Squamous cell carcinoma diagnosed as a suspected neuroendocrine tumor by gallium-68 DOTA-Tyr 3 -octreotate positron emission tomography scan: A case report

Introduction

The diagnosis of secretory and nonsecretory neuroendocrine tumors (NETs) is based on a combination of clinical presentation, biochemical testing, imaging, and histomorphology. Although histologic review is necessary for definitive diagnosis, tissue sampling prior to tumor resection is not always feasible due to technical difficulty (especially fine needle aspiration (FNA) procedures) and possible complications such as catecholamine crisis, hemorrhage, risk of capsular disruption, and fibrotic replacement.^1,2 Therefore, not uncommonly, NETs are treated despite biopsy confirmation, relying heavily upon biochemical and radiologic findings.

Multiple imaging modalities are available for evaluation of NETs and may include computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)/CT, single-photon emission CT (SPECT), and SPECT/CT. Choice of imaging depends on the pattern of presentation. For a palpable nodule, for example, CT radiography is the initial imaging modality to assess the nodule size, location, and suggest tissue of origin. MRI can follow CT if there is a question about the content of the nodule. However, while CT and MRI are valuable for establishing anatomical detail of the tumor and surrounding structures, like all diagnostic modalities, there are advantages and disadvantages to both. For example, MRI shows improved detection of pancreatic NETs and liver and bone metastases, but it falls short of CT sensitivity for primary small bowel lesions and lymphadenopathy.^3,4 In addition, CT and MRI are less practical when evaluating multiple locations or when there are clinical symptoms supported by positive laboratory testing of a biologically active tumor in which the primary location is unknown. In situations where multiple sites need to be assessed, especially for biologically active entities, PET/CT or SPECT are the modalities of choice. These modalities utilize the high expression of somatostatin receptors (SSTRs) on neuroendocrine cells paired with a radiopharmaceutical that targets the cell surface of the receptors, one of which is gallium-68 DOTA-Tyr³-octreotate (⁶⁸Ga-DOTATATE). The following case is an example where a right neck mass was suggested to be an invasive NET per ⁶⁸Ga-DOTATATE PET, but subsequently diagnosed as squamous cell carcinoma (SCC) per cytomorphology by FNA and core biopsy.

Case presentation

A 64-year-old male with a 20-pack-year smoking history presented to our institution for a biopsy with rapid on-site evaluation (ROSE) for a 2.7 × 3.0 cm partially cystic and pulsatile right neck mass in August 2024. It was initially described 13 months prior as a mobile mass at the level of carotid bifurcation (soft tissue X-ray showing a soft tissue mass without distinguishing markings), but the patient had normal hematologic and metabolic panels and absence of B symptoms, so he was deemed low risk for cancer and not re-evaluated until 6 months later. At the follow-up evaluation, CT-angiography (CTA) of the neck was performed due to the lesion’s persistence and pulsatile nature. The radiologic interpretation described a hypervascular, partially cystic mass overlying the right carotid space at the level of the carotid bifurcation, favoring a paraganglioma, with the differential diagnosis of a metastatic lesion being less likely. An otorhinolaryngology consultation was subsequently ordered.

During consultation, the patient additionally endorsed experiencing one episode of dizziness lasting 15 minutes. A flexible laryngoscopy was performed and revealed no abnormalities or lesions of the oropharynx. Ancillary testing was ordered for suspicion of a paraganglioma, resulting in increased plasma-free normetanephrine levels at 1.13 nmol/L (reference range >0.89 nmol/L). Afterward, the patient was presented at our institution’s head and neck tumor board with differential diagnoses including vagal paraganglioma, carotid body tumor, and malignant vagal paraganglioma. ⁶⁸Ga-DOTATATE PET scan was deemed necessary with the radiologic interpretation (performed 11 months after the initial evaluation) indicating increased tracer activity in the lesion with a second lesion identified in the right tonsil, which led to the possibility of metastasis from a primary tonsillar NET (Figure 1).

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Figure 1.

DOTATATE PET images showing large area of avidity in the anterolateral right neck (a), and smaller area of avidity in the right tonsil (b).

