Synchronous Invasive Ductal Carcinoma with Neuroendocrine Features and Metastatic Gastrointestinal Neuroendocrine Tumor: A Rare Case Report

Synchronous Invasive Ductal Carcinoma with Neuroendocrine Features and Metastatic Gastrointestinal Neuroendocrine Tumor: A Rare Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Synchronous Invasive Ductal Carcinoma with Neuroendocrine Features and Metastatic Gastrointestinal Neuroendocrine Tumor: A Rare Case Report Suhas Kataveni, Sumanth Varma Pamidipati, Srilekha Kollipara This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7557731/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract We report a rare case of a 58-year-old African-American woman who presented with abdominal pain and was found to have a well-differentiated gastrointestinal neuroendocrine tumor (NET) metastatic to the liver. During her workup, a left breast mass was detected. Core biopsy of the breast lesion revealed invasive ductal carcinoma (IDC) with neuroendocrine differentiation (ER-positive, PR-negative, HER2-negative). ^68Ga-DOTATATE PET/CT confirmed somatostatin receptor–positive lesions in the liver, bone, and mesentery, consistent with metastatic NET, but did not show additional uptake in the breast. The patient underwent partial mastectomy of the breast mass and subsequently received peptide receptor radionuclide therapy (PRRT) with ^177Lu-DOTATATE for her metastatic NET. This case illustrates an unprecedented synchronous presentation of primary IDC with neuroendocrine features together with a metastatic gastrointestinal NET within the same breast, highlighting the diagnostic challenge and the utility of ^68Ga PET/CT imaging and PRRT in management. Oncology Internal Medicine Invasive ductal carcinoma Neuroendocrine breast carcinoma Metastatic neuroendocrine tumor Synchronous malignancies Peptide receptor radionuclide therapy (PRRT) ^177Lu-DOTATATE ^68Ga-DOTATATE PET/CT Breast conservation surgery Diagnostic dilemma Rare case report Introduction Neuroendocrine neoplasms of the breast (BNEN) are extremely rare and have only recently been clearly defined in the WHO classification [ 1 , 2 , 3 ]. Historically, primary neuroendocrine breast carcinomas were defined by having > 50% of tumor cells expressing neuroendocrine markers [ 4 ], but the current WHO 2019 criteria require > 90% of cells with neuroendocrine morphology and marker expression [ 3 ]. Primary breast neuroendocrine tumors comprise only a small fraction of breast cancers, roughly 0.1–5% of cases [ 3 ], and they typically present in older, postmenopausal women as ER-positive, HER2-negative (luminal-type) tumors [ 3 ]. In contrast, metastases to the breast from extramammary primaries are very uncommon, accounting for only about 0.1–2% of breast malignancies overall. Neuroendocrine tumors (NETs) of gastrointestinal or pulmonary origin rarely metastasize to the breast, but when they do, they most often occur in older women and mimic primary breast cancer [ 1 ]. The distinction between a primary breast neuroendocrine carcinoma and a metastasis from a nonmammary NET is critical, as management and prognosis differ greatly. We present a unique case of synchronous tumors: a primary left breast IDC with neuroendocrine differentiation and a metastatic gastrointestinal NET involving the breast. We discuss the diagnostic considerations, imaging findings, and therapeutic approach, including the role of ^68Ga-DOTATATE PET/CT and peptide receptor radionuclide therapy (PRRT), in this complex presentation [ 3 , 5 ]. Case Presentation A 58-year-old African-American woman with no significant past medical history presented with several months of vague upper abdominal pain. An abdominal ultrasound and contrast-enhanced CT revealed multiple hepatic lesions. Biopsy of a liver lesion showed a well-differentiated neuroendocrine tumor. Endoscopic evaluation suggested a gastrointestinal origin (not detailed), and a diagnosis of metastatic gastroenteropancreatic NET (grade 1) was made. During this evaluation, a palpable mass was noted in the left breast on physical examination. Diagnostic mammography and ultrasound confirmed a 2.5 cm spiculated mass in the upper outer quadrant of the left breast. Ultrasound-guided core needle biopsy of the breast mass demonstrated invasive ductal