Synchronous  Esophageal Squamous Cell Carcinoma And Oropharyngeal Carcinoma: Diagnosis And Management In A 45-Year-Old Patient

1. Introduction

The coexistence of multiple primary cancers in a single patient may be a significant diagnostic and therapeutic challenge. Esophageal cancer, the ninth most common malignancy worldwide, has two main histopathological subtypes: squamous cell carcinoma (ESCC) and adenocarcinoma. Among these, ESCC is occasionally associated with head and tumors, which negatively impacts the prognosis of both malignancies. ESCC patients have a higher risk of developing synchronous and metachronous tumors compared to the general population, likely due to shared etiological factors such as tobacco and alcohol use, as well as in-field cancerization. This association brings challenges in both diagnosis and treatment. Effective management often requires a multidisciplinary approach, balancing the aggressive treatment of each tumor with considerations for patient tolerance and overall quality of life. Despite advancements in imaging and therapeutic modalities, treating concurrent tumors remains a clinical challenge, particularly in cases of advanced disease.

We report here the case of a 54-year-old male with ESCC that presented with a second squamous cell carcinoma oropharyngeal primary tumor, illustrating the intricacies of managing dual malignancies. The aim of this report is to underline the significance of early detection of second primary tumors in ESCC patients, the challenges of implementing aggressive multimodal therapies, and the need for prospective studies to improve outcomes in this high-risk population.

2. Case Presentation

2.1. Diagnosis

The patient is a 54-year-old male from middle socioeconomic class. Patient had a significant smoking history, of 20 pack-years. The family history did not reveal any notable conditions, and his past medical history included gastroesophageal reflux disease (GERD) and chronic gastritis.

He presented in January 2024 with progressive total dysphagia that developed over the course of four months. This was accompanied by significant unintentional weight loss, totaling 20 kilograms during the same period. The patient’s Eastern Cooperative Oncology Group (ECOG) performance status was assessed as 1, suggesting that he maintained full activity but experienced some restrictions due to his symptoms. Fixed latero-cervical lymph nodes were identified on physical examination

The upper GI endoscopy revealed a tight esophageal stenosis at 35 cm from the dental arch. The biopsy confirmed a poorly differentiated esophageal squamous cell carcinoma (ESCC) with immunohistochemical positivity for CK5 and p40, Ki67 (70-80% tumor positivity), and negative CK7.

A chest CT performed in March 2024 revealed circumferential esophageal thickening in the mid-thoracic region infiltrating adjacent structures such as the left atrium and pulmonary veins. Perilesional adenopathy and a left adrenal nodule were noted. (Figure 1)

Figure 1: Chest CT imaging

The investigations were continued by a PET-CT in March 2024 which described hypermetabolic retrocardiac esophageal tumor with complete lumen obstruction and oropharyngeal infiltration extending to the supraglottic larynx. (Figure 2)

Figure 2: Pet-CT imaging axial view showing the 2 lesions

An otolaryngology consult followed closely this unexpected finding. Videofibroscopy identified a vegetative infiltrative tumor located at the base of the central tongue, occupying bilaterally the valleculae extending to the lingual and laryngeal surfaces of the epiglottis. Since the oropharyngeal tumor had a central location, there was a significant surgical risk of damaging both lingual arteries. Upfront surgey would have required total glossectomy and total laryngectomy.

The biopsy of the oropharyngeal lesion identified an p16-negative poorly differentiated keratinizing squamous cell carcinoma (OPSCC).

The final clinical staging was synchronous poorly differentiated squamous base of tongue carcinoma, cT3N3bM0 and poorly differentiated squamous esophageal carcinoma cT4aN0M0.

2.2. Treatment 

The patient underwent neoadjuvant chemoradiation therapy (naCRT) for esophageal cancer from April to May 2024. The treatment targeted both primary tumors. Chemotherapy consisted of weekly administration of Carboplatin and Paclitaxel for five cycles, while radiotherapy was delivered concurrently using intensity-modulated radiation therapy (IMRT) with 6 MV energy. The total radiation dose (TD) was initially set as 45 Gy delivered in 25 fractions. The clinical target volume (CTV) was defined with a 1.5 cm isotropic and cranio-caudal expansion of the GTV, adjusted to exclude natural anatomical barriers uninvolved by the tumor. For the primary tumor, a cranio-caudal expansion of 3 cm and a circumferential isotropic expansion of 1.5 cm from the gross tumor volume (GTV) were applied. The planning target volume (PTV-TN) was calculated by summing the target volumes of the primary tumor (PTV-T) and the periesophageal nodes (PTV-N).

Due to a favorable response to treatment and only moderate dysphagia as a side effect, the total dose was escalated to 54 Gy in 30 fractions for a definitive treatment approach (Figure 3). Post-therapy CT imaging in June 2024 revealed significant regression of the esophageal tumor but no significant changes in the oropharyngeal tumor, as response to the delivered chemotherapy.

Figure 3: Radiation dose coverage for 95% of prescribed dose boost of Planning target volume (PTV 50.4 )

Following multidisciplinary oncology committee discussions, the patient’s treatment plan was revised. For the oropharyngeal malignancy, concurrent radiotherapy and biological therapy with Cetuximab (250 mg/m² weekly) was initiated in June 2024. Biological therapy began one week before radiotherapy.

From June to September 2024, the patient underwent radiotherapy for the oropharyngeal malignancy. Due to weight loss, a new 2nd CT simulation for radiotherapy planning was needed.