Due to unequivocal metanephrines testing in the absence of well-established symptoms, FNA and core biopsy of the neck mass were performed by Interventional Radiology with ROSE by cytopathology. Three needle passes were obtained, yielding adequate sampling of lesional cells. Three Romanowsky-stained smears were prepared on-site with morphologic findings of isolated and clusters of pleomorphic cells with a high nuclear to cytoplasmic ratio, irregular nuclear contours, and dense eosinophilic cytoplasm in a background of necrotic debris. Two Papanicolaou-stained smears were also prepared, which showed “tadpole cells” with irregular, hyperchromatic nuclei and dense, eosinophilic cytoplasm. These findings were deemed suspicious for SCC in contrast to a NET, which would exhibit single or loosely cohesive groups of monotonous cells with round, smooth nuclei, and fine chromatin (“salt and pepper” appearance), with rosette formation. Cell block and core biopsy sections, hematoxylin and eosin stains, demonstrated similar tumor cells arranged in small sheets with a background of anucleated squamous cells and necrosis. SCC was supported by immunohistochemical positive staining of p40 and p16 (block-like) and negative staining for synaptophysin and chromogranin (neuroendocrine markers; Figure 2).

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Figure 2.

Fine needle aspiration and core biopsy findings. (a) Romanowsky-stained smear demonstrating a cluster of pleomorphic cells with a high N:C ratio and dense “robin egg blue” cytoplasm. (b) Papanicolaou-stained smear highlighting prominent nuclear irregularities, some keratinization (orangeophilic cells), and elongated “tadpole” cells. (c) Biopsy H&E demonstrating a cluster of pleomorphic cells with predominantly dense nuclei with high N:C ratio and eosinophilic cytoplasm in a necrotic background. Anucleated squamous cells can be observed in the periphery. (d) Positive p40 nuclear staining. (e, f) Negative neuroendocrine stains (chromogranin and synaptophysin, respectively).

Given the unexpected diagnosis and unconfirmed primary, additional CT imaging of the neck was performed, further classifying the right tonsillar mass, previously demonstrated on PET imaging. Biopsy sampling (performed 2.5 weeks after biopsy of the neck mass) of the right tonsillar mass revealed a p16-positive SCC with expression of high-risk HPV (by in-situ hybridization), establishing a primary site. Three and a half weeks post-tonsillar biopsy and 15 months from initial presentation, the patient underwent transoral robotic surgery tonsillectomy and right neck dissection with removal of a 3.0 cm mass. Histologic evaluation demonstrated a mass measuring 1.2 cm in greatest dimension, consisting of sheets of epithelioid neoplastic cells with pleomorphism, increased nuclear to cytoplasmic ratio, eosinophilic cytoplasm, and prominent nucleoli. Focal necrosis, brisk mitoses, and apoptotic bodies were identified. No lymphovascular or perineural invasion was present. Lymph node levels 2A, 2B, 3, and 4 were resected and contained 24 lymph nodes ranging from 0.5 to 2.3 cm in greatest dimension, and included a nodal conglomerate (4.4 cm) with metastatic carcinoma (histologic findings similar to the primary mass with minimal residual lymphoid tissue identified); the remaining lymph nodes were negative for metastasis. The final diagnosis was SCC, non-keratinizing, HPV-associated, with pathologic stage classification (AJCC Eighth Edition): pT1 pN1 pMNA. All margins were negative. After resection, the patient received 60 Gy adjuvant radiation 10.5 weeks post-resection with 6-month follow-up PET/CT imaging pending (Figure 3).

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Figure 3.

(a) Tonsil biopsy H&E demonstrates pleomorphic epithelioid neoplastic cells with prominent nucleoli and eosinophilic cytoplasm. Occasional keratinization is identified. (b, c) Tonsillectomy specimen H&E: similar findings as biopsy with multiple large cells and brisk mitoses identified. (d) Nodal conglomerate H&E: similar findings as biopsy and surgical specimen with necrosis identified.

