Abstract
Significance statement
Large-cell neuroendocrine carcinoma of the parotid gland is an exceptionally rare and aggressive malignancy, with fewer than 15 reported cases, posing significant diagnostic and therapeutic challenges. This case underscores the critical role of advanced imaging, immunohistochemical analysis, and multidisciplinary collaboration in ensuring accurate diagnosis and optimizing treatment. The findings contribute to the limited literature, emphasizing the efficacy of adjuvant chemoradiotherapy and the need for further research to establish standardized management guidelines and improve patient outcomes.
Case Report
A 75-year-old male with a history of recurrent urothelial carcinoma of the bladder, type 2 diabetes mellitus, and hypertension presented with a 2-month history of painless, rapidly enlarging right parotid swelling. Physical examination revealed a large, tender mass without regional lymphadenopathy or facial nerve palsy. Magnetic resonance imaging (MRI) showed a parotid mass with radiologic features suggestive of aggressive behavior. Positron emission tomography-computed tomography showed no evidence of suspicious lymphadenopathy or distant metastases. Cervical ultrasonography revealed a heterogeneous, predominantly cystic mass. Although fine-needle aspiration (FNA) cytology was inconclusive, findings suggested a high-grade, poorly differentiated malignant tumor.
Following a multidisciplinary team discussion, the patient underwent parotidectomy with ipsilateral neck dissection. Histopathological analysis confirmed large-cell neuroendocrine carcinoma (LCNEC) of the parotid gland, staged as pT3 pN0 cM0, with positive surgical margins. Examination revealed well-organized nests of neoplastic cells with abundant eosinophilic cytoplasm (Figure 1A). Foci of necrosis were present, and the mitotic rate was elevated (14 mitoses per 2 mm2). Immunohistochemical staining demonstrated positivity for synaptophysin and CD56 (Figure 1B and C), with a Ki-67 proliferative index approaching 90% (Figure 1D), confirming the neuroendocrine nature of the tumor.
Histopathologic interpretation. (A) Well-organized nested growth pattern with delicate fibroconnective bands displaying an inflammatory component. Neoplastic cells exhibit abundant eosinophilic cytoplasm and polarized nuclei with prominent nucleoli (hematoxylin and eosin stain, 200× magnification). (B, C, and D) Immunohistochemical staining demonstrates strong positivity for the neuroendocrine markers chromogranin (B) and synaptophysin (C), with a Ki-67 proliferative index approaching 90% (D) (400× magnification).
Due to lymphovascular invasion and positive surgical margins, the patient underwent adjuvant chemoradiotherapy. The treatment protocol consisted of radiotherapy, delivering 66 Gy in 33 fractions to the tumor site, 59.4 Gy in 33 fractions to intermediate-risk areas, and 52.8 Gy in 33 fractions to prophylactic cervical lymph node regions, combined with 3 cycles of concomitant chemotherapy with carboplatin and etoposide. At 3-month follow-up, there was no evidence of recurrence or metastasis.
Discussion
Neuroendocrine carcinomas (NECs) of the head and neck are rare, comprising less than 3% of all head and neck malignancies, with the larynx being the most common site, accounting for 0.5 to 1% of laryngeal tumors.1-6 By contrast, NECs of the major salivary glands are exceptionally rare, representing only 1% to 3% of all salivary gland malignancies.3-5 The 2022 WHO Classification categorizes epithelial neuroendocrine neoplasms into well-differentiated and poorly differentiated types, with poorly differentiated NECs further classified as small cells or LCNEC. 7
LCNEC is the rarer subtype in the parotid gland, with fewer than 15 reported cases, primarily in isolated case reports or small case series. First described by Hui et al, LCNEC is less common than small-cell NEC in the parotid gland. 3 Earlier WHO classifications did not distinguish between small-cell and LCNEC subtypes. 7 The rarity of LCNEC presents significant diagnostic and management challenges.
The median age at presentation is 68 years, with a male predominance. 8 Patients typically present with a painless, rapidly growing parotid mass, occasionally accompanied by facial nerve involvement but without invasion of adjacent structures. Paraneoplastic syndromes are rarely associated with parotid NECs, with only one case reported by Meacham et al describing ataxia, dysarthria, and visual disturbances.8-10
Diagnostic workup for LCNEC includes MRI and computed tomography imaging, with cervical ultrasound guiding FNA for preliminary diagnosis. Histologically, LCNEC is characterized by abundant cytoplasm, large nuclei with prominent nucleoli, rosette cells, and areas of necrosis.3,5,9 Key WHO criteria include more than 10 mitoses per 2 mm2, a Ki67 index greater than 20% (often >50%), and large cell cytomorphology. 7 Confirmation of the neuroendocrine component requires positivity for at least one neuroendocrine marker, such as synaptophysin, chromogranin-A, neuron-specific enolase, or neural cell adhesion molecule CD56.5,9
According to the 2022 WHO classification, synaptophysin is the most sensitive biomarker, while chromogranin-A is the most specific for neuroendocrine neoplasms. 7 The guidelines discourage the use of nonspecific markers like CD56 and neuron-specific enolase, emphasizing the importance of these primary markers for accurate diagnosis. 7 Immunohistochemistry is essential for distinguishing LCNEC from other malignancies, including adenoid cystic carcinoma, mucoepidermoid carcinoma, lymphoma, and metastatic tumors.2,4,5,8,11
Due to the rarity of LCNEC, there is no established consensus on treatment. Some authors advocate radiochemotherapy as the first-line approach, while others prioritize surgical resection.5,8 Parotidectomy with neck dissection is recommended when lymph node metastasis is suspected.2,3,11 Adjuvant therapy, including radiotherapy alone or combined with chemotherapy, is frequently utilized, although evidence supporting improved outcomes remains limited.1,9
The prognosis for LCNEC is unclear, with recent studies indicating poorer survival rates compared to other head and neck malignancies, though it appears less aggressive than NECs in other anatomical sites.9,12 Patients who survived at 1 and 2 years had early-stage tumors, including an incidentaloma in an asymptomatic patient and a tumor in a patient under follow-up for previously diagnosed laryngeal squamous cell carcinoma. 9
Conclusion
LCNEC of the parotid gland is an exceptionally rare malignancy with no definitive management guidelines or established long-term prognosis. Accurate differentiation from other high-grade parotid malignancies is crucial for guiding appropriate treatment. Multidisciplinary collaboration among surgeons, radiotherapists, and oncologists is essential to optimizing outcomes in the absence of a standardized approach.
