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

1. Introduction

Esophageal cancer, the eighth most common malignancy worldwide, has two main histopathological subtypes: squamous cell carcinoma (ESCC) and adenocarcinoma (1). ESCC is occasionally associated with head and tumors, which negatively impacts the prognosis of both malignancies (2). 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 (3). 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 was diagnosed with synchronous squamous cell oropharyngeal carcinoma, 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 oropharyngeal and esophageal 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

We presented the diagnosis and management of a patient with synchronous ESSC and oropharyngeal squamous cell carcinoma. Both tumors were loco-regionally advanced, but he most symptomatic was the esophageal cancer, so it was the first investigated and confirmed.

The prevalence of multiple primary cancers for head and neck cancers and esophageal cancers was previously reported. A Dutch nationwide registry cohort found that approximately 1 in 20 patients diagnosed with esophageal cancer had also other cancers, most of them in the head and neck region. Among all multiple primary tumors, most were synchronous (4). The opposite, meaning the incidence of esophageal cancer in head and neck primaries, was estimated reported in some cohort studies, especially from Asian countries. Synchronous primaries incidence in head and neck cancers was 1.43% in an Indian study, more than half being esophageal tumors (5). In Europe, the 10-years cumulative incidence of esophageal second primaries in head and neck cancer was 2.9% and the endoscopic surveillance of high risk head and neck squamous cell carcinomas was considered justified (6).

In our case, the endoscopy confirmed the esophageal cancer, but the PET-CT performed for staging had an important role in detecting the head and neck synchronous primary and influenced the case management. According to a systematic review and meta-analysis the sensitivity of detecting second primaries in head and neck cancers was significantly lower for esophageal compared to lung cancers (0.47 vs 0.92 respectively). As a result, additional screening methods such as esophagoscopy is recommended (7). A similar conclusion was stated by an Indian group, who identified age over 62 and smoking history as significant risk factors which would justify screening endoscopy in patents with head and neck cancers (5).

The patient’s treatment had several particularities. The carboplatin-paclitaxel chemotherapy given for the esophageal tumor was not efficient for the oropharyngeal tumor. This prompted a switch to cetuximab instead of concurrent cisplatin during the radiotherapy for the oropharyngeal cancer. 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.

The patient was a surgical candidate for the esophageal cancer, but the head and neck tumor also had to be treated. Treating at the same time both primaries with radiotherapy was not feasible due to excessively large volume that would have had to be covered. Considering that up to one third of patients who receive surgery achieve pathological complete response, the multidisciplinary team chose “active surveillance” followed by potential salvage surgery for esophageal cancer surgery and proceeded with treating the oropharyngeal tumor (8).

The NeoRes II trial compared standard (4-6 weeks) to prolonged time to surgery (10-12 weeks) after neoadjuvant chemoradiotherapy for esophageal cancer. The prolonged time had a strong trend to worse survival and did not improve pathological complete response (9). However, an interesting retrospective study compared the outcomes of esophageal cancer who did not undergo surgical resection after neoadjuvant chemoradiotherapy to those who did. They divided the non-surgical patients in three categories according to the reason of not performing surgery (disease progression, poor general condition and patient refusal, respectively). Overall, patients who did not receive surgery had a lower overall survival compared to those who did (34% vs 56% at 3 years), based on low values for first two categories. When comparing those who refused surgery to the surgical group by propensity score matching, the difference was not significant (56% vs 58%) (10).

Two ongoing trials (SANO and ESOSTRATE) investigate if active surveillance is a safe and feasible approach in case of clinical complete response after neoadjuvant chemoradiotherapy in esophageal cancer patients (11). The NOSANO study evaluated patients’ motive to opt for either active surveillance or for standard immediate surgery. Those from the first category tend to cope with the cancer threat by confiding their bodies and good outcomes and having the mindset of “enjoying life now”. Those preferring surgery tend to cope with minimizing uncertainty and the mindset is “don’t give up, act now”. The quality of life was better in the active surveillance group (12).

Data from retrospective case series showed that patients diagnosed with synchronous esophageal and head and neck cancers receiving concurrent chemoradiotherapy had 1-year and 2-year survival rates of 52% and 13% respectively. Univariate analysis showed that early ESCC stage, non-T4b disease, and salvage surgery were significantly associated with better survival. In multivariate analysis, ESCC stage represented an independent prognostic factor (13).

Adapted treatment strategies take into account clinical presentation, available resources, patient’s response to therapy, personal preference and priorities. The patient is scheduled for close follow-up for both cancer sites, trying to maximize benefit and minimize toxicity.

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.

Abbreviations

CT- computed tomography

CTV – clinical target volume

ECOG – Eastern Cooperative Oncology Group

ESCC – squamous cell carcinoma

GTV – gross tumor volume

IMRT – intensity-modulated radiation therapy

naCRT – neoadjuvant chemoradiation therapy

PEG – Percutaneous Endoscopic Gastrostomy

PET-CT – positron-emission computed tomography

PTV-N – periesophageal nodes

PTV-T – primary tumor

PTV-TN – planning target volume

Statements

Authors’ contributions: All authors equally contributed to writing the manuscript

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors.

Conflict of interests: The authors declare no conflict of interest.

Funding Sources: None

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

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