Via Research Recognition Day 2024 VCOM-Carolinas

Clinical Case-Based Reports

Synchronous Neuroendocrine Tumors in the Lung and Ileum: A Case Report Quang-Minh Dang, OMS-III, Michael A. Spandorfer, MD Roper St. Francis Healthcare, Interventional Pulmonology and Bronchoscopy, Charleston, South Carolina

Introduction

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Discussion

Neuroendocrine tumors can be classified as malignancies involving dense core granules, which store amines in serotonergic neurons, and the synthesis of secretion of these monoamines. 1 This case study describes a patient with neuroendocrine tumors (NETs) of the right middle lobe (RML) and the terminal ileum with concern for synchronous NETs vs metastatic disease process. NETs are rare, consisting of approximately 2% of all malignancies with an incidence rate of 6.98 cases per 100,000 per year. Lung NETs are 1-2% of all lung malignancies, and 20-30% of all NETs, with an incidence of 1.49 per 100,000 per year. Gastroenteropancreatic NETs have an incidence rate of 3.56 cases per 100,000 per year. 2 Due to the rarity of synchronous and metachronous NETs, epidemiology could not be ascertained based on current literature review. A thorough investigation via the PubMed database yielded no case studies with synchronous NETs of the lung and ileum. Further search was done to collect background information for this report and yielded several case studies with synchronous NETs. 3-6 While synchronous NETs are rare, several studies indicate that NETs are predictive of a secondary primary malignancy (SPM). 7-9 A 64-year-old female presented to her primary care office for evaluation of hemoptysis accompanied by 6 months of exertional breathlessness. Initial physical exam and laboratory findings were inconclusive. Chest Computed Tomography (CT) with contrast imaging revealed a 1.4 cm pulmonary nodule of the RML with noted mild enlargement compared to a prior coronary CT Angiogram of 2021. Previously the nodule demonstrated long-term stability compared to a prior study of 2012. The CT also revealed a 20mm right thyroid nodule. Thyroid Ultrasound revealed an isoechoic, solid 3 x 1.6 x 1.8cm right thyroid nodule. Fine needle biopsy was performed, and pathology revealed atypia of unknown significance that was determined, with gene sequencing, to be benign. The patient received a Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scan that revealed mild hypermetabolic activity in the RML nodule and thyroid nodule. A Navigational Bronchoscopy procedure was performed demonstrating malignant neoplasia. The nodule tested positive for cytokeratin (AE1/AE3), chromogranin, synaptophysin, thyroid transcription factor 1 (TTF-1), and Ki-67 3%, consistent with NET favoring carcinoid. Subsequent 64-Copper Dotatate PET was obtained and revealed a newly avid lesion in the terminal ileum in addition to biopsy-proven lung lesion. The patient underwent laparoscopic ileocecectomy and pathologic examination revealed two well-differentiated NETs, 1.3cm and 0.3cm, positive for cytokeratin (AE1/AE3), synaptophysin, chromogranin, CDX2, and Ki-67 3.2%. Two months later, patient underwent robotic right middle lobectomy with removal of a 2.6cm well-differentiated NET. She did well postoperatively for both operations. Throughout her entire disease process, she did not experience carcinoid symptoms, such as skin flushing, diarrhea, and difficulty breathing or rapid heartbeat at rest. The patient did not receive any chemotherapy or radiation in her treatment of synchronous NETs. She follows closely with her Hematology/Oncology team and has plans for genetic counseling with the Medical Genetics team. Case Presentation

Conclusions It is important to complete a comprehensive clinical, histopathological, immunohistochemical, and radiologic workup when approaching possible metastasis vs synchronous or metachronous NETs. Clinicians must consider these possibilities as part of their differential diagnosis when diagnosing NETs, as prognosis and further workup may differ. Genetic testing may play a crucial role in determining risk for recurrence or other syndromes associated with NETs. Surveillance for any development of NETs, SPMs, and thyroid enlargement will be paramount for early diagnosis and treatment. In this patient, immunohistochemical staining revealed different tumor markers, favoring synchronous NETs. This case study reports the first case of synchronous NETs of the lung and ileum. The lung NET was relatively indolent for more than a decade before causing the presenting symptoms of hemoptysis and exertional breathlessness in the patient. The combination of F18-FDG PET-CT and 64Cu-DOTATATE PET-CT was invaluable to the detection of NETs in this patient and provided lead time for appropriate treatment. Immunohistochemical staining indicated TTF-1 positive, a marker for primary lung cancer, and CDX2 negative lung NET, and TTF-1 negative and CDX2 positive, a marker for primary intestinal cancer, ileal NETs. 10,11 This staining profile supported the diagnosis of synchronous primary lung NET and primary ileal NETs, rather than metastasis. Initially, Cardiothoracic Surgery and Hematology/Oncology believed this case to be an oligometastatic disease process and had concerns for micrometastatic disease. Cardiothoracic Surgery followed National Comprehensive Cancer Network (NCCN) guidelines for treatment of NETs. For Lung NETs that are Stage 1 or 2, NCCN recommended lobectomy and lymph node dissection. For NETs in the terminal ileum, NCCN recommended bowel resection with removal of regional lymph nodes. 12 Hematology/Oncology recommended observation and imaging as there was no lymph node involvement, and the patient remained asymptomatic with no carcinoid symptoms status post lobectomy and ileocecectomy. One main difference in management of synchronous NETs and metastatic disease process was consideration for genetic counseling. It will also be prudent to monitor for SPM, as there is significant risk for development. 7-9 Early detection and diagnosis will allow for lead time in treatment. Given that synchronous NETs of the lung and ileum have never been reported, this case may prove insightful in the workup and treatment of a rare presentation. However, the lack of publications may mean this case could be underreported, or a coincidental event.

