Abstract
Neuroendocrine tumors (NETs) represent neoplastic growths that arise from cells of neuroendocrine differentiation. They constitute a clinical spectrum from low-grade NETs with an indolent course to the aggressive undifferentiated high-grade neuroendocrine carcinoma. We report a rare case of axillary neuroendocrine carcinoma of unknown primary site. The patient underwent axillary nodal excision followed by radiation therapy with good tolerability. However, distant cerebellar metastatic recurrence was evident 9 months later. We additionally review the literature on cases of axillary NETs. Their heterogenous behavior depict the need for strict clinical surveillance to allow for early identification of occult secondary metastasis and improve prognostic outcomes.
Introduction
Neuroendocrine tumors (NETs) are a diverse entity of neoplasms that can be broadly classified into 2 main groups; well-differentiated NETs and poorly differentiated neuroendocrine carcinomas. 1 They constitute a rare class of neoplastic processes, comprising 0.5% of all newly diagnosed malignancies with an incidence rate of 8.52/100 000 individuals in the United States.2,3 Their name arises from their resemblance to serotenergic neuronal cells through harboring dense secretory granules detected by immunohistochemical staining. Their ‘endocrine’ qualities stem behind their ability to secrete physiologically active monoamines into the blood stream. 2 There are 3 main pathologic hallmarks that govern the clinical behavior of NETs. First, the histologic grade outline the aggressive nature of such neoplasms, defined by the number of mitoses and Ki67 indices. 4 These properties would further classify the tumor as low, intermediate, or high grade, with high grade possessing the most aggressive behavior and termed neuroendocrine carcinoma. Second, their differentiation outline the degree of resemblance of neuroendocrine cells to their surrounding native tissues from which they have originated. The third hallmark used is stage, which is defined by the tumor node metastasis system, with early stage being amenable to surgical resection, and advance stage demonstrating its unresectable nature or metastatic properties. 4 These elements provide further prognostic implications and guide management. Axillary neuroendocrine carcinomas are exceptionally rare and have a variable clinical course. Herein, we present a case of axillary neuroendocrine carcinoma and reviewed the current literature to further recognize its prognostic implications.
Case Description
An 84-year-old male, with a history of type 2 diabetes mellitus, chronic kidney disease, and squamous cell carcinoma (SCC) of the right wrist, status post-Mohs micrographic surgery with negative margins 1 year prior, presents to the outpatient clinic with a right axillary lump. Review of systems was unremarkable. Physical exam was notable for a large nontender, right axillary mass with no evidence of surrounding edema nor discharge. A fine-needle aspiration was performed, disclosing atypical cells suggestive of malignancy. Lymph node flow cytometry was negative for monoclonal B-cell populations. Diagnostic mammogram was negative for calcifications or mammographic evidence of malignancy in bilateral breasts. In view of high suspicion of underlying malignant neoplastic process, a subsequent positron emission tomography/computed tomography (PET/CT) scan was performed that revealed an intensely metabolically active right axillary lymph node measuring 18.9 × 28.3 mm with a standardized uptake value of 10.6 (Figures 1 and 2). No evidence of pulmonary nodularity, nor suspicious adenopathy in head and neck.
(A) Axial CT section demonstrating an enlarged right axillary node measured 18.9 × 28.3 mm. (B) Axial PET revealing an intensely active right axillary lymph node.
PET scan at MIP disclosing a right axillary hypermetabolic lymph node (arrowed). MIP, maximum intensity projection.
The patient subsequently underwent a whole lymph node excision without evidence of extra nodal disease. Histopathological findings revealed high-grade neuroendocrine carcinoma involving 1 lymph node measuring 1.5 cm in size. The neoplastic cells demonstrated positivity for cell adhesion molecule 5.2, cytokeratin AE1/AE3, chromogranin, synaptophysin, p16, and cluster of differentiation 56 (Figure 3). In view of his age, co-morbidities, including underlying chronic kidney disease with sensorineural hearing loss, the patient was not a good candidate for platinum-based chemotherapy. Hence, he underwent adjuvant radiation therapy with repeated CT scans showing no evidence of disease recurrence. Nine months later, the patient presents to the clinic with a 1 week history of nausea, vomiting, and diplopia. A follow-up MRI brain was performed revealing 3.9 × 3 cm left cerebellar mass with surrounding vasogenic edema and compression of fourth ventricle, suspicious for metastatic recurrence. After further discussion, the patient opted to pursue a comfort care approach with hospice services.
(A) Histologic microscopic appearance of right axillary lymph node specimen under Hematoxylin eosin staining at ×20 magnification. (B) Immunoreactivity to CAM 5.2 at ×40 magnification. (C) Immunoreactivity to CD56 at ×40 magnification. (D) Immunoreactivity to synaptophysin at ×40 magnification. (E) Immunoreactivity to p16 at ×40 magnification. CAM, cell adhesion molecule; CD, cluster of differentiation.
Materials and Methods
A review of the literature was conducted to identify all cases of axillary neuroendocrine carcinomas. In order to perform a sensitive search, key words were developed using MeSH terms in the databases PubMed and Scopus in November 2025. The search strategy included the search terms ‘axilla’, ‘axillary’, ‘neuroendocrine tumors’, and ‘neuroendocrine carcinoma’. The review was performed using the ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ algorithm. 5 We have included all relevant articles (observational studies, case series, case reports) published from the year 1948 to 2025. No language restrictions were implemented. All cases that involve the axilla as the primary site of identification of NET were selected. For every selected article, we have extracted data involving year of publication, patient’s age, gender, primary site of identification, secondary identifiable sites, immunohistochemical markers identified, treatment modality, and outcomes. Articles were excluded if insufficient data was found, were not related to NET, involved nonneoplastic growths, or those with nonaxillary NET.
