A Rare Case of Primary Small Cell Carcinoma of the Esophagus

Abstract

Small cell carcinoma of the esophagus is a rare and aggressive variant of esophageal cancer. We report a case of a 69-year-old female who presented with dysphagia to solid food for 6 months and underwent esophagogastroduodenoscopy, which revealed an ulcerated mass in the proximal esophagus. Biopsy findings were consistent with esophageal small cell cancer. The patient was found to have distant metastasis to the gastric lymph nodes on staging studies. She was treated with chemotherapy, resulting in initial disease resolution, but 4 years later, she presented with metastatic disease to the lungs and brain. This case underscores the need to establish treatment guidelines for this malignancy with a poor prognosis, given the paucity of randomized clinical trials.

Introduction

Small cell carcinoma of the esophagus (SCEC) is a rare neuroendocrine neoplasm, accounting for ~0.5% to 2.4% of all esophageal cancers.^1-5 It is a highly aggressive cancer and entails a poor prognosis. ¹ Most cases are metastatic at the time of diagnosis. ² We present a rare case of primary SCEC with initial metastatic disease to the epigastric lymph nodes, which was treated with chemotherapy. However, the patient developed metastatic disease to the lungs and brain after 4 years, while undergoing maintenance immunotherapy.

Case Presentation

A 69-year-old female with a past medical history of atrial fibrillation, hypertension, hyperlipidemia, anxiety, hypothyroidism, type 2 diabetes mellitus, Chronic Obstructive Pulmonary Disease (COPD) on home oxygen, lung cancer status post chemoradiation and right upper lobectomy with rib resection 19 years ago (with no evidence of recurrence), nonrheumatic aortic valve insufficiency, gastroesophageal reflux disease (GERD) without esophagitis, hiatal hernia, age-related osteoporosis, a 50 pack-year smoking history and chronic alcohol use, presented to the emergency department with progressive dysphagia to solid food for 6 months. She was able to tolerate soft and liquid foods. She also reported odynophagia, nausea, melena, and intermittent diarrhea but denied chest pain, palpitations, fever, chills, weight loss, abdominal pain, dysuria, or syncope. Her past surgical history included cholecystectomy and right lung lobectomy. Family history was significant for her mother with “throat cancer.” On examination, vital signs were blood pressure 142/71 mm Hg, pulse 72/min, respiratory rate 18/min, oxygen saturation 100% on 3 L oxygen, temperature 97.9 °F. The remainder of the exam was unremarkable. Labs were significant for hemoglobin 9.5 g/dL, WBC 7.9 × 10⁹/L, and platelet 461 × 10⁹/L. The patient underwent esophagogastroduodenoscopy (EGD), which revealed an ulcerated esophageal tumor at 20 cm with food debris (Figure 1). The scope could not proceed further. A prior EGD, performed 5 years ago, showed GERD, but was negative for Helicobacter pylori infection.

Figure 1.

Esophagogastroduodenoscopy showing ulcerated tumor in the proximal esophagus with obstruction (marked with red arrow).

A Computed Tomography (CT) chest, abdomen, and pelvis with IV contrast showed an irregular esophageal mass measuring ~3.8 × 2.7 cm arising from the left portion of the esophagus and extending intraluminally, accompanied by the interval development of epigastric lymphadenopathy. Biopsy from EGD was consistent with small cell cancer of the esophagus (Figures 2 and 3). A diagnosis of stage IV SCEC was made due to metastatic spread resulting in epigastric lymphadenopathy. There were no lung lesions suspicious for primary disease, other than emphysematous changes throughout both lungs and a stable subcentimeter calcified right hilar lymph node. CT head and subsequent MRI of the brain did not show any occult metastasis. PET scan showed esophagealhypermetabolic mass measuring ~4.2 × 2.7 × 2.1 cm with Standardized Uptake Value (SUV) 19.4 (Figure 4) with distant metastasis to paragastric, retrocaval, and gastrohepatic lymph nodes (Figure 5). Molecular profiling of the tumor specimen (CARIS Molecular Intelligence®, Irving, TX) revealed a 96% probability of a neuroendocrine malignancy. Additional immunohistochemical stains supported the diagnosis of SCEC, with tumor cells positive for synaptophysin, chromogranin, pancytokeratin, CD56, and negative for leukocyte common antigen and p40. The tumor was rarely positive for thyroid transcription factor 1 on immunohistochemistry (IHC). IHC was also significant for programmed death ligand 1 (PD-L1) tumor proportion score of 5%, making her eligible for pembrolizumab monotherapy. A second opinion slide review confirmed the small cell diagnosis. Next generation sequencing could not be performed due to insufficient tissue.

