Neuroendocrine tumor

Neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) of the jaws are malignant neoplasms of neuroendocrine lineage that arise either as rare primary lesions of the oral and maxillofacial region or, more commonly, as metastatic deposits from distant sites such as the lung, gastrointestinal tract, or pancreas.[1][2] The WHO classification divides neuroendocrine neoplasms (NENs) into well-differentiated NETs (grades G1–G3) and poorly differentiated NECs (small cell and large cell types), a framework now applied across anatomic sites including the head and neck.[3][4] In the jaws, most cases represent metastatic disease—particularly from gastrointestinal or pulmonary primaries—and present as destructive osseous lesions.[2][5] Primary poorly differentiated NEC of the oral cavity is exceedingly rare, with fewer than 30 cases documented in the literature through 2020.[1] Radiographically, jaw involvement typically produces an aggressive radiolucent lesion with ill-defined margins and bone destruction.[2][6] Management depends on whether the lesion is primary or metastatic and on differentiation grade, ranging from surgical resection with adjuvant therapy for primary disease to systemic chemotherapy for disseminated NEC.[1][7]

Current Classification

The 5th edition WHO Classification of Endocrine and Neuroendocrine Tumours (2022) and the 2018 IARC/WHO consensus framework establish a unified nomenclature for NENs across all anatomic sites:[3][8][9]

• Neuroendocrine tumor (NET): well-differentiated; graded G1, G2, or G3 based on mitotic rate and Ki-67 index[3][7]
• Neuroendocrine carcinoma (NEC): poorly differentiated; subdivided into small cell NEC (SCNEC) and large cell NEC (LCNEC); high grade by definition[3][7]
• Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN): contains both neuroendocrine and non-neuroendocrine components, each comprising at least 30% of the tumor[7]

Obsolete and Alternate Terms

Older terminology includes "carcinoid" (well-differentiated), "atypical carcinoid" (moderately differentiated), and "small cell carcinoma" (poorly differentiated).[10] In the head and neck, the term "small cell undifferentiated carcinoma" has been used interchangeably with SCNEC.[11] The umbrella term "neuroendocrine neoplasm" (NEN) encompasses both NETs and NECs.[12]

• NENs of the head and neck are rare, accounting for approximately 0.3% of all head and neck cancers. The most common head and neck sites are the larynx, paranasal sinuses, and salivary glands; the oral cavity is among the rarest primary sites.[1][13][14]
• Primary poorly differentiated NEC of the oral cavity: a pooled literature review identified only 29 cases (26 SCNEC, 3 LCNEC) reported between 1972 and 2020, with a mean age of 58.9 years and male predominance (65.5%). Over half were smokers.[1]
• Metastatic NENs to the jaws are also uncommon. Metastatic tumors comprise approximately 1% of all jaw malignancies, with the mandible affected far more often than the maxilla, particularly the premolar–molar region. In approximately 30% of cases, the jaw metastasis is the first sign of the primary malignancy.[5][15]
• Among primary oral cavity NECs, the tongue is the most common subsite, followed by the gingiva.[1]

Presentation

• Primary oral NEC: typically presents as a rapidly enlarging, painful mass with tenderness. Ulceration of the overlying mucosa is common. Approximately 20% of patients have systemic metastases at initial presentation.[1][6]
• Metastatic NET/NEC to the jaws: presents with progressive swelling, pain, paresthesia or numbness of the lower lip (numb chin syndrome), loosening of teeth, or a gingival mass that may mimic a reactive or inflammatory lesion such as pyogenic granuloma. Trismus may occur with condylar involvement. Bleeding from the lesion has been reported.[2][15][16]

Tempo and Complications

• Poorly differentiated NECs pursue a rapidly aggressive course with early locoregional and distant metastasis via lymphatic and hematogenous routes. Common metastatic sites include brain, liver, and bone.[1][14]
• Well-differentiated NETs metastatic to the jaw may follow a more indolent course depending on grade, but jaw involvement itself signals advanced disease.[2]

Red Flags

• Lower lip paresthesia in a patient with a jaw lesion is a sinister sign suggesting malignant infiltration of the inferior alveolar nerve.[17]
• Rapid tooth mobility without obvious periodontal disease warrants investigation for an underlying malignancy.[16]

Location and Distribution

• The posterior mandible (body, angle, ramus) is the most common jaw site for both primary and metastatic neuroendocrine neoplasms, consistent with the general predilection of metastatic tumors for the molar region of the mandible. Maxillary involvement is less frequent.[2][5]
• Primary intraosseous NEC of the jaw is exceptionally rare; most reported gingival NECs are soft-tissue–based masses that may secondarily involve underlying bone.[6][18]

Periphery and Shape

• Jaw NETs/NECs characteristically produce ill-defined, irregular margins without a corticated border, reflecting their aggressive biologic behavior.[15][16]
• A moth-eaten pattern of bone destruction is the most commonly described peripheral appearance, consistent with a permeative malignant process.[15][16]

Internal Architecture

• The internal pattern is predominantly radiolucent (osteolytic), reflecting high osteoclast activity. A honeycomb-like radiolucent pattern with internal bony septations has been described in a mandibular NET metastasis.[2][15][19]
• Calcification within the lesion is not a recognized feature.[20]
• Occasional cases of metastatic neuroendocrine neoplasms may produce osteoblastic (radiopaque) or mixed lytic-blastic lesions, particularly paraganglioma-related neuroendocrine tumors. However, purely lytic destruction is far more common in jaw involvement.[15][19][21]

Effects on Teeth and Adjacent Structures

• Root resorption of adjacent teeth may occur but is not consistently reported.
• Tooth displacement and pathologic mobility are common findings, sometimes mimicking advanced periodontal disease.[15][16]
• Widening of the periodontal ligament space may be an early radiographic sign.

