Neuroendocrine Carcinoma of the Submandibular Gland in an Older Adult: A Rare Case and Literature Review

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies arising from neural crest cells that exhibit neuroendocrine differentiation [1]. These tumors can develop in various organs and tissues, with the digestive and respiratory tracts being the most affected regions. In the head and neck region, the incidence of NETs is 0.3% and most frequently involves the larynx, particularly the supraglottic region, with nearly 700 cases reported in the literature to date [1]. Other sites include the paranasal sinuses, accounting for approximately 10% to 20% of cases, and the salivary glands. Primary NETs of the salivary glands are exceedingly rare, accounting for only 1% to 3% of major salivary gland malignancies [1,2]. Conversely, NETs of the sublingual and minor salivary glands are exceptionally uncommon and pose diagnostic challenges due to their resemblance to NETs originating from the surface mucosa of the upper aerodigestive tract. These variations in incidence reflect the differential distribution of neuroendocrine cells across these anatomical regions [3]. According to the 4th Edition of the World Health Organization (WHO) Classification of Head and Neck Tumors [4], two histological subtypes of salivary gland NETs fall under the category of poorly differentiated carcinomas: small cell neuroendocrine carcinomas (SCNECs), which represent most salivary gland NETs, and large cell neuroendocrine carcinomas (LCNECs), which are exceedingly rare [5]. These considerations highlight the rarity and complexity of NETs in the head and neck region. Due to their overlapping histological features, primary salivary gland NECs must be distinguished from metastatic neuroendocrine carcinomas (NECs), particularly those originating from the lung or skin (Merkel cell carcinoma). Diagnosis requires a combination of histopathological analysis, immunohistochemical profiling, and imaging technique, such as computed tomography (CT), positron emission tomography CT (PET-CT), and magnetic resonance imaging (MRI) to exclude secondary lesions [6]. In this report, we describe the case of a 78-year-old man with NEC of the submandibular gland, review existing literature, and discuss the diagnostic challenges, treatment strategies, and prognosis for this rare malignancy.

Case Report

A 78-year-old White man with no history of smoking or alcohol use and with no relevant comorbidities presented with a painless voluminous neoplasm measuring 6×4.5 cm in diameter (Figure 1) with rapid growth in the last month. The lesion, as shown in the contrast-enhanced CT images, exhibited a large central area of necrosis and extended to the subcutaneous plane, in close contiguity with the left submandibular gland (Figure 2). Histological examination of a large-core needle biopsy obtained via tru-cut revealed fibrous tissue diffusely replaced by neoplastic cells, consistent with the morphological and immunohistochemical characteristics of NEC. Immunohistochemical analysis demonstrated tumor cell positivity for CD56, 34beta12, pan cytokeratin (CK), synaptophysin, chromogranin, and leukocyte common antigen. The high proliferative index, evaluated by mind bomb 1/Ki-67, reached 90%, confirming the high aggressiveness of the tumor. A total-body CT scan excluded metastatic lesions in other sites, confirming the neoplasm’s primary origin. The case was subsequently discussed in the multidisciplinary tumor board of the hospital, where the treatment strategy was planned. Based on the tumor board’s recommendations, the patient underwent surgical resection, including total removal of the left submandibular gland and the overlying skin and an ipsilateral modified radical neck dissection (levels I–V) (Figure 3).

Histopathological analysis of the neoplasm revealed a malignant neoplasm with features consistent with a high-grade NEC of the submandibular gland (Figure 4). Hematoxylin and eosin–stained sections (Figure 4A–4D) demonstrated trabeculae and large nests of tumor cells composed of elements with a high nucleus-to-cytoplasm ratio, scant cytoplasm, marked nuclear hyperchromasia, and finely granular chromatin, occasionally coarse. The tumor showed high mitotic activity, with numerous mitotic figures, abundant apoptotic debris, and extensive areas of necrosis. At higher magnification, neoplastic cells displayed prominent nucleoli, further supporting the diagnosis of a poorly differentiated malignant neoplasm. Immunohistochemical investigation further clarified the characterization of the tumor tissue.

Staining with chromogranin A demonstrated diffuse cytoplasmic positivity, with a distinctly perinuclear dot-like pattern, suggesting a neuroendocrine differentiation of the tumor (Figure 4E). Similarly, immunostaining with CKAE1/AE3, used to confirm the epithelial origin of the neoplasm, revealed perinuclear dot-like positivity, further supporting the diagnostic suspicion (Figure 4F). To exclude a lymphoproliferative disorder, staining for leukocyte common antigen was performed, which resulted in complete negativity, confirming the non-hematological nature of the neoplasm (Figure 4G). Staining with CD56, a marker frequently expressed in neuroendocrine neoplasms, demonstrated diffuse membranous positivity across tumor cells, providing additional support for the diagnosis (Figure 4H). The Ki-67 proliferative index was markedly elevated, reaching approximately 80% in hot-spot areas, consistent with the high proliferative activity and aggressive behavior of the neoplasm (Figure 4I). Finally, tumor cells showed fine granular cytoplasmic positivity for synaptophysin (Figure 4J). These histomorphological and immunophenotypic features were diagnostic of high-grade NEC, according to current WHO/International Agency for Research on Cancer (IARC) classification criteria. Representative photomicrographs at high magnification are provided to clearly illustrate the diagnostic features.

