Rare but distinct: A systematic review of primary neuroendocrine tumors of the breast according to WHO 2019 guidelines.

Primary breast neuroendocrine tumors (BNETs) represent < 1% of breast cancers. Diagnosing BNETs can be challenging, and a limited amount of cohort data currently exists in literature. We aimed to describe primary BNET characteristics, treatment modalities, and survival outcomes through the National Cancer Database (NCDB). A retrospective cohort analysis was performed using the NCDB from 2004 to 2017. BNET cases were compared with patients with invasive ductal carcinoma (IDC). A matched IDC cohort was created by matching patient age, race, and disease stage. Kaplan-Meier analysis was performed, and hazard ratios (HR) were calculated through the bootstrap sampling method. A total of 1389 BNET and 1,967,401 IDC cases were identified. When compared with IDC patients, BNET patients were older, had more comorbidities, and were more often male (p < 0.01). BNETs were larger, higher grade, and more frequently hormone receptor negative (p < 0.01). While BNET patients were treated with surgery and radiotherapy (p < 0.01) less often compared with IDC patients, they presented at later disease stage (p < 0.001) and received systemic treatment more frequently (53.5% vs. 40%, p < 0.01). Patients with BNET had increased mortality compared with the matched IDC cohort: stage 1 HR 1.8, stage 2 HR 2.0, stage 3 HR 1.8, and stage 4 HR 1.5 (p < 0.001 for all). Patients with BNET tend to present at higher clinical stages, are more frequently hormone receptor negative, and have inferior overall survival compared with patients with IDC. Further treatment strategies and studies are needed to elucidate optimal therapies to maximize patient outcomes.

BackgroundNeuroendocrine carcinomas mainly affect the bronchopulmonary and the gastrointestinal systems. Breast localizations are very rare. They represent less than 0.1% of all breast cancers. A definitive diagnosis relies on histological and immunohistochemical examinations.Case presentationCase 1We report a case of primary neuroendocrine carcinoma of the breast in a 71-year-old Arabic woman who presented with a 3 cm palpable and mobile tumor of the right breast. Clinical and radiological assessment excluded any other primary tumor. Radical mastectomy and axillary lymph node resection were performed. A histopathological examination disclosed the diagnosis of primary breast neuroendocrine tumors, with negative surgical margins and lymph nodes (18 N-/18 N). The tumor cells were positive for neuroendocrine markers, a weak Ki-67 proliferation index and negative Her2/neu. Our patient received adjuvant hormonal treatment with anti-aromatase for 21 months. She is on regular follow-up, and she remains free of disease to date.Case 2A 48-year-old Arabic woman consulted for a right breast nodule. She underwent lumpectomy with right axillary lymphadenectomy. The diagnosis was breast neuroendocrine tumor. Systemic treatment was proposed, but she was lost to follow-up. She consulted 1 year later for a mass in the same breast. A histological and immunohistochemical examination of a mammary biopsy was consistent with a recurrence of the previous neuroendocrine tumor. A radiological assessment showed a large mass in her right breast, ipsilateral axillary lymphadenopathies, and hepatic and pulmonary metastases. She received first-line metastatic chemotherapy, with good clinical and radiological improvement. She refused the mastectomy and was given hormone therapy. One year later, the tumor expanded clinically and radiologically, and she underwent second-line metastatic chemotherapy, with good clinical progress and radiological stability, and she then underwent maintenance hormonal therapy.ConclusionDue to the rarity of primary breast neuroendocrine tumors, no standard therapy exists and the prognosis remains difficult to determine. Studies, including larger series, are needed in order to understand the biological behavior of these tumors.