carcinoma with neuroendocrine features. Immunohistochemistry on the breast biopsy was positive for estrogen receptor (> 90% nuclei), negative for progesterone receptor, and negative for HER2/neu. Synaptophysin staining was positive in most tumor cells, while chromogranin was focally positive, consistent with neuroendocrine differentiation. No ductal carcinoma in situ was identified. To assess the extent of neuroendocrine disease, a ^68Ga-DOTATATE PET/CT scan was performed. This whole-body scan demonstrated intense uptake in multiple liver lesions, pelvic mesenteric lymph nodes, and a bone lesion in the pelvis, confirming extensive somatostatin receptor–positive metastatic NET. Importantly, there was no abnormal DOTATATE uptake in the left breast mass or axilla, suggesting that the breast carcinoma component might not be strongly somatostatin-receptor–expressing. Given these findings, the breast lesion was managed as a primary breast malignancy. The patient underwent a left partial mastectomy with sentinel lymph node biopsy. Final surgical pathology confirmed invasive ductal carcinoma with neuroendocrine differentiation, 2.3 cm in greatest dimension, with negative margins and no lymph node metastasis. Histologic review also identified foci of metastatic NET within the breast lesion, indicating a collision of two tumor types in the same breast (primary IDC with NE features and adjacent GI-NET metastases). For systemic treatment, the patient received four cycles of ^177Lu-DOTATATE PRRT (7.4 GBq per cycle at 8-week intervals) targeting her metastatic neuroendocrine disease, along with monthly long-acting octreotide. Adjuvant endocrine therapy (letrozole) was also initiated for the ER-positive breast carcinoma. At the time of this report, the patient is on surveillance, with stable disease in the liver and no evidence of breast cancer recurrence on follow-up imaging. Discussion This case represents an extremely unusual “collision” of two distinct neoplasms in one breast: a primary invasive ductal carcinoma with neuroendocrine differentiation and metastatic lesions from a gastrointestinal NET. Breast metastasis from extramammary NET is rare and often poses a diagnostic dilemma. In one series of 116 reported cases of NET metastases to the breast, the majority were older women with GI primaries, and metastasis often mimicked primary breast carcinoma on imaging and histology [ 1 ]. In our patient, the known GI-NET with liver metastases and the PET scan’s failure to show somatostatin-avid disease in the breast suggested two separate processes. Pathological differentiation : Primary neuroendocrine breast carcinomas are morphologically and immunohistochemically defined by neuroendocrine features. According to the WHO, a neuroendocrine breast tumor must have > 90% of cells exhibiting neuroendocrine differentiation, typically confirmed by synaptophysin and chromogranin staining [ 3 ]. These tumors are usually ER-positive and HER2-negative, aligning with the luminal type profile [ 3 ], as seen in our patient’s ER+, HER2– tumor. In contrast, metastatic NET cells to the breast tend to resemble the primary NET histology and express markers of their site of origin. Immunohistochemical stains can be pivotal: primary breast tumors usually express breast-lineage markers (e.g. GATA3, mammaglobin, GCDFP15) while non-breast primaries often express markers like CDX2 (intestinal) or TTF-1 (pulmonary) [ 3 ]. In our case, no ductal carcinoma in situ (DCIS) component was identified, and careful review revealed clusters of both ductal carcinoma and separate NET within the resected tissue. The presence of DCIS can support a primary breast origin, whereas its absence (particularly in the context of known extramammary NET) raises suspicion for metastasis [ 3 ]. Here, the lack of DCIS and the known GI-NET mandated recognition of a composite lesion. Imaging and staging : ^68Ga-DOTATATE PET/CT is now the imaging standard for well-differentiated NETs, allowing whole-body detection of somatostatin receptor–expressing lesions [ 2 ]. In this patient, the DOTATATE scan identified multifocal metastases (liver, bone, mesentery), confirming the extent of the GI-NET, but did not reveal uptake in the breast tumor. This differential uptake supports the interpretation that the breast carcinoma