Metastatic Neuroendocrine Tumors Research Articles

Breast metastasis from large cell neuroendocrine carcinoma of the lung: a case report

Abstract Background Primary breast carcinoma is far more common than breast metastases. Common breast metastases usually come from lymphoma, leukemia, melanoma, and ovarian cancers. Breast metastases from neuroendocrine carcinomas are considered an exceeding rare entity. It has been reported in the literature that the pathological presentation of this particular metastatic tumor is very challenging as it shares many morphological characteristics with primary breast carcinoma. Case presentation We report a case of a patient with large cell neuroendocrine carcinoma of the lung metastasizes to both breasts. The patient was initially presented with brain metastasis of unknown origin. Further radiological imaging workup showed multiple bilateral breast masses and bilateral lymphadenopathy, which raised concern for secondary lymphoma of the breast. The histopathology of this case was challenging, particularly when triple negative invasive ductal carcinoma diagnosis had been made. Multidisciplinary meetings between medical oncologists, radiologists, and pathologists profoundly helped confirming the diagnosis of metastatic large cell neuroendocrine tumor to the breast. Conclusion Large cell neuroendocrine carcinoma of the lung is a relatively uncommon diagnosis with generally poor prognosis. Large cell neuroendocrine carcinoma that metastasizes to the breast is even scarcer. Correlation between clinical assessment, radiological imaging, and pathological evaluation is the key in making such an unusual and complex diagnosis. Additionally, radiologists should be aware of metastatic presentations of the breast and avoid confusion with mimicking benign entities or primary breast carcinomas.

Distinctive grade based on Ki67 index and immune microenvironment of metastatic pancreatic neuroendocrine tumors responding to capecitabine plus temozolomide

BackgroundKi67 index changes during the treatment of metastatic pancreatic neuroendocrine tumor (PanNET) treatment. The study aimed to detect alterations of grade based on Ki67 index and immune microenvironment in PanNET responding to capecitabine/temozolomide (CapTem).MethodRetrospective data of patients with PanNET were collected. In control group, 35 patients underwent surgery immediately after biopsy. In CapTem group, 38 patients received CapTem after biopsy and responded well to treatment (defined as either stable disease or partial response), and subsequently underwent surgery. All patients have pathological Ki67 index at biopsy and after surgery. CD163 + CD68 + CD206 + M2 macrophages, CD68 + CD86 + CD80 + M1 macrophages, CD11b + CD33 + myeloid-derived suppressor cells, and CD4 + CD25 + regulatory T cells were stained using multiplex immunofluorescence.ResultsIn control group, the paired grade based on Ki67 index directly after surgery showed no upgrade or downgrade compared to biopsy. In patients who responded well to CapTem, the grade based on Ki67 index before and after CapTem was altered. Thirteen patients had upgraded Ki67 index and 11 patients had downgraded. The proportion of stable disease was higher in the upgraded group compared to downgraded group (p = 0.0155). And upgraded group had a significantly shorter mPFS than patients in the downgrade group (8.5 months vs. 20 months, HR 4.834, 95% CI 1.414 to 16.53, p = 0.012). M1 macrophages was significantly lower in the downgraded group than in the Ki67 upgraded group (p < 0.001).ConclusionGrade based on Ki67 index and immune environment change in PanNET patients responding well to CapTem. Patients with downgraded had longer mPFS compared to those with upgraded. It is necessary to reassess the Ki67 index after CapTem treatment, even in patients responding well to CapTem.

Efficacy of standard methods in the treatment of prolactin-secreting pituitary carcinoma

Pituitary carcinoma (metastatic neuroendocrine tumor of the pituitary gland) is the pituitary tumor with confirmed craniospinal and/or systemic metastases. These tumors are extremely rare accounting for only 0.1% to 0.5% of all pituitary tumours and are characterized by high mortality. In the presented case, pituitary carcinoma with intracranial metastasis was diagnosed in a young patient 25 years after manifestation of an aggressive recurrent prolactin-secreting pituitary tumor. Standard therapy (removal of metastasis, radiation therapy, cabergoline therapy) resulted in a long-term remission of the disease.

Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy.