Discussion

As head and neck NETs are rare entities that comprise <1% of head and neck tumors, a strong clinical suspicion must be present before pursuing testing for neuroendocrine origin.^5,6 This may be established by symptoms of hypercatecholinemia (flushing, hypertension, headache, sweatiness, shaking, etc.) or elevated serum or urine catecholamines in the absence of symptoms. When interpreting plasma-free metanephrine levels, a fourfold upper limit of reference values should be set as a threshold for indicating NETs. ⁷ In the case of our patient, the parameter of a fourfold increase was not met. However, only 3%–4% of head and neck paragangliomas secrete catecholamines, making catecholamine testing less contributory in our patient’s case. ⁸ Therefore, proper diagnosis of a NET relies heavily on radiologic testing, so it is vital that appropriate radiologic testing is ordered by clinicians.

When evaluating neck masses, multiple factors are taken into consideration to determine the appropriate initial imaging modality. The age of the patient, chronicity of the lesion, characteristics of the lesion, and clinical presentation are key components. For example, neck masses in children are likely infectious and acute, and do not warrant further investigation. However, persistent neck masses, especially within adults, are likely neoplasms and require imaging. A non-pulsatile neck mass warrants a contrast-enhanced CT, and a pulsatile neck mass warrants a contrast-enhanced CT and contrast-enhanced CT angiography.^9,10

Our patient presented with a mobile, pulsatile neck mass, which led clinicians to obtain CTA due to concern for a carotid artery aneurysm. Differentials of pulsatile neck masses include aneurysm, tortuosities, pseudoaneurysm, arteriovenous fistula, carotid body tumor, and enlarged lymph node or mass that compresses arteries. ¹¹ While SCC is not specifically known for causing pulsatility, compression of vascularity by the mass may be contributory. Additionally, the CTA was interpreted as a hypervascular, partially cystic mass within the carotid space at the level of bifurcation, and was given differential diagnoses of paraganglioma, or carotid body tumor, instead of the correct diagnosis of nodal metastasis, the second differential. Multiple references explain that metastatic SCC may have cystic features and given that it is the most common head and neck cancer, we believe metastatic SCC should have been the highest on the differential.^12–15

In this particular case, the patient’s dental amalgam and arterial phase of contrast of the CTA limited the evaluation of the tongue base and tonsils, obscuring the primary tumor. In addition, the location of a carotid body tumor is typically described as splaying the carotid bifurcation, which this mass did not demonstrate. In retrospect, the recommendation for initial radiologic testing would be to obtain a CT neck with contrast, rather than CTA, as this would show a carotid artery aneurysm and potential head and neck primary tumor if metastasis is suspected (Figure 4).

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Figure 4.

(a) Arterial phase axial CT image with arrow indicating soft tissue fullness of right lingual tonsil partially obscured by dental amalgam. (b) Arterial phase axial CT image with arrow indicating the carotid bifurcation, the mass is seen lateral to the internal carotid at this level.

Further emphasizing caution, according to the American College of Radiology, when interpreting ⁶⁸Ga-DOTATATE PET/CT, one situation to be aware of is the increased possibility of false positives, especially in epithelial tumors of the head and neck. This is likely due to increased SSTR2 expression within these tumors, as ⁶⁸Ga-DOTATATE primarily binds to SSTR2 receptors.^16–19 Given both head and neck epithelial tumors and NETs express SSTR2 receptors, a different modality in which other SSTRs expressed by NETs should be considered, such as FDG–PET imaging, to avoid the diagnostic pitfall of over-diagnosing NETs when clinical findings are less suggestive of neuroendocrine origin (Supplemental Material).

Conclusion

While ⁶⁸Ga-DOTATATE PET serves as an important tool in diagnosing suspected NETs, its utilization in detecting SSTRs can be a pitfall when assessing other malignancies that exhibit increased SSTR avidity. Increased awareness of SSTR-avid tumors, such as SCC, may improve overall diagnostic accuracy. In addition, histologic examination is paramount to confirm a diagnosis of NET in instances with increased uptake on ⁶⁸Ga-DOTATATE and equivocal clinical and biochemical findings.

Supplemental Material