Expression of somatostatin receptors, SSTR2A and SSTR5, in 108 endocrine pituitary tumors using immunohistochemical detection with new specific monoclonal antibodies

Anaplastic spheno-orbital meningioma: rapid growth after extensive exenteration

Introduction Neuroendocrine tumours (NET) are thought to arise from cells throughout the diffuse endocrine system and can occur almost everywhere in the body. Most NETs arise from the gastrointestinal tract, lung, thymus, and pancreas. Primary neuroendocrine carcinoma (NEC) of the breast is a rare and under-recognized subtype, accounting for less than 1% of breast carcinomas. Only a few small studies and case reports have been reported and there are no clear diagnostic criteria and established treatment options. World Health Organization (WHO) classification of tumor series’ fifth edition was published in 2019 and adopted ‘Neuroendocrine neoplasm (NEN)’ as a term encompassing all tumour classes with predominant neuroendocrine differentiation. NENs of the breast are classified into invasive ductal carcinoma (IDC) with neuroendocrine differentiation (NED), NET, and NEC of small cell or large cell types. Thus we aim to report pathologic reviews and treatment outcomes of patients with NENs of the breast at a single center. Methods We retrospectively screened the medical record of 34,370 patients diagnosed with breast cancer from 2007 to 2022 by Corporate Data Warehouse (CDW) and revealed there were 22 patients diagnosed with primary breast NEN. The pathologist reviewed the pathology slides and reclassified the diagnosis according to the WHO classification of tumor series’ fifth edition. Clinical characteristics, treatment modalities, and therapeutic outcomes were reviewed retrospectively. Results We reviewed pathology slides of 22 patients with histologically proven diagnoses of primary breast NEN from 2007 to 2022. We found only 8 patients meet the criteria of primary breast NEC (large cell 2, small cell 6), 3 patients with NET, and 3 patients with IDC with NED. We excluded 8 patients who did not fulfill the criteria of NEN. The median age of NEN was 48.5 years (range, 31-70) and 6 patients (42.9%) were postmenopausal women. The median follow-up duration was 25.3 months (Interquartile range(IQR), 15.0-54.7). All patients underwent surgery, 3 patients underwent a mastectomy and 11 patients underwent breast-conserving surgery (BCS) with a curative aim. Five patients had lymph node metastasis. There was no expression of the human epidermal growth factor receptor 2 (HER2) in all 14 cases. Hormone receptor expression was shown in 4 of NECs (50%) and all NETs or IDC with NED patients. Patients with primary breast NEC had a median recurrence-free period (RFP) of 14.6 months (95% confidence interval (CI), 11.0-18.2) and median overall survival (OS) of 52.1 months (95% CI, 0.0-120.0). Patients with NET or IDC with NED had an overall favorable outcome, none of the patients died and only one patient with IDC with NED experienced disease progression. The median PFS and OS were not reached in NET or IDC with NED subgroups. Conclusion NETs are rare tumours with a wide range of clinical presentations according to the site of involvement. Primary breast NENs are extremely rare and there are no specific guidelines for treatment. NENs are often underdiagnosed, as neuroendocrine markers are not routinely tested in breast cancer. In this retrospective single-center study, the incidence of primary breast NENs was 0.04% (14 of 34,370 patients) and primary breast NEC was associated with poor prognosis compared with breast NET or IDC with NED. Identifying innovative treatment strategies is needed to overcome poor outcomes of primary breast NEC. Citation Format: Young Kyung Jeon, Ji-Yeon Kim, Jin Seok Ahn, Young Hyunk Im, Kyue-Hee Choi, Sun Young Jeong, Yeji Jung, Jae Yeon Jang, Daeho Choi, Joohyun Hong, Hyo Jung Kim, Soo Youn Cho, Yeon H. Park. Primary neuroendocrine carcinoma of the breast: A case series by WHO classfication in 2019 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-07.

Focal neuroendocrine differentiation can be found in diverse histological types of breast tumors. However, the term, neuroendocrine breast tumor, indicates the diffuse expression of neuroendocrine markers in more than 50% of the tumor cell population. The imaging features of neuroendocrine breast tumor have not been accurately described due to extreme rarity of this tumor type. We present a case of a pathologically confirmed, primary neuroendocrine breast tumor in a 42-year-old woman, with imaging findings difficult to be differentiated from that of invasive ductal carcinoma.