cells were not strongly somatostatin-receptor–positive, whereas the GI-NET cells were. The Ga-DOTATATE scan was critical both for staging and for planning therapy. It exemplifies the theranostic paradigm in NETs: demonstrating receptor expression to guide ^177Lu-PRRT therapy [ 2 ]. Treatment approach : Given the patient’s dual pathology, we combined standard management for both tumor types. Early-stage breast cancer (including neuroendocrine variant) is typically treated like conventional IDC [ 5 ]. In accordance with guidelines, we performed breast-conserving surgery with clear margins and sentinel node evaluation. Adjuvant systemic therapy was tailored by receptor status: endocrine therapy for ER-positive carcinoma. Chemotherapy was not given given the favorable grade of both tumors and the efficacy of available targeted therapies. For her metastatic GI-NET, the patient received PRRT with ^177Lu-DOTATATE. PRRT has revolutionized treatment of advanced somatostatin-receptor–positive NETs, significantly prolonging progression-free survival and improving symptoms [ 6 ]. In the NETTER-1 trial, ^177Lu-DOTATATE plus octreotide markedly improved median PFS compared to high-dose octreotide alone [ 6 ]. More broadly, PRRT is now indicated for gastroenteropancreatic NETs with confirmed receptor positivity [ 5 , 6 ]. Of note, neuroendocrine breast carcinomas may also express somatostatin receptors: one series found 71% of BNENs positive for SSTR2A/SSTR5, suggesting potential PRRT targets [ 3 ]. Although our patient’s breast carcinoma was managed surgically, it is conceivable that if it were ER-negative or inoperable, PRRT might have offered an additional treatment vector given its neuroendocrine differentiation [ 3 , 6 ]. Overall, treatment of this patient followed a multimodal strategy: surgical resection of the breast cancer component, endocrine therapy for the ER-positive tumor, and targeted radionuclide therapy for the disseminated NET. This approach is supported by expert reviews recommending conventional breast cancer therapy for neuroendocrine breast tumors, with individualized addition of NET-specific treatments (such as PRRT) in the metastatic setting[ 5 ]. Conclusion This case underscores the importance of a thorough diagnostic workup when encountering an unusual breast lesion, especially in a patient with a known NET. Awareness that well-differentiated gastroenteropancreatic NETs can metastasize to the breast (though rare) is critical to avoid misdiagnosis and overtreatment. The use of ^68Ga-DOTATATE PET/CT was pivotal in identifying the extent of NET metastasis and confirming receptor status for therapy[ 2 ]. Management required a tailored, multidisciplinary approach: local treatment of the breast carcinoma and systemic PRRT for the metastatic NET. This synchronous presentation of two distinct pathologies in one breast lesion is exceedingly rare, and to our knowledge has not been previously reported. It highlights the need for coordinated care between oncologic surgeons, pathologists, and nuclear medicine specialists. Further study of such cases will improve understanding of optimal diagnostic strategies and therapeutic combinations for patients with multiple coexistent malignancies. Declarations Written informed consent was obtained from the patient for publication of this case report and any accompanying clinical details. References Urrego Díaz JA, González M, Romero-Rojas AE, Strosberg J, Jiménez-Vásquez P Neuroendocrine Tumor Metastases to the Breast: A Case Report and Review of the Literature. Cureus [Internet]. 2023 June 20 [cited 2025 Sept 7]; Available from: https://www.cureus.com/articles/150023-neuroendocrine-tumor-metastases-to-the-breast-a-case-report-and-review-of-the-literature Hofman MS, Lau WFE, Hicks RJ Somatostatin Receptor Imaging with 68 Ga DOTATATE PET/CT: Clinical Utility, Normal Patterns, Pearls, and Pitfalls in Interpretation. RadioGraphics [Internet]. 2015 Mar [cited 2025 Sept 7];35(2):500–16. Available from: http://pubs.rsna.org/doi/ 10.1148/rg.352140164 Vinod A, Mahajan I, Ghose A, Sreeram S Primary neuroendocrine breast cancer—an unusual occurrence. ecancer [Internet]. 