Based on tumor board recommendations, the patient received complementary carboplatin chemotherapy. At 5-year follow-up, the patient remains disease-free with no clinical or radiological evidence of recurrence (Figure 5).

Discussion

This case report provides valuable insight into the diagnosis and management of primary NEC of the submandibular gland, emphasizing the importance of considering this rare entity in the differential diagnosis of submandibular masses, the role of immunohistochemistry in establishing a definitive diagnosis, and the potential benefit of a multidisciplinary therapeutic approach.

Neuroendocrine neoplasms comprise a heterogeneous spectrum of tumors showing neuroendocrine differentiation, ranging from indolent, well-differentiated neoplasms, historically referred to as carcinoids in some organ systems, to highly aggressive NECs, with an estimated incidence of 2 to 5 cases per 100 000 person-years worldwide [8]. Epidemiological data indicate a significant increase in the incidence of neuroendocrine neoplasms over recent decades, with age-adjusted rates in some populations rising from approximately 1.6 to over 8.5 per 100 000. Well-differentiated NETs constitute most cases, while high-grade NECs represent a smaller but clinically important subset due to their aggressive behavior [9]. To reduce inconsistency across site-specific classifications, the WHO/IARC expert consensus proposes a common framework applicable across anatomic locations, primarily distinguishing well-differentiated NETs from poorly differentiated NECs. In most organ systems, NETs are graded (G1–G3) according to mitotic count and/or Ki-67 labeling index (and sometimes necrosis), whereas NECs are high-grade by definition and associated with rapid growth, extensive necrosis, and a worse prognosis [10]. Clinically, neuroendocrine neoplasms occur most frequently in the gastroentero-pancreatic tract and lungs, while primary involvement of the head and neck is rare [9,11].

NECs of the submandibular gland are exceedingly rare, with only 27 well-documented cases reported in the literature. Given the low density of neuroendocrine cells in the salivary glands, primary NECs in this region are an exceptional finding. We conducted a comprehensive review of the scientific literature, including PubMed, Scopus, Web of Science, and Google Scholar databases, and identified 27 cases with sufficient clinical, histopathological, and therapeutic data [3,6,7,12–24]. The selection included case reports, case series, and retrospective analyses published in peer-reviewed journals (Table 1). As shown in Table 1, high-grade salivary gland NEC primarily affects adults: most cases occur between the fifth and eighth decades of life, with few patients aged under 40 years. The disease shows a male predominance, with a male-to-female ratio of approximately 2–3: 1. Clinically, it typically presents as a rapidly enlarging neck mass in the submandibular gland (level IB) or as a swelling of the floor of the mouth. Most tumors exceed 2 cm at diagnosis, although smaller lesions are occasionally detected owing to their superficial and easily palpable location. Mascitti et al reported a case of LCNEC of the submandibular gland in a young adult, characterized by aggressive behavior, with multiple local and distant recurrences despite surgical treatment, highlighting the malignant potential of high-grade NECs in this location [21]. In contrast, Petrone et al described a moderately differentiated NET (NET grade 2) of the submandibular gland in an older adult patient, showing a more indolent clinical course following surgical resection, thereby supporting the prognostic relevance of tumor grade and proliferative index [2]. Yamamoto et al reported one of the first well-documented cases of LCNEC of the submandibular gland, treated with radical surgery and neck dissection, with no evidence of disease at short-term follow-up, although the authors emphasized the lack of standardized adjuvant treatment protocols and the need for careful long-term surveillance [17]. Similar to previously reported cases, the present case shares the typical clinical presentation of a rapidly enlarging, painless submandibular mass and the characteristic histopathological features of high-grade NEC, including a high mitotic rate, necrosis, and diffuse expression of neuroendocrine markers. However, unlike many published cases reporting early recurrence or disease-related mortality, at 4-year follow-up, our patient had achieved long-term disease control after radical surgical resection and adjuvant therapy, suggesting that early diagnosis, complete en bloc resection, and a multidisciplinary treatment strategy can significantly influence outcomes even in high-grade submandibular NEC.

