern C. Three cases showed regional lymph node metastasis. Thirteen patients were disease-free at the end of the follow-up, while the ISMC patient with concurrent SCNEC developed distant metastasis. Fifteen cases (15/18) had PD-L1 expression with CPS≥1, and 7 cases (7/18) had PD-L1 TPS≥1%. One case of HER2 3+ and one case of HER2 2+ were both positive for FISH amplification; two cases HER2 1+, 14 cases HER2 0. Conclusions: Cervical ISMC is rare, has a wide spectrum of morphology, and can coexist with other types of cervical cancer. PD-L1 is positive in most of the ISMC cases, while HER2 is amplified or lowly expressed in a small portion of them. Thus, it is possible to treat ISMC patients with therapies targeting PD-L1 and therapy targeting HER2.