2023 Mar 16 [cited 2025 Sept 7];17. Available from: https://ecancer.org/en/journal/article/1520-primary-neuroendocrine-breast-cancer-an-unusual-occurrence Kumar M, Singh A, Vimal J, Kumar V (2022) Primary neuroendocrine breast carcinoma: A rare case report. Indian J Health Sci Biomed Res KLEU [Internet]. [cited 2025 Sept 7];15(2):176. Available from: https://journals.lww.com/ 10.4103/kleuhsj.kleuhsj_389_21 Inno A, Bogina G, Turazza M, Bortesi L, Duranti S, Massocco A et al Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives. The Oncologist [Internet]. 2016 Jan 1 [cited 2025 Sept 7];21(1):28–32. Available from: https://academic.oup.com/oncolo/article/21/1/28/6401242 Harris PE, Zhernosekov K (2022) The evolution of PRRT for the treatment of neuroendocrine tumors; What comes next? Front Endocrinol [Internet]. Oct 31 [cited 2025 Sept 7];13:941832. Available from: https://www.frontiersin.org/articles/ 10.3389/fendo.2022.941832/full Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7557731","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":511467118,"identity":"ccc596e6-3ea1-4707-8e98-c20c916a4999","order_by":0,"name":"Suhas Kataveni","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYBAC+QYeIFnAkGDAwNj+4QOQzcZOQIvBAZAWA5AW5jbGGSAtzIS0MMC1sLcxg9gMBLVI5B78+MPALs9cIrHtsc2vbfJ8zAyMHz7m4PHLjLxkaR6D5GLLGYntxrl9tw3bmBmYJWduw2PNjRwDaQYD5sQNNxIbpHN7bjMCtbAx8+LXYvzzh0E9RItlz217YrSYSfAYHAZpaZNm+HE7kaAWgzNvzKx5DI4XW/Y8bDbsbbid3MbM2IzXL/LtOcY3f1RU55mzpz988OPPbdv57c0HP3zE5zAUwNgGJhuIVQ8Cf0hRPApGwSgYBSMFAAAGplLap888vAAAAABJRU5ErkJggg==","orcid":"","institution":"Gandhi Medical College and Hospital, Secunderabad","correspondingAuthor":true,"prefix":"","firstName":"Suhas","middleName":"","lastName":"Kataveni","suffix":""},{"id":511467119,"identity":"61749238-bbb5-419f-8a7d-97983ea8bb75","order_by":1,"name":"Sumanth Varma Pamidipati","email":"","orcid":"","institution":"Gandhi Medical College and Hospital, Secunderabad","correspondingAuthor":false,"prefix":"","firstName":"Sumanth","middleName":"Varma","lastName":"Pamidipati","suffix":""},{"id":511467120,"identity":"e492a1ed-439f-44a3-99e1-80d7ad5ab9df","order_by":2,"name":"Srilekha Kollipara","email":"","orcid":"","institution":"Mediciti Medical College and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Srilekha","middleName":"","lastName":"Kollipara","suffix":""}],"badges":[],"createdAt":"2025-09-07 16:55:59","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7557731/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7557731/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90993449,"identity":"ab1184a5-9335-43a5-9b2a-6ecb25481154","added_by":"auto","created_at":"2025-09-10 11:59:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":285111,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7557731/v1/0442b7b9-4ccc-44e3-9f93-b39e7aedaea4.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eSynchronous Invasive Ductal Carcinoma with Neuroendocrine Features and Metastatic Gastrointestinal Neuroendocrine Tumor: A Rare Case Report\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeuroendocrine neoplasms of the breast (BNEN) are extremely rare and have only recently been clearly defined in the WHO classification [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Historically, primary neuroendocrine breast carcinomas were defined by having\u0026thinsp;\u0026gt;\u0026thinsp;50% of tumor cells expressing neuroendocrine markers [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], but the current WHO 2019 criteria require\u0026thinsp;\u0026gt;\u0026thinsp;90% of cells with neuroendocrine morphology and marker expression [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Primary breast neuroendocrine tumors comprise only a small fraction of breast cancers, roughly 0.1\u0026ndash;5% of cases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and they typically present in older, postmenopausal women as ER-positive, HER2-negative (luminal-type) tumors [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In contrast, metastases to the breast from extramammary primaries are very uncommon, accounting for only about 0.1\u0026ndash;2% of breast malignancies overall. Neuroendocrine tumors (NETs) of gastrointestinal or pulmonary origin rarely metastasize to the breast, but when they do, they most often occur in older women and mimic primary breast cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The distinction between a