Primary Well-Differentiated Neuroendocrine Tumor of the Breast: A Case Report and Literature Review

Introduction

PATHOLOGICAL DEFINITION OF BREAST NEUROENDOCRINE NEOPLASMS (NEN):

Previously, the WHO classification of breast neuroendocrine carcinomas required more than 50% of cells to have neuroendocrine features, but this has been changed over the years. In 2019, the WHO classified NENs of the breast, like other organs, into well-differentiated neuroendocrine tumors (NETs), highly aggressive neuroendocrine carcinomas (NECs), and invasive breast cancers of no special type (IBCs-NST) with neuroendocrine differentiation [4].

There are several markers for identification of neuroendocrine lineage, including synaptophysin, chromogranin A, somatostatin receptors, and INSM1. Other immunohistochemical markers can identify the primary source, which include estrogen receptors, progesterone receptors, HER-2 neu receptors, and cytokeratins [5].

Case Report

TREATMENT SUMMARY:

The patient underwent breast-conserving surgery and sentinel lymph node biopsy. Final pathology revealed a breast primary neuroendocrine tumor measuring 2.8 cm with clear margins, and 2 lymph nodes from the left axilla were negative for malignancy. After discussing the risks and benefits of chemotherapy, the decision was made to forego chemotherapy. Subsequently, she underwent adjuvant radiation therapy, receiving 42 Gray in 16 fractions and 8 Gray boost over 4 fractions. She was prescribed adjuvant anti-estrogen therapy with anastrozole with the planned treatment duration of 5–7 years.

After a few months of anti-estrogen therapy, she discontinued it because of adverse effects, primarily hot flashes and joint stiffness, and was lost to follow-up until she presented to the hospital 2 years later with low back pain and severe hypercalcemia (serum calcium level >15 mg/dL). A workup revealed a 5.8-cm right upper-lobe lung mass, pathologic mediastinal adenopathy, and multifocal osseous metastatic disease throughout the ribs, spine, and scapula (Figure 6). Her back pain was the result of a pathologic compression fracture of the T7 vertebral body with extraosseous extension (Figure 7). Bronchoscopy biopsy and immunohistochemical (IHC) stains revealed malignant cells that were GATA3-positive and TTF-1/p40-negative (Figure 8A, 8B). This profile was most consistent with a breast carcinoma metastasis, similar to her earlier diagnosis of breast NET. She declined all further therapy, entered hospice care, and died 1 month later.

Discussion

Several retrospective analyses of breast NEN have been conducted over the past 2 decades. Most studies are hampered by small sample sizes and comparison with historical controls, making it difficult to generalize the data to the wider population of breast NENs (Table 1). The largest such retrospective analysis of the National Cancer Database was published in Surgical Oncology by Martinez et al, in which a sample of 1389 patients were evaluated and compared to IDC of the breast. Most of those patients were over the age of 50 years. The characteristics analyzed showed that, although there was a higher proportion of estrogen receptor-negative and progesterone receptor-negative patients in the breast NET cohort than invasive ductal cancer, most NETs were ER-positive, as in our patient. Systemic chemotherapy was also given more often in the NET group. The 5-year overall survival was worse than for invasive ductal carcinoma at every stage, with a hazard ratio of 1.5–2 [5].

Earlier studies also appear to show that breast NETs have worse outcomes than IDCs. This was studied by Wang et al in a retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) database from 2003 to 2009 with a sample size of 142. Similarly, estrogen receptor- and progesterone-negative tumors were more often seen in the neuroendocrine cohort, and 5-year overall survival was 53.6% for NET versus 79.8% for invasive mammary carcinomas (IMC). Once again, at each stage, the overall survival was inferior in the neuroendocrine cohort [6].

Other studies are summarized in Table 2, but because of small sample sizes, definitive conclusions are difficult. However, they are worthy of discussion, given the relative paucity of data on these cancers. Sapino et al analyzed prognostic markers for NECs and found that low-grade ER-/PR-positive expression and mucinous differentiation are associated with a favorable prognosis [7].

Rovera et al evaluated NETs (defined as >50% positivity for NE markers) and compared them to ductal carcinomas with <50% NE markers. They did not find NETs have a worse prognosis compared to the IDCs with minor neuroendocrine marker positivity. They also compared NEC to IDC and ILC, finding that patients with NEC did not have cancer recurrences, showing that NECs were less aggressive. This has not been shown in any other studies and hence is an outlier. The small sample size makes it difficult to draw definitive conclusions [8].

The overall incidence and prevalence of all neuroendocrine tumors have been steadily growing, owing to better diagnostic testing and early stages of diagnosis due to better screening techniques. Simultaneously, survival of all neuroendocrine tumors has also been improving, especially because of improved systemic treatments and early detection. However, there is very little data on breast neuroendocrine cancers in this study of the SEER database from 2009 to 2012 [6].

Oncotype Dx and Mammaprint molecular testing have become essential tools for risk stratification and determination of chemotherapy benefit for ER-positive and HER-2 negative breast cancers. Neither study identified NEC in their subset analysis to enable use of these tools for risk stratification. The role of chemotherapy in these cancers is unclear due to a lack of relevant data from these studies [9,10].

A significant aspect of our case was the early discontinuation of anti-estrogen therapy, which could have affected the relapse and mortality of our patient. A meta-analysis published in 2023 by Eliassen et al analyzed non-adherence or early discontinuation (non-persistent) of anti-estrogen therapy in estrogen receptor-positive breast cancer patients. Out of 10 studies, 7 showed significantly poorer event-free survival for the non-adherent or non-persistent patient groups, with hazard ratios (HRs) ranging from 1.39 (95% CI, 1.07 to 1.53) to 2.44 (95% CI, 1.89 to 3.14). Seven out of 10 studies also demonstrated significantly reduced overall survival in the groups with non-adherence and non-persistence, with HRs ranging from 1.26 (95% CI, 1.11 to 1.43) to 2.18 (95% CI, 1.99 to 2.39) [11].

CDK 4/6 inhibitors like abemaciclib have been approved for the adjuvant treatment of hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence based on the MONARCH-E clinical trial [12,13]. Ribociclib has also received approval for use in Stage 2 and 3 ER-positive breast cancers with high-risk features [13]. However, neither study had any data on neuroendocrine differentiation. A case report published by Zouki et al in a patient with metastatic breast NEC demonstrated a positive response to endocrine therapy with palbociclib and triptorelin [12,14]. Therefore, the clinical benefit of these novel agents in the treatment of NENs must be further investigated.

Conclusions

Our case illustrates a typical presentation of a neuroendocrine tumor of the breast, most of which are estrogen- and progesterone receptor-positive and HER2-negative. The treatment approach is similar to that of invasive ductal carcinoma, with a combination of therapeutic options that include surgery, chemotherapy, radiation, and anti-estrogen therapies. Because of a lack of prospective randomized control trials, whether this approach is adequate or excessive cannot be determined.

The role of novel CDK 4/6 inhibitors in the adjuvant therapy of estrogen receptor-positive breast NEN has not been established. There have not been any randomized clinical trials to compare outcomes with and without chemotherapy. Molecular analysis using Oncotype DX or Mammaprint is also lacking to determine the risk of recurrence and to understand the benefit of systemic chemotherapy. Universal testing for neuroendocrine markers could identify a larger subset of breast neuroendocrine tumors that could be better studied using prospective randomized controlled clinical trials.