This study evaluated the prognostic value of basal and interim [68Ga]Ga-DOTA-TOC PET/CT in patients with locally advanced or metastatic neuroendocrine tumour (NET) who received peptide receptor radionuclide therapy (PRRT). Patients with NET who received PRRT with [177Lu]Lu-DOTA-TATE at our institution were retrospectively reviewed. Among them, patients who underwent both basal and interim (after two cycles of PRRT) [68Ga]Ga-DOTA-TOC PET/CT were included. Alongside clinicopathologic parameters, PET parameters of maximum standardised uptake value (SUVmax), tumour-to-liver ratio (TLR), whole tumour volume (WTV) and total receptor expression (TRE: WTV multiplied by mean standardised uptake value) were obtained from basal and interim [68Ga]Ga-DOTA-TOC PET/CT, and their proportional changes (∆) were assessed for associations with progression-free survival (PFS) using Kaplan-Meier analysis, log-rank tests, and a Cox proportional-hazards regression model. Twenty-four patients were finally included (10 men and 14 women, median age of 56.5 years, age range 32-74 years). Among them, 16 patients (66.7%) experienced disease progression. In univariate analysis, high ∆WTV (≥ -10%, hazard ratio [HR] = 3.053 [1.003-9.289], p = 0.049) and high ∆TRE (≥ -21%, HR = 3.567 [1.144-11.122], p = 0.028) were significantly associated with shorter PFS. In multivariate analyses adjusted for WHO grade, high ∆WTV (HR = 3.345 [1.055-10.601], p = 0.043) and high ∆TRE (HR = 3.894 [1.194-12.695], p = 0.024) were significant predictors of shorter PFS. The study demonstrates that basal and interim [68Ga]Ga-DOTA-TOC PET/CT scans, through proportional changes in WTV and TRE, effectively predict PFS in neuroendocrine tumour patients receiving PRRT. Question Peptide receptor radionuclide therapy is utilised for patients with somatostatin receptor-positive well-differentiated neuroendocrine tumours; however, prognostic predictors are not well established. Findings Progression-free survival was significantly associated with the proportional change in whole tumour volume and total receptor expression between basal and interim [68Ga]Ga-DOTA-TOC PET/CT. Clinical relevance Interim [68Ga]Ga-DOTA-TOC PET/CT can serve as a valuable imaging method to predict prognosis of peptide receptor radionuclide therapy.

Treatment indicators and prognostic factors in colorectal neuroendocrine neoplasms and adenocarcinoma with neuroendocrine differentiation: a single center retrospective study.

This study compared survival and metastasis occurrence between colorectal neuroendocrine neoplasms (cNEN) and colorectal adenocarcinoma with neuroendocrine differentiation (cNED) and further explored their prognostic factors and treatment indicators. Patients diagnosed as cNEN and cNED in West China Hospital from January 2009 to December 2020 were enrolled. The diagnosis and metastasis rates were calculated. Univariate and multivariate Cox analyses were conducted for progression-free survival (PFS) in cNEN surgical patients, and generalized linear regression was used for metastatic disease. The study enrolled 435 patients, including 257 neuroendocrine tumors (NET), 52 neuroendocrine carcinomas (NEC), 29 mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), and 97 NED patients, of whom 202 received local resection, and 233 received radical resection. Metastasis rates were higher in MiNEN and NEC groups compared to other groups (NED: 28.9%, MiNEN: 58.6%, NEC: 65.4%, NET: 8.6%, p < 0.001). The liver is the main metastatic site in cNEN, whereas cNED metastasized to various sites. For NEC and MiNEN patients, colon location (p = 0.002) and T stage > 2 (p = 0.040) were associated with disease progression separately. Independent risk factors for metastatic NET included tumor grade G2/G3 (p < 0.001), colon location (p = 0.001), size ≥ 1cm (p = 0.005), and CK20 partial positive (p < 0.001). cNEN show high metastatic capacity and are challenging to diagnose. More aggressive treatment and follow-up strategies are necessary for those patients. NET tumor grade higher than G2, size larger than 1cm, or located in the colon should be managed with radical surgery.

68Ga-DOTATATE and 18F-FDG PET/CT in a Rapidly Progressing Lymphoma.