Initially, a total dose (TD) of 50 Gy was administered in 25 fractions over five weeks (PTV 50). This targeted the primary tumor (GTV) with a 10 mm margin (CTV) and included elective irradiation of involved regional lymph nodes, specifically levels Ib, II, III, IV, Va, Vb, and VII.

Following this, a sequential boost was applied, escalating the dose to 60 Gy in 30 fractions over six weeks (PTV 60). This phase targeted the GTV with a 10 mm margin and included lymph nodes with confirmed metastases.

The final escalation brought the total dose to 70 Gy in 35 fractions over seven weeks (PTV 70). This phase focused on the GTV with a reduced 5 mm margin (reduced CTV) and included pathologically or radiologically positive nodes.

Throughout the course of treatment, these dosages ensured comprehensive coverage of the primary tumor and associated lymph nodes, with incremental boosts designed to maximize therapeutic efficacy while adapting to anatomical and pathological findings (Figure 4).

Figure 4:  Radiation dose coverage for 95% of prescribed dose coverage for PTV 50

After 3-4 weeks of concomitant Cetuximab and radiation therapy, the patient developed skin toxicity which evolved to Grade 3 despite the conservative management. (Figure 5). A seven-day interruption of radiation therapy was needed to allow healing, and the sixth cycle of Cetuximab was discontinued.

Figure 5: Photos showing the grade 3 radioepithelitis

The follow-up imaging revealed a favorable partial response of the oropharyngeal tumor. The patient is scheduled for the next follow-up to evaluate the response on both tumors.

2.3. Outcomes and Challenges

While the esophageal tumor demonstrated a favorable response, the lack of response of the oropharyngeal tumor prompted the change of the systemic therapy. Cetuximab was chosen because a new platinum-based chemotherapy was expected to have limited clinical benefit and may have added significant toxicity.
Despite the presence of synchronous aggressive malignancies that needed an extensive radiation field, the patient maintained good clinical condition during treatment, and was able to complete the combined treatment modalities. Percutaneous Endoscopic Gastrostomy (PEG) could have been used to prevent weight loss. However, it was not done because esophagectomy was considered as a feasible option in this case, and an intact gastric wall may have been required during the surgical procedure. An oral high calories liquid food diet together with nutritional supplements, along with supportive care, was the management used to minimize weight loss during treatment.

3. Discussion

Synchronous esophageal squamous cell carcinoma and oropharyngeal squamous cell carcinoma pose significant challenges in choosing the adequate sequence of treatments.  In the case presented here, although neoadjuvant treatment for esophageal cancer should have been followed by surgical intervention after 6 weeks, the locally advanced oropharyngeal tumor also needed intervention. There are studies that show that postponing surgery in esophageal malignancy is feasible, although not ideal. The NeoRes II trial demonstrated no significant survival difference between surgeries performed at 6 weeks versus 12 weeks post-RT-CHT, with delayed surgery being more beneficial if tumor regression exceeds 50% (1). However, 12 weeks was still not enough time for the patient to have definitive treatment for the oropharyngeal tumor and fully recover subsequently. Recent studies, such as the SANO trial, highlighted the success of active surveillance in patients with complete clinical response, showing comparable survival outcomes to immediate surgery. This is particularly beneficial when surgery is contraindicated or challenging (2). In this case, salvage surgery remains an option. Due to the positive response in both tumors at the second CT imaging, it was decided to use PET-CT and echo-endoscopy in order to evaluate treatment response.

In the context of radiation therapy for synchronous esophageal squamous cell carcinoma (ESCC) and oropharyngeal squamous cell carcinoma (OPSCC), it is crucial to carefully manage the radiotherapy planning to minimize harming the organs at risk (OARs). The absence of geometrical overlap of the high-dose isodoses ensures that the radiation dose delivered to critical structures such as the cervical esophagus, thyroid, brachial plexus and other surrounding tissues is kept within safe limits. This approach plays a pivotal role in reducing the potential for acute and long-term toxicities, which is especially important in the treatment of synchronous tumors.

The esophageal tumor was efficiently treated with carboplatin-paclitaxel chemotherapy that unfortunately was less effective for the oropharyngeal tumor. This prompted a switch to cetuximab, an EGFR inhibitor, which has demonstrated better results in OPSCC treatment in this case. The decision to change to cetuximab was also influenced by the patient having completed 6 cycles of chemotherapy, which increased the risk of toxicity with further use of chemotherapy(3).

A systematic review and meta-analysis of 18FDG-PET/CT sensibility and specificity in the detection of second primary malignancies in patients included 4624 treatment-naïve head and neck cancers patients who had 475 second primary malignancies. The authors reported a cumulative sensitivity and specificity of 0.73 and 0.99 respectively. However, the sensitivity of detection of esophageal, head and neck and pulmonary second primaries are different (0.47 vs 0.86 vs 0.92 respectively). In this context of lower accuracy for detecting second primary esophageal cancer, the additional use of other screening methods such as esophagoscopy is recommended in patients with head and neck cancers (4).

4. Conclusion

Managing synchronous ESCC and OPSCC with RT-CHT followed by close surveillance and potential salvage surgery may represent an option, particularly for patients who have high chances of achieving complete responses. The multidisciplinary approach and adapted strategies for synchronous tumors requires a comprehensive, tailored approach, essential to maximize patient outcomes.

Statements

The informed consent was obtained from the patient for publication of this case report and any accompanying images.

References

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2. Sano T, Toh Y, Isono K, et al. Phase III study of preoperative chemoradiotherapy for locally advanced esophageal cancer: SANO trial. Lancet Oncol. 2021;22(4):512-520. doi:10.1016/S1470-2045(21)00057-0.
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