Abstract
Primary neuroendocrine carcinoma of the breast (NECB) is a rare malignant tumor with controversial biological behavior and a lack of data guiding treatment decisions due to its scarcity. Cancer gene-expression profiling tests provide a better indication of clinical prognosis and help determine the best clinical management versus the traditional clinical and pathological parameters. This is a report of a NECB with a genetic assay that showed a low-risk tumor despite high-grade and poorly differentiated histopathological features. Patient outcomes correlate with the low risk classification without the need for adjuvant chemotherapy despite the standard clinical-pathologic approach. Analysis of cancer related genes expression and outcomes in historical NECB may elucidate new insight of this rare disease.
Introduction
Neuroendocrine carcinoma of the breast (NECB) is a rare subtype of invasive breast carcinoma, making up <1% of breast epithelial tumors [1]. The World Health Organization (WHO) defines NECB as tumors which neuroendocrine markers are expressed to a greater or lesser degree, with evidence of ductal carcinoma in situ component and other primary sites ruled out [1]. NECB are morphologically similar to neuroendocrine tumors (NET) of the gastrointestinal tract (GI) and lungs [2], and commonly misdiagnosed as metastatic NET to the breast, which has negative clinical management implications. Aside from the diagnostic challenge, there is scarce literature on NECB outcomes, indicating further studies are required to better understand management strategies, prognosis, and outcomes. Cancer gene-expression profiling tests provide practitioners a better indication of clinical prognosis and help determine best clinical management versus traditional clinical and pathological parameters [3,4].
Oncotype DX® (ODX) breast cancer assay is a commercially available genomic predictor test evaluating mRNA expression level of 16 cancer-related genes (proliferation, invasion, estrogen signaling) and 5 reference genes. It reports a single recurrence score (0–100) that is significantly associated with the 10-year risk of distant recurrence and classifies risk groups: low (<18), intermediate (≥18, <31), and high risk (≥31) [5]. High-risk patients have the greatest 10-year risk of distant recurrence, after 5 years of hormonal therapy alone (7%, 14%, and 31%, respectively), and benefit with the addition of chemotherapy with a 12% decrease in the 10-year risk of distant recurrence (95% CI: 6%–18%) [6].
The ODX test is validated and indicated in ductal or lobular breast carcinoma, estrogen-receptor positive, HER-2 negative, and limited nodal involvement (0–3 positive nodes) when treated with endocrine therapy alone [7]; whether the findings apply to other patients outside this criterion, as in NECB, remains unknown.
We report outcomes of a rare case of primary NECB with conflicting pathological features of a poorly differentiated, high-grade neuroendocrine carcinoma presenting with a low Oncotype DX® Breast Recurrence assay score.
Case report
A 57-year-old female with a history of hypothyroidism, presented in October 2014, with an abnormal mammogram showing multiple nodules with circumscribed margins in both breasts. Further diagnostic workup revealed a 1.5
A right breast lumpectomy with sentinel lymph node biopsy was performed December 2014. Final pathology reported infiltrative neoplasm with nested and trabecular architecture, vesicular nuclei, necrosis, abundant mitotic figures (up to 23 mitoses per 10 high-power field), and extensive lymphovascular invasion without breast in situ components. Immunohistochemical staining (IHC) of tumor cells was positive for membranous E-cadherin labeling, synaptophysin (strong), chromogranin-A (focal), and ER/PR (>90%) with 75% Ki-67 proliferation index. IHC was negative for HER-2, p63, smooth muscle myosin heavy chains (SMMHC), and calponin. A high-grade neuroendocrine carcinoma, solid type, was diagnosed based on morphology, immunophenotype, high mitotic rate, and necrosis; however, an in situ breast component was absent. The lesion did not display histologic features of a small-cell carcinoma or a large-cell neuroendocrine carcinoma. Additional IHC was negative for CDX-2, TTF-1, and WT-1, and positive for mammaglobin-A. Results confirmed high-grade, poorly-differentiated breast neuroendocrine carcinoma (Fig. 2, E-H). Sentinel lymph nodes were negative and computed tomography from chest, abdomen and pelvis with contrast was negative for metastatic disease. The tumor was staged pT2N0M0 (stage IIA), according to the 7th edition American Joint Committee on Cancer staging system [8].
The National Comprehensive Cancer Network guidelines do not address management of NECB due to the paucity of clinical trial data [9]. ODX testing performed showed a low risk recurrence score of 3, which does not indicate adjuvant chemotherapy, although, ODX is not validated for NECB [6]. Systemic chemotherapy was offered, based on treatment of high-grade NET, with platinum and etoposide [10]. The patient refused chemotherapy, was treated with radiation and hormonal blocking therapy (letrozole 2.5 mg daily), and remains disease-free more than two years after surgical resection.