primary breast neuroendocrine carcinoma and a metastasis from a nonmammary NET is critical, as management and prognosis differ greatly. We present a unique case of synchronous tumors: a primary left breast IDC with neuroendocrine differentiation and a metastatic gastrointestinal NET involving the breast. We discuss the diagnostic considerations, imaging findings, and therapeutic approach, including the role of ^68Ga-DOTATATE PET/CT and peptide receptor radionuclide therapy (PRRT), in this complex presentation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 58-year-old African-American woman with no significant past medical history presented with several months of vague upper abdominal pain. An abdominal ultrasound and contrast-enhanced CT revealed multiple hepatic lesions. Biopsy of a liver lesion showed a well-differentiated neuroendocrine tumor. Endoscopic evaluation suggested a gastrointestinal origin (not detailed), and a diagnosis of metastatic gastroenteropancreatic NET (grade 1) was made. During this evaluation, a palpable mass was noted in the left breast on physical examination. Diagnostic mammography and ultrasound confirmed a 2.5 cm spiculated mass in the upper outer quadrant of the left breast. Ultrasound-guided core needle biopsy of the breast mass demonstrated invasive ductal carcinoma with neuroendocrine features. Immunohistochemistry on the breast biopsy was positive for estrogen receptor (\u0026gt;\u0026thinsp;90% nuclei), negative for progesterone receptor, and negative for HER2/neu. Synaptophysin staining was positive in most tumor cells, while chromogranin was focally positive, consistent with neuroendocrine differentiation. No ductal carcinoma in situ was identified.\u003c/p\u003e\u003cp\u003eTo assess the extent of neuroendocrine disease, a ^68Ga-DOTATATE PET/CT scan was performed. This whole-body scan demonstrated intense uptake in multiple liver lesions, pelvic mesenteric lymph nodes, and a bone lesion in the pelvis, confirming extensive somatostatin receptor\u0026ndash;positive metastatic NET. Importantly, there was no abnormal DOTATATE uptake in the left breast mass or axilla, suggesting that the breast carcinoma component might not be strongly somatostatin-receptor\u0026ndash;expressing. Given these findings, the breast lesion was managed as a primary breast malignancy. The patient underwent a left partial mastectomy with sentinel lymph node biopsy. Final surgical pathology confirmed invasive ductal carcinoma with neuroendocrine differentiation, 2.3 cm in greatest dimension, with negative margins and no lymph node metastasis. Histologic review also identified foci of metastatic NET within the breast lesion, indicating a collision of two tumor types in the same breast (primary IDC with NE features and adjacent GI-NET metastases).\u003c/p\u003e\u003cp\u003eFor systemic treatment, the patient received four cycles of ^177Lu-DOTATATE PRRT (7.4 GBq per cycle at 8-week intervals) targeting her metastatic neuroendocrine disease, along with monthly long-acting octreotide. Adjuvant endocrine therapy (letrozole) was also initiated for the ER-positive breast carcinoma. At the time of this report, the patient is on surveillance, with stable disease in the liver and no evidence of breast cancer recurrence on follow-up imaging.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case represents an extremely unusual \u0026ldquo;collision\u0026rdquo; of two distinct neoplasms in one breast: a primary invasive ductal carcinoma with neuroendocrine differentiation and metastatic lesions from a gastrointestinal NET. Breast metastasis from extramammary NET is rare and often poses a diagnostic dilemma. In one series of 116 reported cases of NET metastases to the breast, the majority were older women with GI primaries, and metastasis often mimicked primary breast carcinoma on imaging and histology [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In our patient, the known GI-NET with liver metastases and the PET scan\u0026rsquo;s failure to show somatostatin-avid disease in the breast suggested two separate processes.