The pathophysiology and the optimal treatment of breast neuroendocrine tumours (NETs) are unknown. We compared the mutational profiles of breast NETs (n = 53) with those of 724 publicly available invasive ductal carcinoma (IDC) and 98 pancreatic NET (PNET) cases. The only significantly different pathogenetic or unknown variant rate between breast NETs and IDCs was detected in the TP53 (11.3% in breast NETs and 41% in IDCs, adjusted p value 0.027) and ADCK2 (9.4% in breast NETs vs. 0.28% in IDCs, adjusted p value 0.045) genes. Between breast NETs and PNETs, different pathogenetic or unknown variant frequencies were detected in 30 genes. For example, MEN1 was mutated in only 6% of breast NETs and 37% in PNETs (adjusted p value 0.00050), and GATA3 pathogenetic or unknown variants were only found in 17.0% of breast NETs and 0% in PNETs (adjusted p value 0.0010). The most commonly affected oncogenic pathways in the breast NET cases were PI3K/Akt/mTOR, NOTCH and RTK-RAS pathways. Breast NETs had typically clock-like mutational signatures and signatures associated with defective DNA mismatch repair in their mutational landscape. Our results suggest that the breast NET mutational profile more closely resembles that of IDCs than that of PNETs. These results also revealed several potentially druggable targets, such as MMRd, in breast NETs. In conclusion, breast NETs are indeed a separate breast cancer entity, but their optimal treatment remains to be elucidated.

Neuroendocrine Tumor of the Breast in a Young Woman with MEN2A Syndrome

Patient: Female, 61-year-oldFinal Diagnosis: Primary breast neuroendocrine tumorSymptoms: Breast lumpClinical Procedure: —Specialty: OncologyObjective: Rare diseaseBackgroundPrimary breast neuroendocrine neoplasms (NENs) are extremely rare, comprising 1–5% of diagnosed breast cancers. The goal of this paper is to describe the current literature on these cancers, along with treatment options and survival data from prior studies.Case ReportA 61-year-old woman presented with a palpable lump in the breast, which upon biopsy was proven to be a primary breast neuroendocrine tumor. This was treated with breast-conserving surgery with sentinel lymph node dissection, followed by adjuvant radiation. She refused anti-estrogen therapy, and 2 years later she presented with metastatic disease, chose not to receive any additional treatment, and died.Several retrospective analyses have illustrated that breast neuroendocrine tumors have a slightly worse prognosis compared to invasive ductal carcinomas (IDCs) when stratified by stage. However, most of the studies had small sample sizes, which makes interpretation of data from these studies difficult to generalize to the overall population of breast NENs.ConclusionsRoutine testing for neuroendocrine markers could identify a larger population of neuroendocrine tumors (NETs). Currently, because of the rarity of these tumors, prospective trials are not available to study them as a distinct entity to evaluate and optimize treatments. Reports indicate that these tumors have overall inferior survival compared to IDCs. Further studies are needed to evaluate this rare entity to improve patient outcomes.

Primary neuroendocrine tumors in the ovary are rare. These tumors arise from the neuroendocrine cell system of ovarian stroma and surface epithelium, and may also arise from teratoma. We present four primary ovarian neuroendocrine tumors and compare clinicopathologic findings based on tumor histogenesis and site of origin. Four primary ovarian neuroendocrine tumors were identified from our 10-year departmental archives. H&E slides and immunostains were reviewed and the diagnoses were confirmed. Clinical history, imaging studies, and follow-up data were obtained from medical records. Patients' ages ranged from 26 to 63. All patients presented with abdominal discomfort and unilateral or bilateral ovarian masses. MRI and CT scans from cases 1 and 2 revealed a solid ovarian mass with no extra-ovarian extension. In case 1, the patient also had a cystic mass in the opposite ovary and an elevated urine 5-HIAA. Microscopically, case 1 revealed a well-differentiated carcinoid tumor with no surface epithelial involvement, and a mature teratoma in the contralateral ovary. Case 2 revealed a stromal carcinoid within the ovarian parenchyma. Imaging studies from cases 3 and 4 showed large complex masses with peritoneal implants and ascites. In both cases 3 and 4, tumor grossly involved both ovarian parenchyma and surface epithelium with multiple pelvic implants. In addition, liver metastases were present in case 4. Microscopically, these tumors were poorly differentiated carcinoma with neuroendocrine differentiation. Histologic sections revealed extensive necrosis, and both cases showed positivity for neuroendocrine markers. Primary neuroendocrine tumors in the ovary are rare and consist of a group of heterogeneous malignancies that express similar immunohistochemical markers. Primary neuroendocrine tumors that are limited to the ovarian parenchyma often arise from ovarian stroma and teratoma, and are carcinoid tumors with a good prognosis. Neuroendocrine tumors that arise from surface epithelium or dedifferentiate from de novo carcinoma often involve both ovarian stroma and surface epithelium and clinically present as aggressive malignancies with poor prognoses.

Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20%

INSM1 expression in primary and metastatic neuroendocrine neoplasms at distinct locations

Simple SummaryBreast tumors exhibiting neuroendocrine differentiation are a heterogeneous group of tumors that have been variously defined in previous World Health Organization (WHO) classifications. In the WHO Classification of Tumours, 5th edition, neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) of the breast, both of which are invasive cancers, are classified as neuroendocrine neoplasms (NENs) of the breast. However, the clinical significance of NE differentiation in breast cancers, especially in NETs of the breast, is not yet fully understood, and a large overlap appears to exist between breast cancers showing NE differentiation and invasive breast cancer of no special type (IBC-NST). While breast NECs show distinct clinical and morphological features, diagnosis of NETs based on the morphological characteristics alone can be challenging; one reason is that breast NETs do not necessarily have the same morphological characteristics as those of NENs arising in other organs. Thus, the heterogeneity of breast tumors with neuroendocrine differentiation and the changes in their classifications over the years have left many open issues that still need to be resolved. In this review, we shall summarize the history of breast “NENs,” including of mixed types of tumors and the characteristics of these tumors, and discuss their differences from NENs arising in other organs.Breast tumors with neuroendocrine (NE) differentiation comprise an uncommon and heterogeneous group of tumors, including invasive breast cancer of no special type (IBC-NST) with NE features, neuroendocrine tumors (NETs), and neuroendocrine carcinoma (NEC). The most recent World Health Organization (WHO) classification in 2019 defined neuroendocrine neoplasms (NENs) of the breast (Br-NENs) as tumors in which >90% of cells show histological evidence of NE differentiation, including NETs (low-grade tumors) and NEC (high-grade). Due to the low prevalence of these tumors and successive changes in their diagnostic criteria over the years, only limited evidence of these tumors exists, derived mainly from case reports and retrospective case series. Breast tumors with NE differentiation are usually treated like the more commonly occurring IBC-NSTs. Immunohistochemistry (IHC) of breast tumors with NE differentiation usually shows a hormone receptor (HR)-positive and human epidermal growth factor type 2 (HER2)-negative profile, so that hormonal therapy with cyclin-dependent kinase (CDK)4/6 inhibitors or other targeted agents would be reasonable treatment options. Herein, we present a review of the literature on breast tumors with NE differentiation as defined in the latest WHO 2019 classification, and discuss the clinical management of these tumors.

Background: Neuroendocrine breast tumors may be primary or secondary with a fairly rare frequency; The diagnosis is based on the results of the pathological findings and the characterization between the primary and secondary origin is guided by the data of radiology (echomammography), the pathological and immunohistochemistry examinations as well as the data reported by the octreoscanner. Case presentation: We describe here a case of a 70-year-old patient who had a dorsal pain for six months. A Scan of rachis showed a tumoral process of the vertebral body of D2 extending intramedullarily. The realization of a thoraco abdomino-pelvic CT scan as part of an assessment of extension, revealed the presence of a left mammary nodule with diffuse liver metsatases. Liver and breast biopsy evoking a localization of a neuroendorin tumor. Conclusion: This presentation reveals that the Differentiation between primary or secondary neuro endocrine breast tumor is based on the results of the pathological, immunohistochemical findings and radiological characteristics. In the absence of a generalized metastatic disease, the treatment is similar to Invasive breast tumors, under metastasis conditions. The treatment consists of various therapetical modalities including chemotherapy, hormonotherapy targeted therapies.

Primary neuroendocrine tumor (NET) of the breast is very rare. We present a case of a pathologically confirmed, primary breast NET in a 49-year-old woman with 68Ga DOTANOC PET/CT imaging findings. 68Ga DOTANOC PET/CT revealed somatostatin receptors expressing active lesions in primary right breast NET with metastases to multiple bilateral axillary and right cervical lymph nodes, bilateral lungs, and multiple skeletal sites.