68Ga-DOTATATE PET/CT targeting somatostatin receptors is commonly utilized in the imaging of neuroendocrine tumors. However, other malignancies such as lymphomas (both Hodgkin and non-Hodgkin) also have expression of somatostatin receptors, albeit to a lesser degree compared with the neuroendocrine tumors, and thus can be positive on a 68Ga-DOTATATE PET/CT. We describe an atypical presentation of an aggressive large B-cell lymphoma mimicking a metastatic neuroendocrine tumor at initial presentation with high somatostatin receptor expression demonstrated on the 68Ga-DOTATATE PET/CT and a rapidly progressing course on the subsequent 18F-FDG PET/CT.

7117 Cushings Conundrum: Taming The Hormone Hurricane

Abstract Disclosure: S. Syed: None. A. Poloju: None. A. Krueger: None. C. O'connor: None. Ectopic ACTH syndrome is a rare disease that presents with severe hypercortisolism that can be challenging to treat. This case reviews a patient with high- grade metastatic neuroendocrine tumor causing ectopic ACTH-related Cushing's syndrome and describes navigating these treatment challenges with an evidence-based and patient centered strategy to try to optimize care.Clinical case: This 32-year-old male, with a history of metastatic pancreatic neuroendocrine tumor and liver metastases, initially presented with dyspnea, hyperglycemia, and metabolic derangements. Agitated, with a systolic blood pressure of 190mm Hg, he exhibited notable hypokalemia (2.5mmol/L), hyperglycemia (508mg/dL), and elevated beta-hydroxybutyrate (3.60mmol/L). Random cortisol was 85.9ug/dL and ACTH 472pg/ml. Urgent cortisol control prompted etomidate infusion, lowering cortisol to 27ug/dL in 24 hours. Ketoconazole was initiated but discontinued later due to rising liver enzymes, Metyrapone and spironolactone were initiated and etomidate infusion titrated off. Hemorrhagic shock, DKA, and mental status changes complicated his course.Interventional radiology-guided hepatic artery embolization was performed. Post-procedure cortisol levels improved, metyrapone and spironolactone were stopped. Dexamethasone was initiated given concern for relative adrenal insufficiency during this time and was later switched to hydrocortisone, and eventually discontinued with normalizing cortisol levels. Octreotide and later lanreotide maintained stability for a year. He was readmitted with uncontrolled diabetes, hypertension, and vertebral compression fractures, requiring rapid control with etomidate infusion again. Metyrapone was reintroduced, facilitating etomidate tapering. Spironolactone was re-initiated. Bilateral adrenalectomy was discussed as definitive treatment for the ectopic ACTH syndrome (neuroendocrine cancer was deemed incurable, however he was considered elevated risk for surgery given other co-morbidities. Even with normalization of cortisol, he intermittently refused cares/medications. Conclusion: Managing ACTH-producing neuroendocrine tumors necessitates a multidisciplinary approach. In severe Cushing’s syndrome, etomidate infusion quickly normalizes cortisol but requires intensive care due to sedation risks. Ketoconazole and levoketoconazole carry a hepatotoxicity risk. Metyrapone and mitotane are alternatives but supply challenges exist. Osilodrostat, studied for short-term use, has limited data in ectopic ACTH syndromes. Bilateral adrenalectomy is an option if surgical risks are acceptable. Patient history influences therapeutic decisions, highlighting the need for a patient-centered approach. Presentation: 6/3/2024

6799 RZ358 Therapy. A Novel Approach to Hyperinsulinemia in Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. W. Madeleine: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

9286 RZ358 Therapy. A Novel Approach To Hyperinsulinemia In Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. M. Welsh: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

6799 RZ358 Therapy. A Novel Approach To Hyperinsulinemia In Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. W. Madeleine: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

9286 RZ358 Therapy. A Novel Approach to Hyperinsulinemia in Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. M. Welsh: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