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePathological differentiation\u003c/b\u003e: Primary neuroendocrine breast carcinomas are morphologically and immunohistochemically defined by neuroendocrine features. According to the WHO, a neuroendocrine breast tumor must have \u0026gt;\u0026thinsp;90% of cells exhibiting neuroendocrine differentiation, typically confirmed by synaptophysin and chromogranin staining [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These tumors are usually ER-positive and HER2-negative, aligning with the luminal type profile [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], as seen in our patient\u0026rsquo;s ER+, HER2\u0026ndash; tumor. In contrast, metastatic NET cells to the breast tend to resemble the primary NET histology and express markers of their site of origin. Immunohistochemical stains can be pivotal: primary breast tumors usually express breast-lineage markers (e.g. GATA3, mammaglobin, GCDFP15) while non-breast primaries often express markers like CDX2 (intestinal) or TTF-1 (pulmonary) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In our case, no ductal carcinoma in situ (DCIS) component was identified, and careful review revealed clusters of both ductal carcinoma and separate NET within the resected tissue. The presence of DCIS can support a primary breast origin, whereas its absence (particularly in the context of known extramammary NET) raises suspicion for metastasis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Here, the lack of DCIS and the known GI-NET mandated recognition of a composite lesion.\u003c/p\u003e\u003cp\u003e\u003cb\u003eImaging and staging\u003c/b\u003e: ^68Ga-DOTATATE PET/CT is now the imaging standard for well-differentiated NETs, allowing whole-body detection of somatostatin receptor\u0026ndash;expressing lesions [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In this patient, the DOTATATE scan identified multifocal metastases (liver, bone, mesentery), confirming the extent of the GI-NET, but did not reveal uptake in the breast tumor. This differential uptake supports the interpretation that the breast carcinoma cells were not strongly somatostatin-receptor\u0026ndash;positive, whereas the GI-NET cells were. The Ga-DOTATATE scan was critical both for staging and for planning therapy. It exemplifies the theranostic paradigm in NETs: demonstrating receptor expression to guide ^177Lu-PRRT therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eTreatment approach\u003c/b\u003e: Given the patient\u0026rsquo;s dual pathology, we combined standard management for both tumor types. Early-stage breast cancer (including neuroendocrine variant) is typically treated like conventional IDC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In accordance with guidelines, we performed breast-conserving surgery with clear margins and sentinel node evaluation. Adjuvant systemic therapy was tailored by receptor status: endocrine therapy for ER-positive carcinoma. Chemotherapy was not given given the favorable grade of both tumors and the efficacy of available targeted therapies. For her metastatic GI-NET, the patient received PRRT with ^177Lu-DOTATATE. PRRT has revolutionized treatment of advanced somatostatin-receptor\u0026ndash;positive NETs, significantly prolonging progression-free survival and improving symptoms [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In the NETTER-1 trial, ^177Lu-DOTATATE plus octreotide markedly improved median PFS compared to high-dose octreotide alone [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. More broadly, PRRT is now indicated for gastroenteropancreatic NETs with confirmed receptor positivity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Of note, neuroendocrine breast carcinomas may also express somatostatin receptors: one series found 71% of BNENs positive for SSTR2A/SSTR5, suggesting potential PRRT targets [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although our patient\u0026rsquo;s breast carcinoma was managed surgically, it is conceivable that if it were ER-negative or inoperable, PRRT might have offered an additional treatment vector given its neuroendocrine differentiation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOverall, treatment of this patient followed a multimodal strategy: surgical resection of the breast cancer component, endocrine therapy for the ER-positive tumor, and targeted radionuclide therapy for the disseminated NET. This approach is supported by expert reviews recommending