Growth Pattern, Cortical Involvement, and Extent

• These lesions demonstrate an aggressive, infiltrative growth pattern with cortical destruction and frequent extension into surrounding soft tissues.[2][22]
• Cortical expansion and perforation are characteristic; periosteal reaction has been reported in a minority of maxillofacial metastases.[22]
• Extension along the inferior alveolar canal may produce widening or destruction of the canal, correlating with clinical paresthesia.[17]

Variants

• Well-differentiated NET metastases may appear somewhat better defined than poorly differentiated NECs, though both produce destructive lesions.[2]
• Rare osteoblastic variants have been described in neuroendocrine tumors with paraganglioma differentiation, producing a radiodense or mixed-density lesion that may simulate osteosarcoma on panoramic radiography.[21]

CT

• Contrast-enhanced CT demonstrates a soft-tissue–density mass with bone destruction and variable enhancement. Paranasal sinus NECs show isodense to mildly hyperdense lesions on unenhanced CT with moth-eaten bone destruction. In jaw lesions, CT delineates the extent of cortical destruction, soft-tissue extension, and relationship to the inferior alveolar canal and mental foramen more precisely than panoramic radiography.[6][11][20][23][24]

MRI

• MRI is preferred for evaluating bone marrow invasion, perineural tumor spread along cranial nerves, and soft-tissue extent. Sinonasal SCNECs are typically isointense on T1-weighted images and isointense to mildly hyperintense on T2-weighted images, with mild-to-moderate homogeneous enhancement. Low apparent diffusion coefficient values on diffusion-weighted imaging reflect high cellularity.[11][20][25]

PET/CT and Nuclear Medicine

• FDG-PET/CT is recommended for staging poorly differentiated NECs to evaluate for distant metastases and is associated with higher sensitivity for both nodal and distant disease. Somatostatin receptor (SSTR)-PET/CT using 68Ga-DOTATATE is the preferred functional imaging modality for well-differentiated NETs to assess receptor status and guide SSTR-directed therapy. MIBG scintigraphy may be used in select cases to identify the primary site when a paraganglioma or pheochromocytoma is suspected.[2][7][11]

When an aggressive radiolucent jaw lesion is identified in an adult, particularly in the posterior mandible, the differential must include both primary jaw malignancies and metastatic disease. The absence of a corticated border, moth-eaten destruction, and associated paresthesia or tooth mobility should raise suspicion for malignancy.

The highest-risk diagnostic pitfall is misidentifying a metastatic neuroendocrine carcinoma as a primary jaw malignancy or reactive lesion, which delays identification of the primary tumor and systemic staging. Biopsy with immunohistochemistry including synaptophysin, chromogranin A, INSM1, CK20, and TTF-1 is essential to confirm neuroendocrine differentiation and guide the search for a primary site.[7][28]

Microscopic Features

• Well-differentiated NETs display organoid architecture with nests, trabeculae, and rosettes composed of uniform cells with finely granular eosinophilic cytoplasm and round nuclei with stippled ("salt-and-pepper") chromatin. Mitotic activity and necrosis are low in G1/G2 tumors.[30][31]
• Poorly differentiated NECs (SCNEC) are composed of small cells with high nuclear-to-cytoplasmic ratio, scant cytoplasm, granular chromatin, inconspicuous nucleoli, nuclear molding, and high mitotic activity with frequent necrosis.[1][6][32]
• LCNEC shows larger cells with more abundant cytoplasm, prominent nucleoli, organoid or trabecular patterns, and extensive necrosis.[33]

Immunohistochemistry

A minimum panel of two of three neuroendocrine markers—synaptophysin, chromogranin A, and INSM1—is required for diagnosis, along with a broad-spectrum cytokeratin (e.g., AE1/AE3).[7] Additional markers aid in determining the site of origin and excluding mimics:

• TTF-1 positive / CK20 negative: favors pulmonary origin[28][34]
• CK20 positive (paranuclear dot pattern) / TTF-1 negative: favors Merkel cell carcinoma[28][35]
• CDX2 positive: suggests gastrointestinal origin[36]
• Ki-67 proliferative index and mitotic rate determine grade; Ki-67 is characteristically >20% in high-grade NECs and often 50–100% in SCNEC.[7][32]
• Loss of Rb expression and aberrant p53 staining (overexpression or null pattern) are characteristic of poorly differentiated NECs and help distinguish them from well-differentiated NET G3.[32]

Molecular Features

Poorly differentiated NECs of the head and neck harbor TP53 mutations in approximately 43% and RB1 alterations in 21% of cases, rates lower than in small cell lung cancer, suggesting biologic heterogeneity.[13] PIK3CA pathway mutations and rare FGFR3-TACC3 fusions have been identified as potential therapeutic targets.[13]

Workup and Referral

• Any jaw lesion with aggressive radiographic features and neuroendocrine histology on biopsy requires urgent referral to a multidisciplinary oncology team.[7][11]
• Systemic staging is essential: multiphasic CT of chest/abdomen/pelvis, and FDG-PET/CT for poorly differentiated NECs; SSTR-PET/CT for well-differentiated NETs.[7]
• Brain MRI should be obtained for high-grade NECs given the propensity for cerebral metastases.[1][11]