Figure 2.

Pathology image showing small cell cancer of the esophagus under intermediate magnification (20×). The cells appear small and round, characterized by a high nuclear-to-cytoplasmic ratio. The nuclei display finely dispersed chromatin, often described as “salt and pepper,” and lack prominent nucleoli. Additionally, the cells frequently exhibit nuclear molding, where the nuclei of adjacent cells press against each other (marked with red arrow).

Figure 3.

Pathology image showing small cell cancer of the esophagus under high magnification (40×). Tumor cells show small cell features with apoptosis (marked with red arrow).

Figure 4.

PET CT showing hypermetabolic mass in the proximal segment of esophagus with SUV 19.4 located on the right side of T2 to T4 (marked with red arrow).

Figure 5.

PET CT showing a conglomerate of gastrohepatic nodes measuring 3.3 × 1.6 cm with SUV 13.1 (marked with red arrow).

The patient received 4 cycles of combined chemoimmunotherapy with carboplatin, etoposide, and atezolizumab. A repeat PET scan after treatment showed complete resolution of previous hypermetabolic disease and a new subtle focus in the liver. She was continued on maintenance atezolizumab every 3 weeks. A repeat EGD after 2 years showed no obstructing mass or lesion in the esophagus, and the scope was able to pass through the esophagus without obstruction. The previous mass area was negative for disease on biopsy, showing squamous mucosa with acute inflammation, ulceration, and adherent bacterial aggregates. Serial brain MRI and PET scans showed no evidence of active malignancy or recurrent disease until 4 years later, when an MRI of the brain revealed a new 9-mm enhancing lesion in the left superior parietal lobe with minimal surrounding vasogenic edema and mass effect, likely representing a metastatic focus. She was started on steroids (dexamethasone 4 mg q8 h) and received stereotactic radiation therapy (CyberKnife [Accuray Incorporated, Sunnyvale, CA, USA]) to the brain lesion. A follow-up MRI brain 3 months later showed the brain lesion was non-enhancing and decreased in size to 3 mm. A subsequent PET CT showed an FDG-avid nodule 2 cm in size in the left upper lung with SUV 6.2, and a core biopsy confirmed small cell carcinoma of left upper lobe lung nodule, with a Ki-67 index of 80%, and positive for pancytokeratin, CD56, synaptophysin, chromogranin, and Thyroid Transcription Factor-1 (TTF-1), and negative for p40. Given disease progression on maintenance atezolizumab with metastatic focus now involving the lungs, the patient was treated with a carboplatin and irinotecan regimen. A posttreatment PET scan showed that the left upper lobe nodule had decreased in size to 1.5 cm with SUV 5.4. She subsequently underwent 5 fractions of stereotactic body radiation therapy to the left upper lung lesion. Three months later, a brain MRI showed progression of disease with new enhancing lesions in the brain, the largest measuring 1.5 cm in size in the right temporal lobe, with surrounding vasogenic edema and local mass effect. A PET scan at this time showed progression of disease in the lungs, liver, and right adrenal gland. She subsequently received whole brain radiation therapy and was started on Lurbinectedin. However, she developed septic shock and acute hypoxic respiratory failure complicated by acute respiratory distress syndrome culminating in comfort care measures within a month after detection of progression of disease.

Discussion

Small cell esophageal cancer is an aggressive, high-grade neuroendocrine cancer usually seen in individuals aged 29 to 88 years.^2,6 Florence McKeown first described 2 cases of “oat cell carcinoma” of the esophagus in 1952, citing resemblance to oats, which is now synonymous with small cell carcinoma.^6-8 Since its initial report, only a few hundred cases of SCEC have been documented. ⁹ It is classified into 2 subtypes—pure SCEC and combined SCEC. Combined SCEC includes other histological subtypes such as squamous carcinoma, adenocarcinoma, or large cell carcinoma, in addition to small cell histology. ¹⁰ In a retrospective series, about 86% of cases were of the pure variant. ⁹ The exact mechanism behind the development of SCEC is unclear, with divergent differentiation of stem cells and development from squamous cell carcinoma being some of the proposed mechanisms. SCEC is more common in males, with a male-to-female ratio of 3:2.^6,11 In retrospective studies, the median age of occurrence was 72, with the tumor most commonly located in the lower third of esophagus, followed by the middle third.^4,9 Our case is unique, as the tumor was in the proximal esophagus, whereas most retrospective studies and case series report no tumors in the upper third of the esophagus.^9,11 Other studies have reported that SCEC is almost exclusively located in the middle (40%) and lower (56%) third of the esophagus.^12,13 Increased prevalence of this disease is reported in countries such as Japan, Korea, and China. ¹⁴