conventional breast cancer therapy for neuroendocrine breast tumors, with individualized addition of NET-specific treatments (such as PRRT) in the metastatic setting[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case underscores the importance of a thorough diagnostic workup when encountering an unusual breast lesion, especially in a patient with a known NET. Awareness that well-differentiated gastroenteropancreatic NETs can metastasize to the breast (though rare) is critical to avoid misdiagnosis and overtreatment. The use of ^68Ga-DOTATATE PET/CT was pivotal in identifying the extent of NET metastasis and confirming receptor status for therapy[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Management required a tailored, multidisciplinary approach: local treatment of the breast carcinoma and systemic PRRT for the metastatic NET. This synchronous presentation of two distinct pathologies in one breast lesion is exceedingly rare, and to our knowledge has not been previously reported. It highlights the need for coordinated care between oncologic surgeons, pathologists, and nuclear medicine specialists. Further study of such cases will improve understanding of optimal diagnostic strategies and therapeutic combinations for patients with multiple coexistent malignancies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying clinical details.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUrrego D\u0026iacute;az JA, Gonz\u0026aacute;lez M, Romero-Rojas AE, Strosberg J, Jim\u0026eacute;nez-V\u0026aacute;squez P Neuroendocrine Tumor Metastases to the Breast: A Case Report and Review of the Literature. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.frontiersin.org/articles/\u003c/span\u003e\u003cspan address=\"https://www.frontiersin.org/articles/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fendo.2022.941832/full\u003c/span\u003e\u003cspan address=\"10.3389/fendo.2022.941832/full\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Invasive ductal carcinoma, Neuroendocrine breast carcinoma, Metastatic neuroendocrine tumor, Synchronous malignancies, Peptide receptor radionuclide therapy (PRRT), ^177Lu-DOTATATE, ^68Ga-DOTATATE PET/CT, Breast conservation surgery, Diagnostic dilemma, Rare case report","lastPublishedDoi":"10.21203/rs.3.rs-7557731/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7557731/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe report a rare case of a 58-year-old African-American woman who presented with abdominal pain and was found to have a well-differentiated gastrointestinal neuroendocrine tumor (NET) metastatic to the liver. During her workup, a left breast mass was detected. Core biopsy of the breast lesion revealed invasive ductal carcinoma (IDC) with neuroendocrine differentiation (ER-positive, PR-negative, HER2-negative). ^68Ga-DOTATATE PET/CT confirmed somatostatin receptor\u0026ndash;positive lesions in the liver, bone, and mesentery, consistent with metastatic NET, but did not show additional uptake in the breast. The patient underwent partial mastectomy of the breast mass and subsequently received peptide receptor radionuclide therapy (PRRT) with ^177Lu-DOTATATE for her metastatic NET. This case illustrates an unprecedented synchronous presentation of primary IDC with neuroendocrine features together with a metastatic gastrointestinal NET within the same breast, highlighting the diagnostic challenge and the utility of ^68Ga PET/CT imaging and PRRT in management.\u003c/p\u003e","manuscriptTitle":"Synchronous Invasive Ductal Carcinoma with Neuroendocrine Features and Metastatic Gastrointestinal Neuroendocrine Tumor: A Rare Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-10 11:59:00","doi":"10.21203/rs.3.rs-7557731/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"057a439c-0c7a-486c-8430-8d2d321283a9","owner":[],"postedDate":"September 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54322095,"name":"Oncology"},{"id":54322096,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2025-09-10T11:59:00+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-10 11:59:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7557731","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7557731","identity":"rs-7557731","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}