Discussion
Neuroendocrine carcinoma of the breast (NECB) is a rare malignant breast tumor representing <1% of all breast carcinomas [1,11–14]. It was first described in 1963 by Feyrter et al. [15], however, the WHO did not establish diagnostic criteria until 2003, with the latest update in 2012 [1]. NECB is histopathologically similar to NET of the GI tract and lungs, in which one or more neuroendocrine marker (chromogranin A, synapthopysin, neuron specific enolase) is expressed to a greater or lesser degree [1]. The presence of ductal carcinoma in situ with similar cytological features may confirm diagnosis, in addition to ruling out metastatic NET [1].
Primary NECB generally occur in women during the sixth or seventh decade of life, as a large, advanced stage tumor mass (>20 mm) with high-grade histology [12]. The neuroendocrine differentiation itself is an independent adverse prognostic factor for overall survival (OS) and disease-specific survival (DSS), when compared to invasive mammary carcinoma, not otherwise specified (IMC-NOS) [12]. Wang et al. showed age (>60 years) and positive lymph node status as independent prognostic factors for poor OS, while negative progesterone receptors, positive lymph nodes, and lack of surgical treatment are independent prognostic factors for DSS [12].
Radiological findings in mammography include highly-dense, round, oval, or lobular mass with nonspiculated margins and infrequent calcifications when compared to invasive mammary cancer [14]. Ultrasonography findings include an irregular hypoechoic mass with indistinct margins, with or without enhanced posterior acoustic features [13]. MRI usually reveals an irregular mass with irregular margins and a rim or heterogeneous internal enhancement pattern, in addition to a washout pattern in time-intensity kinetics [14]. Imaging-guided CNB is useful in establishing a diagnosis; however, over two-thirds of the literature report initial misdiagnosis, rectified only after surgery [16].
Histopathologic diagnosis of NECB is based on morphological features and immunohistochemical markers. On microscopic evaluation, morphological features resemble lung and GI NET and characterized by cellular monotony, abundant eosinophilic cytoplasm, nuclei with stippled chromatin, and surrounding dense sparsely cellular collagenous stroma [16]. Immunohistochemical markers, such as chromogranin A, and synaptophysin are indicators of neuroendocrine features [17]; although, due to morphologic overlap between metastatic NET and primary NECB, further histopathological workup is required to determine the most appropriate clinical management and avoiding unnecessary procedures [18].
Due to its rarity, there is no consensus on the treatment of patients with primary NECB and management is usually similar to that of invasive ductal carcinoma (IDC), involving surgery based on tumor location and clinical stage, adjuvant radiotherapy (for which the role is not well known), and chemotherapy (for which the ideal agent has not been determined) [19–21]. Chemotherapy has been the mainstay treatment of high-grade, poorly differentiated NET of the lung, GI tract, and pancreas although, the ideal chemotherapy for GI and pancreatic NET has not been determined [10]. Even with the lack of clinical trial data, it is evident that patients with NET have worse outcomes, even with early stage diagnosis [22].
Results vary when analyzing patient outcomes in NECB. In 2014, Wang et al. published the first and largest population study evaluating 142 cases of primary NECB recorded in the surveillance, epidemiology, and end results (SEER) database from 2003–2009. They reported NECB to be an aggressive mammary carcinoma with poor outcomes when compared to IMC-NOS [12]. Likewise, Wei et al.. reviewed 74 patients with primary NECB finding it more aggressive than IDC, with higher propensity for local and distant recurrence and poorer overall survival [23]. On the other hand, two studies with 35 and 10 patients showed no differences in outcomes, while another three studies with 13, 12, and 7 patients suggest NECB is less aggressive with better survival than infiltrating ductal or lobular carcinoma [11,24–27].
Several factors in our case indicate better prognosis, such as age ≤60 years, negative lymph nodes, strong ER/PR positivity, and low ODX score, despite a high-grade, poorly differentiated tumor without small cell morphologic features. ODX testing was designed to provide prognostic and predictive data regarding chemotherapy benefit in ductal and lobular breast cancers [6]. It takes into account ER/ PR status, Ki 67, and other molecular/genetic results [5] but, it is unclear if this testing holds true in primary NET of the breast that are lymph node negative and hormone receptor positive. So far, patient outcomes correlate with the low ODX recurrence score without the need for adjuvant chemotherapy, despite the standard clinical-pathologic approach of systemic chemotherapy in a high-grade, poorly differentiated NET. Recurrence of poorly differentiated NET typically occurs within two years from diagnosis; however, our patient remains cancer free at 28 months.
Conclusion
The treatment of NECB is not standardized due to a paucity of data given the rarity of the tumor. ODX could potentially be used to better define treatment and outcomes, although further evaluation is needed to determine appropriate chemotherapy regimens. The tracking of NECB patients who undergo genomic testing could provide significant information, guiding treatment strategies, while assessing patient outcomes.
Footnotes
Acknowledgements
The authors will like to thank Michelle Sittig RN and Victoria Eskay for providing language and writing assistance and Roy Hatch for literature and data gathering.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.