The most common site of occurrence for small cell carcinoma is the lungs, with the gastrointestinal tract being the second most common site.^1,4 Risk factors of SCEC include smoking, old age, consumption of a high-salt diet, and alcohol. ⁶ SCEC is theorized to arise from Kulchitsky or amine precursor uptake and decarboxylation cells of neuroectodermal origin.^1,6,15 Symptoms of esophageal small cell carcinoma include dysphagia, odynophagia, weight loss, dyspepsia, and loss of appetite, with a mean duration from the onset of symptoms to diagnosis of about 4 months.^1,2 About half of the cases are metastatic at the time of presentation.^1,15 In a retrospective review, the most common metastatic site was the liver, followed by the lungs. ⁶

Upper gastrointestinal endoscopy is essential for establishing diagnosis by allowing biopsy of the esophageal lesion. CT scans of the abdomen are used for staging, and PET scans help rule out distant metastasis. Histopathologically, small cell carcinoma cells are usually small with round hyperchromatic nuclei, indistinct nucleoli, and thin cytoplasm and exhibit a high mitotic rate.^1,10 Immunohistochemically, small cell carcinoma is positive for synaptophysin and chromogranin A (CgA) as seen in our case. CgA is a glycoprotein marker produced by neuroendocrine tumors, whereas synaptophysin is a membrane glycoprotein that aids in synaptic vesicle transport and exocytosis.^16,17 A high Ki-67 index, often found in SCEC, is associated with increased tumor sensitivity to chemotherapy and improved survival. ¹⁵

Due to its rarity, randomized studies are unavailable, and treatment guidelines for SCEC are lacking. ⁹ Treatment for SCEC is often extrapolated from small cell carcinoma of the lung. Current treatment options include chemotherapy, surgery, radiation, or a combination of these for localized, nonmetastatic disease. SCEC is a systemic disease with a propensity for early dissemination and lymph node metastasis. Chemotherapy plays a critical role, as these tumors are chemosensitive, and chemotherapy has been shown to prolong survival. ¹² Radiotherapy has been used either concurrently or sequentially with chemotherapy. ¹¹ In patients with lymph node-positive, locoregional disease, median and 3-year overall survival (OS) were 17.8 months and 31.6%, respectively, when treated with chemoradiation. ¹⁸ Radiotherapy or surgery alone has been associated with unfavorable outcomes. ¹¹ Platinum-based chemotherapy with cisplatin or carboplatin and etoposide is used in advanced or inoperable cases, as in this case.^5,10 For disease progression, rechallenge with platinum-based chemotherapy, along with irinotecan or oxaliplatin-based agents, has been used as second-line treatment. ¹⁹

With current advances in cancer treatment, immunotherapy targeting the programmed cell death protein 1/PD-L1 pathway has been proposed as a promising treatment option for extensive stage SCEC. In a cohort analysis involving 107 patients, survival analysis detected statistically significant OS and progression-free survival in patients receiving immunotherapy compared to patients who did not receive immunotherapy. ²⁰ While ongoing studies have established the efficacy of combination treatment with platinum-based chemotherapy with immune checkpoint inhibitors such as durvalumab, atezolizumab, or tislelizumab as first-line systemic treatment for small cell lung cancer (SCLC), there is only limited research on the efficacy of these agents in the treatment of either extensive or limited stage SCEC. Studies have proposed that the combination of CD8+ T cell infiltration and PD-L1 expression may determine the benefit of neoadjuvant chemoimmunotherapy in SCEC.^21,22 Tarlatamab is a bispecific T-cell engager immunotherapy drug that connects delta-like ligand 3 protein in tumor cells to CD3 receptor on T cells and is used for the treatment of extensive stage SCLC that progressed after platinum-based chemotherapy. It demonstrated an overall response rate of 42.9% upon median follow-up of 6.7 months in a retrospective study and should be explored as a potential treatment option for SCEC through further research. ²³

Conclusion

SCEC is a rare cancer subtype with poor prognosis and early regional lymph node metastasis. Due to its low incidence and the paucity of randomized clinical trials, optimal treatment strategies remain unclear for SCEC. This case report highlights the need for further research to establish treatment guidelines for this rare and aggressive malignancy.