The diagnosis of salivary gland NET requires a combination of needle biopsy (eg, tru-cut) and radiological imaging (CT, PET-CT, MRI) to confirm their primary nature and exclude metastases. Immunohistochemical analysis plays a crucial role, with positivity for synaptophysin, chromogranin A, and CD56 helping to differentiate NET from other malignant large cell neoplasms, including melanoma and Merkel cell carcinoma [25]. Conversely, negative staining for S-100, human melanoma black 45 (HMB45), and MART-1 helps rule out melanoma. In rare cases, electron microscopy can confirm the presence of dense-core neuroendocrine granules, reinforcing the diagnosis [5]. Given the overlapping histological features of the 2 forms of NEC, primary submandibular NEC must be distinguished from metastatic NEC, particularly from lung carcinoma or Merkel cell carcinoma of the skin [25]. Histologically, these tumors exhibit nests, trabeculae, and sheets of pleomorphic, hyperchromatic cells with necrotic areas. Immunohistochemistry confirms the diagnosis, typically showing positivity for synaptophysin, chromogranin A, CD56, and CKAE1/AE3, along with a high Ki-67 proliferation index (> 80%), indicating aggressive behavior. CK20 negativity can further help rule out Merkel cell carcinoma [10]. Diagnosing salivary gland NEC is particularly challenging in small biopsy samples, in which it can mimic a small round blue cell tumor or other epithelial malignancies. A stepwise diagnostic approach, integrating histomorphologic, immunophenotypic, and molecular analyses, is essential to achieving an accurate diagnosis and preventing misclassification [25].

The WHO classification of tumors has evolved to provide a more nuanced categorization of neuroendocrine neoplasms across various organ systems [4]. The 2022 WHO Classification of Endocrine and Neuroendocrine Tumors distinguishes neuroendocrine neoplasms into 2 primary categories. The first category is well-differentiated NET, which is further graded based on mitotic count and Ki-67 proliferation index into the following 3 grades: grade 1: low-grade tumors with a mitotic count of <2 per 10 high-power fields (HPF) and/or a Ki-67 index <3%; grade 2: intermediate-grade tumors with a mitotic count of 2 to 20 per 10 HPF and/or a Ki-67 index of 3% to 20%; and grade 3: high-grade tumors with a mitotic count >20 per 10 HPF and/or a Ki-67 index >20%, while maintaining well-differentiated morphology. Cases of well-differentiated NET in this region are exceedingly uncommon. The second category includes the poorly differentiated NEC, which is a high-grade malignancy that exhibits poorly differentiated morphology and is subdivided into the following 2 types: SCNEC, which is characterized by small, round, densely packed tumor cells; and LCNEC, which consists of larger cells with abundant cytoplasm and prominent nucleoli.

In the context of the head and neck region, including the salivary glands, the occurrence of NEC is rare but well documented. These tumors predominantly present as poorly differentiated carcinomas classified as either SCNEC or LCNEC. Both the SCNEC and LCNEC are high-grade carcinomas characterized by organoid cellular growth, rapid mitotic activity, and frequent areas of necrosis. Architectural features, such as peripheral palisading, trabeculae, and rosettes, can also be observed. LCNEC cells typically display abundant cytoplasm, large nuclei with coarse chromatin, and prominent nucleoli. The 2022 WHO classification emphasizes the importance of integrating morphological assessment with immunohistochemical and molecular features to accurately classify these neoplasms [26,27].

The treatment of submandibular gland NEC is not standardized, due to its rarity, but management typically involves surgical resection typically followed by neck dissection and adjuvant radiotherapy and/or chemotherapy, particularly in high-grade or advanced cases [4]. Platinum-based chemotherapy (cisplatin/carboplatin plus etoposide) is commonly used for systemic disease [8]. Despite aggressive multimodal treatment, the prognosis remains poor, with a high recurrence rate and low long-term survival rate, particularly in cases with a high Ki-67 proliferation index and lymph node involvement. A detailed summary of treatment strategies and outcomes is provided in Table 2. Close follow-up with imaging (CT, MRI, PET-CT) and clinical examinations are essential to detect early recurrences or metastases.

Conclusions

NEC of the submandibular gland is an exceptionally rare and highly aggressive malignancy posing significant diagnostic and therapeutic challenges due to its low incidence and histopathological overlap with other tumors. Accurate diagnosis requires a multidisciplinary approach to differentiate primary salivary gland NEC from metastatic disease. Radical surgical resection remains the cornerstone of treatment and is often combined with adjuvant therapies based on disease stage and risk factors, although standardized treatment protocols are lacking. Given the aggressive behavior and unfavorable prognosis of high-grade NEC, further research, molecular profiling, and multicenter collaboration are essential to improve diagnostic accuracy, therapeutic strategies, and patient outcomes.