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Figure 1. CT Chest w/o contrast. A) Transverse view of lung lesion, central component, 9mm. B) Transverse view of lung lesion, peripheral component, 14mm. C) Coronal view of lung lesion. D) Sagittal view of lung lesion, 26mm.

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Figure 2. F18-FDG PET-CT and 64Cu-DOTATATE PET-CT Skull Base to Mid Thighs. A) Q.Clear Coronal and B) Transverse 10.06 mCi F18-FDG PET-CT revealed right middle lobe nodule that is radiotracer avid. No abnormal focus of uptake present in terminal ileum. C) Q.Clear Coronal and D) Transverse 4.4 mCi 64Cu-DOTATATE (Detectnet) PET-CT revealed relatively slight activity in previously noted right middle lobe nodule. Intense increased uptake present in terminal ileum without corresponding mass on CT.

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Figure 3. H&E and Immunohistochemical Staining of Lung and Colon. A) H&E stained slide of lung lesion. The neoplasm is composed of round to spindle shaped cells lacking pronounced nuclear atypia/pleomorphism, individual cell necrosis, and increased mitotic activity. B) Immunohistochemical staining of lung lesion. C) H&E stained slide of colon lesion. The neoplasm is composed of nests, cords, and trabecular arrangements of cells exhibiting relatively uniform nuclei without significant atypia/pleomorphism. There is no evidence of tumor necrosis. D) Immunohistochemical stain of colon lesion.

1. Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia . 2017;19(12):991-1002. doi:10.1016/j.neo.2017.09.002 2. Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol . 2017;3(10):1335-1342. doi:10.1001/jamaoncol.2017.0589 3. Kamath SM, Pingali S, Girish G, Harish K. Primary synchronous mesenteric neuroendocrine tumors: Report of a rare case with review of literature. J Cancer Res Ther . 2015;11(3):662. doi:10.4103/0973-1482.138108 4. Tsunenari T, Aosasa S, Ogata S, et al. Synchronous neuroendocrine tumors in both the pancreas and ileum: A case report. Int J Surg Case Rep . 2016;22:47-50. doi:10.1016/j.ijscr.2016.03.028 5. Loharkar S, Basu S. Metachronous Adenocarcinoma of the Lung in the Setting of Metastatic Gastric Neuroendocrine Tumor: Value of Elucidating Discordance on Dual-Tracer PET/CT with Ki-67 Index. J Nucl Med Technol . 2023;51(1):75-77. doi:10.2967/jnmt.121.263415 6. Song IH, Lee YS, Sun DI, Hong YK, Lee KY. Metachronous double primary neuroendocrine tumors in larynx and lung: a case report. J Int Med Res . 2020;48(11):300060520962928. doi:10.1177/0300060520962928 7. Verrico M, Rossi L, Tomao S, Colonna M, Vici P, Tomao F. Metachronous and Synchronous Cancers in Patients with Neuroendocrine Tumors. Oncology . 2020;98(1):10-15. doi:10.1159/000502384 8. Prommegger R, Ensinger C, Steiner P, Sauper T, Profanter C, Margreiter R. Neuroendocrine tumors and second primary malignancy--a relationship with clinical impact?. Anticancer Res . 2004;24(2C):1049-1051. 9. Russell B, White BE, Rous B, et al. Second Primary Malignancies in Patients with a Neuroendocrine Neoplasm in England. Neuroendocrinology . 2023;113(8):811-821. doi:10.1159/000530238 10. Srodon M, Westra WH. Immunohistochemical staining for thyroid transcription factor-1: a helpful aid in discerning primary site of tumor origin in patients with brain metastases. Hum Pathol . 2002;33(6):642-645. doi:10.1053/hupa.2002.124910 11. Saad RS, Ghorab Z, Khalifa MA, Xu M. CDX2 as a marker for intestinal differentiation: Its utility and limitations. World J Gastrointest Surg . 2011;3(11):159-166. doi:10.4240/wjgs.v3.i11.159 12. Guidelines Detail. NCCN. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448

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