Results
The search strategy resulted in the identification of 740 articles across PubMed and Scopus (Figure 4). After excluding duplicates, a total of 720 articles were initially screened for eligibility based on their title and abstracts with those requiring reassessments performed under the bases of full-text. Following the initial screen, 42 articles fulfilled the initial inclusion criteria and were further analyzed for eligibility. After excluding articles based on the predetermined exclusion criteria, a total of 8 articles were selected for inclusion in the review (Table 1). Seven of the articles were case reports and 1 being a case-series. The ages of the aforementioned cases were between 46 and 69 years with females representing two-thirds of the cases. Out of the 9 cases identified, 5 cases did not reveal other secondary identifiable sites of metastasis. In terms of therapeutic modalities implemented, the majority underwent surgical excision followed by radiation therapy ± chemotherapy.
Flow diagram outlining the literature search implement using the PRISMA 2020 algorithm. Met, metastatic; MTC, medullary thyroid carcinoma; NET, neuroendocrine tumor; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Demographics, Primary Site, Secondary Sites, Immunohistochemical Marker Positivity, Treatment, and Follow Up Outcomes of All Cases Included in the Review.
Abbreviations: AE, antibody clones; A&W, alive and well; CAM, cell adhesion molecule; CD, cluster of differentiation; Ch, chromogranin; ck, cytokeratin; CTx, chemotherapy; ER, estrogen receptor; F, female; GATA-BP3, GATA-binding protein 3; Grim, grimelius; ICI, immune checkpoint inhibitor; L, left; LN, lymph node; LWK, low weight keratin; M, male; NA, not available; NSE, neuron specific enolase; p53, tumor protein 53; PD, progression of disease; PR, progesterone receptor; R, right; RM, radical mastectomy; Sy, synaptophysin; TKI, tyrosine kinase inhibitor; WLE, wide local excision; XRT, radiotherapy.
Discussion
NETs represent a heterogenous group of rare neoplastic processes derived from tissues of neuroendocrine differentiation. They are known for their variable clinical behavior, guided by their histologic tumor grading and differentiation. There are inherited risk factors associated with NETs including a family history and certain genetic syndromes such as multiple endocrine neoplasia (MEN) type 1, MEN type 2, von Hippel-Lindau syndrome, and neurofibromatosis type 1. 14 However, the majority of the cases arise sporadically with no identifiable germline mutations. Pancreatic, gastrointestinal, and respiratory tracts are the most common primary sites for such neoplasms to arise. 15 NETs of unknown primary site represent an uncommon entity that constitute <5% of all cancers of unknown primary site. 16 In a series of 750 patients diagnosed with NET that were followed over a period of 24 years, only 10% were classified arising from an unknown primary site. 17 Our patient exhibited an unusual location for a neuroendocrine carcinoma, with no other locations of hypermetabolic activities based on PET/CT scan. Although a Dotate G86 PET scan may have been utilized to identify the primary site, the primary oncology team decided to defer further scans because the high-grade neuroendocrine carcinoma exhibited high fluoro-deoxyglucose avidity on PET/CT. Furthermore, given the anatomic drainage pattern, metastatic disease of the patient’s remote history of right-hand SCC with neuroendocrine transformation could also be plausible. However, histological specimens of the right-hand SCC were not available to allow for microscopic comparison with the patient’s newly diagnosed high-grade neuroendocrine carcinoma.
In terms of the treatment of poorly differentiated neuroendocrine carcinomas, comprehensive investigations should be pursued to determine the resectability of the tumor. For cohorts amenable to surgical resection, treatment should broadly entail surgical resection followed by adjuvant chemotherapy and radiation therapy. 18 Based on the cases reviewed, 5 out of the 9 cases received chemotherapy and radiation therapy. Our patient was not deemed to be a good candidate for platinum-based chemotherapy secondary to his underlying chronic kidney disease and sensorineural hearing loss. Despite treatment, prognosis tends to be poor as 4 of the cases analyzed demonstrated disease progression. Furthermore, a trial involving the use paclitaxel, carboplatin, and etoposide in poorly differentiated neuroendocrine carcinoma including those of unknown primary found a complete response rate in 15% of patients with a median survival of 14.5 months. 19
Conclusion
NETs are a spectrum of a heterogenous group of neoplasms associated with variable presentations and outcomes. Axillary neuroendocrine carcinoma of unknown primary is a rare clinical entity known for its aggressive clinical course and poor prognosis. The presented case and literature review highlight the transient sensitivity of such tumors to chemotherapy and radiation treatment. A multidisciplinary clinical approach should always be implemented to avoid diagnostic delays and allow for early initiation of treatment. Further research is needed to identify molecular therapeutic targets to improve clinical outcomes.
Footnotes
Acknowledgements
The authors would like to thank Dr Frank Honkanen for providing assistance in the collection and description of histopathology microscopic slides.
Author Note
Prior Presentation of Abstract Statement: The abstract was not presented at other conferences prior to publication of the article.
Ethical Considerations
Our institution does not require ethical approval for reporting of individual cases or case series.
Consent for Publication
A written informed consent was obtained from the patient’s legally authorized representative for their anonymized information to be published in this article.
Funding
The authors received no financial support for the research and authorship of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.