6419 Cushing’s Syndrome due to Metastatic Pancreatic Neuroendocrine Neoplasm With Incidental Pituitary Microadenoma

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. R. Jain: None. N. El Asmar: None. Introduction: Pancreatic neuroendocrine neoplasms (PNENs) are rare with a reported incidence of 1-2/100,000. While the majority are non-functional, insulinomas and gastrinomas are the most common functional PNENs. Our case of ACTH-producing PNENs is extremely rare. Case presentation: A previously healthy 47-year-old female was hospitalized for worsening dyspnea. Her symptoms included rapid weight gain, skin hyperpigmentation, and lower extremity edema. Her exam was notable for elevated blood pressure of 181/120 mmHg, moon facies, purple abdominal striae, and proximal myopathy. Her lab analysis showed a cortisol level of 42 mcg/dL (6.2-19.4), ACTH of 254 pg/ml (7.2-63), DHEA sulfate of 171 mcg/dl (41-243), HbA1C 7%, K of 3 mmol/l and 24H urine cortisol &amp;gt;2100 mcg/24hrs. A post low-dose DST cortisol level was 42.7 mcg/dl. CT chest demonstrated an ill-defined hypodense lesion in the region of the pancreatic head. MRI abdomen revealed a 3 x 2.3 x 2.3 cm mass in the pancreatic head and many small enhancing lesions within the right lobe of the liver. Adrenal glands appeared normal. Subsequent PET CT scan with GA 68 DOTOTATE showed increased uptake in the pancreatic head mass and in the right hepatic lobe. Her pituitary MRI revealed a right pituitary gland 6 mm hypointense lesion, possibly a microadenoma. A high dose DST resulted in a cortisol level of 80 mcg/dl mostly consistent with ectopic ACTH secretion. EUS-guided biopsy of the pancreatic mass showed a well-differentiated neuroendocrine tumor that stained positive for ACTH, chromogranin, synaptophysin, and CD56. Treatment with Ketoconazole 600mg q6h and Octreotide 50mg q6h was started 3 days before surgery to control acute hypercortisolism as she developed acute psychosis. The patient subsequently underwent a Whipple procedure with successful resection of the pancreatic mass. Post-op, her ACTH levels dropped to 19 pg/ml with a cortisol level of 6 mcg/dl. Final pathology showed a well-differentiated grade 3 neuroendocrine tumor with a KI-67 labeling index greater than 20%. After surgery, the patient received a short course of stress dose hydrocortisone which was tapered off over the following 2 months. The patient is being followed for planning further intervention given the aggressive grade of the tumor and hepatic metastases. Conclusion: Ectopic ACTH-producing PNENs are rare. An accurate and timely diagnosis, while challenging, is key. Patients usually present with rapidly progressing symptoms that could cause life-threatening complications such as thrombosis and sepsis. We demonstrated the importance of utilizing a multidisciplinary team approach and starting cortisol-lowering medications early given the complexity of the disease, requiring rapid intervention and lifelong follow-up. Presentation: 6/3/2024

6409 Successful Treatment Of Severe Ectopic ACTH-dependent Cushing’s Syndrome With Osilodrostat

Abstract Disclosure: K.A. Lee: None. C. Mendes Pessoa: None. W. Huang: Consulting Fee; Self; WH, Honoraria from Consulting and Speaking received from Recordati Rare Disease. Background: Cushing’s syndrome due to ectopic ACTH secretion is rare and may progress rapidly, making treatment very challenging. Previous case reports have described therapeutic options including adrenal steroidogenesis inhibitors, bilateral adrenalectomy (BAL), and adrenal embolization with success. Clinical Case: A 27-year-old woman with metastatic neuroendocrine tumor presented with sudden onset and rapidly progressing symptoms of fatigue, muscle weakness, acne and weight gain within two weeks. Laboratory findings confirmed severe Cushing’s syndrome due to ectopic ACTH secretion: AM cortisol 173.4 µg/dL (5-25), ACTH 1425 pg/mL (7.2-63.3), 24 hour urine cortisol 29,498 mcg/24hr (4-50), DHEA-Sulfate 1314 µg/dL (65 - 380), and testosterone 133 ng/dL (0-100). She was also found to have severe hypokalemia, hypocalcemia and hyperglycemia (despite an HbA1C of 6.2 at 2 weeks before presentation). CT- scan showed diffuse thickening of the bilateral adrenal glands. Due to widely metastatic disease in the peritoneum, BAL was considered non-feasible. The patient was admitted to hospital and initiated on osilodrostat at 20mg twice daily (after correction of hypokalemia) with close monitoring of her electrolytes, cortisol, EKG and steroid withdrawal symptoms. There was a rapid improvement of cortisol levels in response to osilodrostat. During treatment, she developed steroid withdrawal symptoms for which she was started on medium dose hydrocortisone. Bilateral adrenal arterial embolization was attempted but ultimately needed to be converted to right only adrenal gland embolization due to a hypertensive urgency and difficulty with catheterization. Her symptoms of Cushing’s syndrome significantly improved with the treatment. During her hospitalization, her hypokalemia was managed with spironolactone and potassium supplement, hypocalcemia with calcium supplement, and hyperglycemia with basal and bolus insulins. With significant improvement of cortisol levels, her hypocalcemia and hyperglycemia resolved and required no further treatment. Her potassium levels normalized and spironolactone was stopped. She remains on potassium supplement to keep K level at upper half of normal range to avoid long QTc. After discharge, her morning cortisol levels (before morning dose of hydrocortisone) continued to decrease and her osilodrostat dose was gradually tapered to 5mg once daily at night. Hydrocortisone was continued as part of the block-and-replace regimen. Conclusion: This case described a unique sudden onset and rapid progression of ectopic ACTH dependent Cushing’s syndrome and successful utilization of a block-and-replace approach by using the steroidogenesis inhibitor osilodrostat in prompt control of the hypercortisolism and related comorbidities. We also explored the feasibility of adrenal embolization for definitive management in the context of unfeasible BAL. Presentation: 6/2/2024

Cardiac Neuroendocrine Tumor Metastases on 68Ga-DOTATATE PET/CT: Identification and Prognostic Significance.

Neuroendocrine tumor (NET) metastases to the heart are found in 1%-4% of NET patients and have been reported primarily in the form of individual cases. We investigated the prevalence, clinical characteristics, imaging features, and outcomes of NET patients with cardiac metastases on 68Ga-DOTATATE PET/CT. Methods: 68Ga-DOTATATE PET/CT of 490 consecutive patients from a single institution were retrospectively reviewed for sites of metastases. The cumulative cardiovascular event rate and overall survival of patients with cardiac NET metastases (CNMs) were compared with those of a control group of metastatic NET patients without cardiac metastases. In patients with CNMs, the cardiac SUVmax with and without normalization to the myocardial background uptake was compared with a separate cohort of 11 patients with active cardiac sarcoidosis who underwent 68Ga-DOTATATE PET/CT for research purposes. Results: In total, 270 patients with metastatic NETs were identified, 9 (3.3%) of whom had CNMs. All 9 patients had grade 1-2 gastroenteropancreatic NETs, most commonly from the small intestine (7 patients). The control group consisted of 140 patients with metastatic grade 1-2 gastroenteropancreatic NETs. On Kaplan-Meier analysis, there was no significant difference in the risk of cardiovascular adverse events (P = 0.91 on log-rank test) or mortality (P = 0.83) between the metastatic NET patients with and without cardiac metastases. The degree of cardiac DOTATATE uptake was significantly higher in CNMs than in patients with cardiac sarcoidosis without overlap, in terms of both cardiac SUVmax (P = 0.027) and SUVmax-to-myocardial background ratio (P = 0.021). Conclusion: Routine 68Ga-DOTATATE PET/CT can be used to identify CNMs in 3% of patients with metastatic NETs. CNMs do not confer added cardiovascular or mortality risk. A distinguishing feature of CNMs is their high degree of DOTATATE uptake compared with focal myocardial inflammation.

The evolutionary history of metastatic pancreatic neuroendocrine tumours reveals a therapy driven route to high-grade transformation.

Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high-grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high-grade disease. We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post-alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with MEN1 inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high-grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden >50 (50%). In comparison, among the eight patients who did not show high-grade progression, 0 had a tumour mutational burden >50 (0%; odds ratio 'infinite', 95% confidence interval 1.8 to 'infinite', p = 0.02). Our findings contribute to broaden the understanding of metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Surgery enhances the effectiveness of peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumors

BackgroundWith the advent of peptide receptor radionuclide therapy, the timing and sequence of surgery in the treatment of metastatic gastroenteropancreatic neuroendocrine tumors merits further study. We hypothesized that surgery before peptide receptor radionuclide therapy might enhance its effectiveness in patients with metastatic gastroenteropancreatic neuroendocrine tumors. MethodsEighty-nine patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors treated with 177Lutetium-dotatate peptide receptor radionuclide therapy between 2018 and 2023 were included. Fifty-six patients underwent surgery (primary tumor resection and/or liver debulking) before peptide receptor radionuclide therapy and 33 patients did not. Primary outcome was progression-free survival according to Response Evaluation Criteria in Solid Tumors. Pretreatment dotatate positron emission tomography/computed tomography was used to calculate tumor volumes. ResultsThe surgery and no-surgery groups were well-matched. Median progression-free survival after peptide receptor radionuclide therapy was 15.6 months (interquartile range, 9.1–22.7 months) in the no-surgery group compared with 26.1 months (interquartile range, 12.7–38.1 months) in the surgery group (P = .04). On subgroup analysis, median progression-free survival was 18.1 months (interquartile range, 11.9–38.4 months) in patients who underwent primary tumor resection only compared with 26.2 months (interquartile range, 14.0–38.1 months) in patients who underwent liver debulking (P = .04). Tumor volume was lowest in patients who underwent liver debulking (median 146.07 mL3) compared with no surgery (median 626.42 mL3) (P = .001). On univariable analysis, a tumor volume <138.8 mL3 was associated with longer progression-free survival (hazard ratio, 2.03; 95% confidence interval, 0.95–4.34, P = .05), with a median progression-free survival of 38.1 months (interquartile range, 16.9–41.3 months) compared with 17.8 months (interquartile range, 10.8–28.7 months). ConclusionSurgery may enhance the effectiveness of 177Lutetium-dotatate in the treatment of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors. This positive effect may be the result of a lower tumor volume in patients after surgery. Our findings fortify the concept of using surgical debulking to improve systemic therapies such as peptide receptor radionuclide therapy.

Comparison of RECIST 1.1, mRECIST and PERCIST for assessment of peptide receptor radionuclide therapy treatment response in metastatic neuroendocrine tumors

PurposeTo compare RECIST 1.1, modified RECIST (mRECIST) and PERCIST for assessment of Peptide Receptor Radionuclide Therapy (PRRT) treatment response in metastatic neuroendocrine tumors. MaterialsIn this IRB-approved, HIPAA compliant retrospective study, patients treated with PRRT between July 2019 and Dec 2022 were identified. Inclusion criteria were presence of at least one pre-and one post-treatment imaging (CT, MRI, Ga 68 or Cu64 DOTATATE PET/CT) within one year of the start and end of PRRT respectively. The imaging was reviewed independently by two radiologists using RECIST 1.1, modified RECIST (mRECIST) and PERCIST criteria. Response of first post treatment scan and presence of disease progression during follow-up were recorded along with the date of best response and disease progression. Statistical analysis was performed to determine inter-reader agreement and agreement between the various response criteria using kappa statistics. ResultsBest response by RECIST 1.1 was recorded in 26 patients (PR-7, SD- 13, PD- 6), by mRECIST in 22 patients (PR-7, SD- 10, PD- 5), by PERCIST in 14 patients (PR-4, SD- 3, PD- 7). Inter-reader agreement was highest for PERCIST (weighted kappa 0.921, standard error 0.078 95% CI 0.769 to 1.000) followed by RECIST 1.1 (weighted kappa 0.897, standard error 0.071 95% CI 0.758 to 1.000) and mRECIST (weighted kappa 0.883, standard error 0.079 95% CI 0.727 to 1.000).

Adrenaline bolus rescue for refractory carcinoid crises during surgical manipulation of metastatic neuroendocrine tumor of pancreas: A case report

Carcinoid crisis is a potentially fatal condition with severe hemodynamic instability. A 25-year-old female with metastatic pancreatic neuroendocrine tumor with recurrent carcinoid crises was posted for surgical debulking. Intraoperatively, the patient was on crisis during manipulation of the lesion by the surgeon, which was unresponsive to octreotide, infusions of phenylephrine, and norepinephrine agents. The patient was then effectively managed with adrenaline blouses at 10 µg along with infusion of adrenaline. Use of inotropes and vasopressors is not encouraged in carcinoid due to release of inflammatory mediators which can precipitate the hemodynamic instability. Here, we managed her with adrenaline boluses and infusion.

Acute Kidney Injury in a Patient with Metastatic Pancreatic Neuroendocrine Tumor.

Acute Kidney Injury in a Patient with Metastatic Pancreatic Neuroendocrine Tumor.

Refractory hypercalcaemia in advanced metastatic pancreatic neuroendocrine tumour controlled on weekly denosumab

Refractory hypercalcaemia in advanced metastatic pancreatic neuroendocrine tumour controlled on weekly denosumab